Hydrogenation Methods

Paul N. Rylander
Engelhard Corporation Edison, New Jersey


(Harcourf Brace Jovanovich. Publishers)

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This book is a guide to provide general information concerning its subject matter; it is not a procedural manual. Synthesis of chemicals is a rapidly changing field. The reader should consult current procedural manuals for state-of-the-art instructions and applicable government safety regulations. The Publisher and the authors do not accept responsibility for any misuse of this book, including its use as a procedural manual or as a source of specific instructions.


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Rylander, Paul N. Hydrogenation methods. (Best synthetic methods) 1. Hydrogenation 2. Chemistry, Organic I. Title II. Series 547'.23 QD281.H8

Rylander, Paul NeIs, Date Hydrogenation methods. (Best synthetic methods) Includes index. 1. Hydrogenation. QD281.H8R93 1985 ISBN 0-12-605365-0 (alk. paper)

PRINTED IN THE UNITED STATES OF AMERICA 85 86 87 88 9 8 7 6 5 4 3 2 1


Foreword Preface Detailed Contents

vii ix xi

Chapter 1. Chapter 2. Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. Chapter 10. Chapter 11. Chapter 12. Chapter 13.

Catalysts, Reactors, and Reaction Parameters Hydrogenation of Olefins Hydrogenation of Acetylenes Hydrogenation of Aldehydes and Ketones Hydrogenation of Acids, Anhydrides, and Esters Reductive Alkylation Hydrogenation of Nitriles and Oximes Hydrogenation of Nitro Compounds Hydrogenation of Carbocyclic Aromatic Compounds Hydrogenation of Anilines, Phenols, and Derivatives Hydrogenation and Hydrogenolysis of Heterocycles Catalytic Dehydrohalogenation Miscellaneous Hydrogenolyses

1 29 53 66 78 82 94 104 117 123 133 148 157

Index of Compounds and Methods



There is a vast and often bewildering array of synthetic methods and reagents available to organic chemists today. Many chemists have their own favoured methods, old and new, for standard transformations, and these can vary considerably from one laboratory to another. New and unfamiliar methods may well allow a particular synthetic step to be done more readily and in higher yield, but there is always some energy barrier associated with their use for the first time. Furthermore, the very wealth of possibilities creates an information retrieval problem: How can we choose between all the alternatives, and what are their real advantages and limitations? Where can we find the precise experimental details, so often taken for granted by the experts? There is therefore a constant demand for books on synthetic methods, especially the more practical ones like "Organic Syntheses," "Organic Reactions/' and "Reagents for Organic Synthesis," which are found in most chemistry laboratories. We are convinced that there is a further need, still largely unfulfilled, for a uniform series of books, each dealing concisely with a particular topic from a practical point of view—a need, that is, for books full of preparations, practical hints, and detailed examples, all critically assessed, and giving just the information needed to smooth our way painlessly into the unfamiliar territory. Such books would obviously be a great help to research students as well as to established organic chemists. We have been very fortunate with the highly experienced and expert organic chemists who, agreeing with our objective, have written the first group of volumes in this series, "Best Synthetic Methods/' We would always be pleased to receive comments from readers and suggestions for future volumes.



It is hoped that the reader will find this a useful work.Preface Hydrogenation is one of the most useful. PAUL N. and reaction conditions are illustrated throughout. Appropriate choices of catalyst. I wish to express my thanks to the management of Engelhard Corporation for their encouragement in this undertaking. broad-scoped reactions available to the synthetic organic chemist. The aim of this work is to give the reader ready access to what can be done with hydrogenation and how to do it. This volume is heavily documented to support these generalities and to make often difficult to find literature readily available. RYLANDER . and where possible. the influence of these factors has been reduced to working generalities. solvent.

2. Loading a Catalyst 1.1.2. Purchased Catalysts 1.12. 14.1.18. Influence of Solvent on Selectivity .18.16. Chiral Homogeneous Hydrogenations 1.17. Hydrogenation Catalysts 3. Solvents . and Reaction Parameters 1. Catalyst Life 1 1 2 4 4 5 5 6 7 7 7 8 8 10 10 11 12 12 13 14 14 15 16 17 18 18 20 20 21 22 23 23 24 24 .12. Choosing a Catalyst 4. High Pressure Reactors 1.17. Economics of Catalyst Use 1.13. Ligand Synthesis . Reactors.3. Synergism 12. Hydrogen-Transfer Reductions 1. Prereduction 9. Cost of Catalyst 1.15.13. Materials of Construction 1. Hydrogenation Reactors 1. Safety .18. Effect of Temperature 8. Reactive Solvents 1. Choosing Conditions Choosing a Catalyst Support 5. Effect of Acidity . Asymmetric Hydrogenation .2.16. Catalyst Preparation Contents 1.12. Catalysts. Catalyst Reuse 1 1 . Atmospheric Pressure Reactors 1.1.1. Catalysts . 14.3. Safety 1.16. Choosing a Metal Concentration 6. Low Pressure Reactors 1.2. Introduction 2. Measurement of Selectivity 10. Homogeneous Catalysts .

6. Consequences of Double^Bond Migration 2.3.2. 3.1. Space-Time Yield 1.5.6. Hydrogenation of Olefins Double-Bond Migration 2.xii 1.6. Aromatic Carbonyls 4. Alcohol Solvents 4. Catalysts Hydrogenation of Aldehydes and Ketones Catalysts Solvents Asymmetric Hydrogenation References 4.3.3. Dienes and Polyenes 2. Axial Alcohols 4. Progargylamines 3.4.1. Selective Reductions of Olefins Effect of Hydrogen Availability and Esters 3. Effect of Solvent 4.1. Stereochemistry Asymmetric Hydrogenation of Olefins References 3.3. Diketones 4. Glycols. Catalyst Modifiers Solvents Influence of Reaction Variables Functionalized Acetylenes Stereochemistry 4. 3.2. Aliphatic Carbonyls 4.1. Mechanism of Olefin Hydrogenation 2.3.4. DETAILED CONTENTS 25 25 25 29 29 31 31 33 34 36 36 40 41 44 45 47 49 53 55 56 57 58 59 60 61 62 62 Acetylenic Carbonyls. Vinylic and Allylic Functions 2. Actual Yield References 2. Acetylenic Epoxides 3. 3.3.1. Catalysts 2.4. Unsaturated Carbonyls Hydrogenolysis 4.4. Olefinic Sulfur Compounds 2. Unsaturated Carbonyl Compounds 2. 66 67 68 68 69 69 70 71 72 73 74 75 . Hydrogenation of Acetylenes 3. Acetylenic Aldehydes and Ketones References 2.4.

5. Oximino Ketones References 95 95 97 98 99 99 100 101 101 7. Solvents 7. Cyclizations Oximes 7.3. Catalysts Olefin Intermediates 117 118 .1. Introduction Catalysts Solvents Amine and Carbonyl Precursors Stereochemistry References 82 86 86 88 91 91 Reductive Alkylation 6.3. 8.4.1. Nitroenamines References 104 104 105 106 107 108 108 109 110 110 Ill 113 114 9.1. 6. Nitriles 7. Hydrogenation of Nitro Compounds 8. Acids Anhydrides Esters References XlU 78 79 80 80 6.5. Anhydrides. 6. Nitronitriles 8. Catalysts 7. Halonitro Aromatics 8.3. Dinitro Compounds 8. 8.3. 6. Catalysts Solvents Influence of Impurities Aromatic Hydroxylamines 8.2.1. Hydrogenation of Nitriles and Oximes 7. 8. 8.3.1. 5.5.DETAILED CONTENTS 5.2. Acetylenic and Olefinic Nitro Compounds 8. 8.1. Catalysts 7.5.2. Cyclic Products Bifunctional Molecules 8. Hydrogenation of Acids.5.2.2. Nitroaldehydes and Nitroketones 8.5. Solvents Hydrogenation of Carbocyclic Aromatic Compounds and Esters 5.1.1. 5.1.

1. Reductive Hydrolysis 10.4. Isoxazolines 11. Synthetic Applications Phenols and Derivatives Deoxygenation 11.1.4. Catalyst Reactivation 10.2. 12. and Derivatives 12.1.1. 12.1.6. Pyrroles Pyridines and Derivatives Isoxazoles 11.1.XlV 9. Oxazoles and Oxazolines References 133 133 134 134 135 136 137 137 137 137 138 139 140 140 143 144 11.2. Decarboxylation Ring Hydrogenolysis 11.2. Regulated Catalysts 12.5.1. Aziridines 11.4.3. Polycyclic Systems 9. Control of Coupling 10.2. Procedure References 148 149 151 153 153 153 154 154 155 . Hydrogenation and Hydrogenolysis of Heterocycles 11.4. Partial Hydrogenation Fused Rings References DETAILED CONTENTS 119 119 120 121 10.2. Oxiranes 11.2. Catalysts Furans 12. Hydrogenation of Anilines.1. 11.6. Indoles 11.3. Catalytic Dehydrohalogenation 12.2. Deoxygenation without Ring Reduction 12. Direction of Ring Opening 11. Anilines Ring Saturation 11. Deoxygenation with Ring Saturation 10. 12.1. Phenols.1.1. Effect of Substrate Structure 9.3. Catalysts Basic and Acidic Media Poly halo Compounds Halonitro Compounds Coupling Reactions Rosenmund Reduction 12. Ring Saturation without Hydrogenolysis References 123 123 124 125 126 126 126 126 127 128 129 130 10. Partial Hydrogenation of Phenols to Cyclohexanones 10.

2.1. Stereochemistry of Hydrogenolysis 13. Carbobenzyloxy Compounds Benzyl Groups Attached to Nitrogen Cyclopropanes 13. Amine Oxides 13.3.2. 13.2.2. 13. Miscellaneous Hydrogenolyses 13.3. Benzyl Groups Attached to Oxygen 13. Azines 13. Hydrazones and Hydrazides Effect of Structure Stereochemistry 13. Catalysts and Environment 13.7. 13. Aromatization Hydrogenolysis of the Oxygen-Oxygen Bond References 157 158 158 160 160 163 163 164 164 165 165 167 167 167 168 168 168 169 170 171 171 172 173 173 173 174 175 176 176 177 13. . /V-Nitrosoamines Reverse Selectivity Vinyl Functions Allylic Functions 13. Azides Hydrogenolysis of the Nitrogen-Oxygen Bond 13. Double-Bond Migration Hydrogenolysis of the Nitrogen-Nitrogen Bond 13.4. C-Nitroso Compounds Hydrogenolysis of the Carbon-Carbon Bond 13.2.7. Steric Factors 13. Promoters 13. 13. 13. Cyclobutanes Effect of Substrate Structure 13. Hydroxylamines CONTENTS XV 13. Catalysts

and stereoselectivity. forming only a single phase. and to impart the conviction that hydrogenation is a powerful. and frequently in high chemo-.1. catalyst preparation secret. equipment. readily handled. It is the purpose of this work to meet these objections. heterogeneous and homogeneous. especially those who have not had the opportunity to use it. and Reaction Parameters 1. Homogeneous catalysts dissolve in the liquid environment.1 Catalysts. to leave a solution free of contaminating reagents. At the conclusion of the reduction. often under mild conditions. The great majority of hydrogenations are done with this type of catalyst. and procedure. broad-scoped procedure of general utility for synthesis in both laboratory and industrial plant. 1. Hydrogenation Catalysts Hydrogenation catalysts are of two types. to acquaint the reader with catalysts. to provide rationale for choice of catalyst and conditions. Catalysts of this type are of relatively recent . In the minds of many. a major disadvantage of using this type of catalyst. operating conditions arbitrary. hydrogen is allowed to escape. the choice of catalyst seems capricious. and the working of the catalyst unfathomable. Reactors. catalytic hydrogenation has acquired an aura of mystery. Heterogeneous catalysts are solids that form a distinct phase in the gas or liquid environment. Introduction Catalytic hydrogenation is one of the most powerful weapons in the arsenal of the synthetic organic chemist. Homogeneous hydrogenation catalysts need to be removed otherwise.2. and the heterogeneous catalyst is filtered from the mixture. regio-. Most functional groups can be readily reduced.

large capital investment. this approach to catalyst selection bears little fruit. continuous production. the vast majority of catalytic hydrogenations are done in a slurry process. and useful approach to catalyst selection is to treat the catalyst simply as if it were an organic reagent showing characteristic properties in its catalytic behavior toward each functionality. which can be suspended readily in a liquid or gas. CATALYSTS. the first example was reported by Calvin in 1939 (27). Slurry or fluidized-bed catalysts are fine powders.3. in the form of cylinders. REACTORS. quick. Laboratory experiments are scaled up easily to industrial productions. invariant feed. a catalyst that bears his name. respectively. For this purpose. However. spheres. A more reliable. Slurry processes permit variations in the substrate as in hydrogenation of unsaturated triglycerides from a variety of sources. For the synthetic chemist. insoluble support in an effort to capture the best features of both types of catalysts (9JOJ 1. easily changed reaction conditions.23. and it is tempting to think that after all this effort there must now exist some sort of cosmic concept that would allow one to select an appropriate catalyst from fundamentals or from detailed knowledge of catalyst functioning. The chemical and catalytic characteristics are chosen to achieve the desired reaction and. AND REACTION PARAMETERS origin. multiuse equipment. and many important bulk chemicals are made in this mode. Fixed-bed processing demands a dedicated unit. intermittent operation. Fixed-bed catalysts are relatively large particles. as an important corollary. the catalyst is considered to be only the primary catalytic metal present. Considerable effort has been expended in recent years in "anchoring" homogeneous catalysts to a solid.44). Choosing a Catalyst The gross physical form of a catalyst is chosen to conform to the type of process to be used.2 1. 1. Heterogeneous catalysts can be divided into two types. 1/32 to 1/4 inch. or granules. but the area remained dormant until interest was spurred by the classic papers of Wilkinson on chlorotris(triphenylphosphine)rhodium(I). Fixed-bed processing is especially suited to largescale production. and relatively quick development time. The literature on catalytic hydrogenation is very extensive. and those for use in^ slurry or fluidized-bed processing. and lengthy development to establish optimum conditions and adequate catalyst life. Support and . to avoid undesired reactions. those for use in fixed-bed processing wherein the catalyst is stationary and the reactants pass upward (flooded-bed) or downward (trickle-bed) over it.

some poor. catalysts. it must undergo an activated adsorption on a catalytic site. or other function). Adsorbability is influenced strongly by steric hindrance. NO2 CH2CHR H (1) R = C 2 H 5 (3) R = CH3 (2) R = C 2 H 5 The simplest guide for choosing a catalyst to achieve a selective reduction in a bifunctional molecule is from among those catalysts that are effective for what is to be achieved. but with the present state of the art no surer means exists short of a catalyst development program. . and the statement applies only to preparations yielding good. some good. Selectivity can be influenced further by the reaction environment. Regardless of how easily a function can be reduced. avoiding those that are also effective for what is to be avoided. For a function to be reduced. solvent. CHOOSING A CATALYST 3 catalyst preparation usually have but secondary influences compared to the metal. and modifiers. these are discussed in other sections. One simply checks the literature to find what type of metal has proved active and selective previously.. selection of a catalyst is no different than selection of any other reagent. many preparations.3. A case in point is the reduction of the aromatic ring in 1 in preference to reduction of the nitro function. i. Many guides to catalyst selection are given throughout this work. producing 2. active. solvent. * There are. when R = CH3 (3) the nitro group was reduced instead. The rate at which a function is reduced is a product of the rate constant and the fraction of active sites occupied by the adsorbed function.* Viewed this way.1. Guides for such a selection may be obtained from the chapters devoted to the chemistry of the functions in question. Theoretically oriented scientists are apt to feel dissatisfied with this purely empirical approach to catalyst selection. of course. and to be reduced selectively it must occupy preferentially most of the active catalyst sites.e. no reduction of that function will occur if all of the sites are occupied by something else (a poison. There is a complication in choosing a catalyst for selective reductions of bifunctional molecules. a fact attributed to a less sterically crowded environment (109). and because of this almost any function can be reduced in the presence of almost any other function in suitably constructed molecules. However.

They provide catalysts that are best by test. that are derived from natural products differ greatly in their effectiveness when used as catalyst supports. Choosing a Catalyst Support Base metals frequently are used in nonsupported form. instead of using laboratory preparations. Certain broad statements. apparently owing to a weaker adsorption of the intermediate B.4 1. but other factors may influence selectivity as well. noble-metal blacks (finely divided metal) or metal oxides are sometimes used. Materials. Choosing a Metal Concentration Metal concentration in hydrogenation catalysts varies from 100% metal to a small fraction of 1%. is the increased cost of making the catalyst. CATALYSTS. or silicaalumina. Large-pore supports that allow ready escape of B may give better selectivities than smaller-pore supports. Supports such as calcium carbonate or barium sulfate may give better yields of B in reactions of the type A -> B -> C.5. but these catalysts are seldom seen in industrial practice. REACTORS. but in industrial processing both have significant impact on economics. such as that carbons with excessive sulfur or ash content tend to make inferior catalysts. to facilitate metal dispersion and to aid in metal recovery. but most of these catalyst have been in a quest for an improved system. alumina. 1. Supported noble metal catalysts are most commonly used in the 3-5% metal . increasing amounts of catalysts are required as metal concentration is decreased. such as activated carbons. exemplified by acetylenes -> ds-olefins. Supporting the noble metals makes a more efficient catalyst on a weight of metal basis and aids in recovery of the metal. More commonly. but it is difficult to delimit the factors present in the carbon that influence performance. The majority of catalyst supports are some form of carbon. The lower the metal concentration the higher the specific rate (rate per unit weight of metal) (Table 1) (48). AND REACTION PARAMETERS 1. To maintain a certain metal level in the system. One of the advantages of buying commercial catalysts. only begin to touch on the problem. Neither of these factors is of much importance in experimental work. except in laboratory preparations. A great many materials have been used as catalyst supports in hydrogenation. but noble metals rarely are. noble metals are supported. In laboratory experiments where economics is not a factor. brought about by low metal concentrations. usually on a high surface material such as carbon or alumina. is that commercial suppliers have solved this problem already by empirical testing of many carbons.4. Offsetting the gains in metal efficiency.

which is one of the great assets of hydrogenation as a synthetic tool. 1.6. coupling. a range apt to give maximum economy when all factors are considered. In general. More concentrated metals are sometimes used despite declining metal efficiency.72 0. If satisfactory results are not achieved. It is very much easier to correct a problem if it can be identified. poisoning. Base metals are much less active and are generally used in much higher metal concentration ranges up to 100%.7. interaction with the solvent. and to facilitate difficult reductions. e. Effect of Temperature Temperature can have an important influence on rate. or overhydrogenation. The quickest way to success is simply to choose conditions that experience and literature deem reasonable and proceed. Choosing Conditions Some hydrogenations require exacting conditions for optimal results but most do not. the rate of hydrogenation rises with increasing temperature. Frequently. Satisfactory results will be obtained very likely. to minimize the amount of catalyst to be filtered. the rate increase will be much larger when the reaction is . There is often a wide range of conditions under which satisfactory results can be obtained. poor selectivity.g. EFFECT OF TEMPERATURE TABLE 1 Effect of Platinum Content on Cyclohexene Hydrogenation % Pt-On-Al2O3 Specific rate 76 96 113 121 1.39 concentration range. and catalyst life..7. These catalysts are used to decrease loss of valuable products by absorption on the carrier. selectivity.52 0.1. potential problems can be identified in advance and corrective measures incorporated in the initial experiments. the most fruitful approach is to ascertain what went wrong. to aid in settling of the catalyst. 1.11 0.

6 1. ^ T-ISK H I r\ CH3 f^V'^^r r\ CH3 ^. A 2% palladium-on-carbon catalyst could be reused repeatedly at 690C without loss in activity in reduction of onitroaniline to o-phenylenediamine in methanol. At times. _ ^SK H 5% Pd-on-C ? EtOH 15psig CH3 ^ J . the catalyst. Prereduction of 5% Pd-on-C was necessary in the hydrogenation of dehydronicotine to nicotine if formation of the aromatized nicotyrine were to be avoided (29). prereductions can usually be omitted and reserved only for those catalysts known to require it. . should the reaction fail to go or if it is proceeding too slowly.86). but in industrial practice the temperature is usually elevated to obtain more economical use of the catalyst and increase the space-time yield of the equipment. CATALYSTS. One purpose of this procedure is to ensure that the measured hydrogen consumption arises only from uptake by the substrate. more of the cz's-/?-decalone was formed from hydrogenation of A1 '9-octal-2-one over palladium when the catalyst was not presaturated than when it was (8). REACTORS. See also Ref. and hydrogen are shaken together before the substrate is added. Prereduction Prereduction of a catalyst is frequently practiced. It is a technique worth resorting to when a system. that is. if reasonable. Catalyst life is often affected adversely by an increased temperature. 34 for a further example of the hydrogenation of bisenones. which literature and experience suggests should work. Activation by prereduction of a catalyst is more likely to be required if the catalyst is to be used under mild conditions. and raise the temperature gradually within bounds. They are always time-consuming. AND REACTION PARAMETERS kinetically controlled than when diffusion limited. fails. For instance. and another is to eliminate induction periods. but at 9O0C much activity was lost after one use (52). a convenient procedure is to begin at ambient temperature.^ Prereductions are usually not necessary and may even be detrimental (85. solvent. Most hydrogenations can be achieved satisfactorily near ambient temperature. Prereductions have been used to suppress unwanted dehydrogenation.8. selectivity of reduction may be changed by this procedure. Another purpose is to activate the catalyst. In laboratory work. 1. As a practical matter.

9. In the latter case. where usually. In either case. Catalyst Reuse In commercial hydrogenations. 1. but not always.1. a catalyst should be used as many times as possible consistent with adequate rates and selectivities. The effect may occur when the two catalytic elements are made into a single catalyst and also when two separate catalysts are used together.11. The only sure way of measuring selectivity is by analysis of the product at or near the theoretical absorption of hydrogen. if one can guess the sequence of steps or the likely inhibitors. Statements of this sort arise from a misunderstanding. Reliance on rate curves as the criterion of selectivity may result in satisfactory reductions being discarded. Neither the rate curve nor the moles absorbed at cessation have necessarily anything to do with selectivity. One could also assume that the second catalyst functions by its superior ability to remove an inhibitor that may form in the reaction. However.10.11. maximal selectivity will occur. Each reuse lowers the cost of operation. Synergism Two catalysts together sometimes give better results than either separately. when mixed with the first. Intervening regenerations may or may not be required between reuses. synergism can be accounted for by the assumption that the reaction involves two or more stages with neither catalyst being optimal for both stages. SYNERGISM 1. in experimental laboratory work the small savings are not worth the uncertainty introduced by reuse. 1. Measurement of Selectivity There appears now and then in the literature a statement to the effect that the hydrogenation was not selective because there was no break in the hydrogenation rate curve or that the hydrogenation was not selective because absorption did not cease at a discreet number of moles of hydrogen. one can guess a reasonable second catalyst that. . will produce synergism (82).

1. Solvents may be one of the best means available for markedly altering the selectivity.12. change viscosity and surface tension (108). and to permit the use of solid substrates.12. CATALYSTS. although fallible. The amount of solvent relative to the amount of total catalyst is usually large.1. for gross amounts of innocuous impurities can be present without untoward effect. Solvents also help to moderate the heat of hydrogenation. Solvents Solvents are often used in catalytic hydrogenation (81). reused. providing one of the best means available for controlling selectivity. One very useful. a lower grade solvent is to be used. AND REACTION PARAMETERS 1. or reclaimed solvents. REACTORS. very small amounts of inhibitors or poisons can have. the rate may be directly proportional to the solubility of hydrogen in the solvent. and the amount of solvent relative to the number of active catalyst sites larger still. Results thus obtained cannot necessarily be extrapolated safely to technical. Solvents influence rate as well as selectivity. The powerful influence of solvent is insufficiently appreciated and its efficacy often overlooked. Influence of Solvent on Selectivity At times. A convenient solvent may be the product itself or the solvent used in a prior or subsequent step. as was shown to be the case for the hydrogenation of cyclohexene over platinum-on-alumina in cyclohexane. selectivity changes drastically with a change in solvent. 1. and a number of factors contribute to it. in commercial practice. Most workers in exploratory experiments use high grade solvents for it helps avoid complicating factors. its effect on the catalyst should be ascertained beforehand. and octane (48). In closely related solvents. Solvent purity per se is of little regard in this connection. If. and alter hydrogen availability at the catalyst surface. methylcyclohexane. The effect on rate can be very great. and serious errors have been made by doing so. . large adverse influences on the rate of reduction. therefore. a fact not sufficiently appreciated. so many that it is difficult to make encompassing generalities. to aid in catalyst handling and recovery. (a) alcohols sometimes should be considered separately. generality is that in a series of solvents the extremes of selectivity will be found at the extremes of the dielectric constant with two provisos. Solvents can compete for catalyst sites with the reacting substrates. There are many examples.

IN NaOH 23 68 84 77 32 16 The basic solution. gives much different results than those obtained in neutral media. a solvent system used with much success in the hydrogenation of 3-oxo-4-ene steroids to the 5/? compounds (JOl).89 ds-2-Decalone is obtained in 99. O Solvent Methanol r-Butanol Dimethylformamide n-Hexane % ds-2-Decalone 41 91 79 48 Dielectric constant 33.0 1.1. which now contains the enolate ion.9 38. The differences in results between methanol and t-butanol is particularly striking since these are closely related compounds. Reasons for these results are discussed by Augustine (7). Selected data of Augustine (7) on the hydrogenation of /J-octalone illustrates appreciable selectivity changes with solvent and the first proviso. Selected data of Wuesthoff and Richborn (112) on the hydrogenation of the vinylcyclopropane 4 further illustrates the effect of solvent on selectivity as well as the reason for the second proviso. More of the hydrogenolysis product (6) is obtained in polar 50% aqueous ethanol than is obtained in the .5% yield by palladium-catalyzed hydrogenation of the octalone in tetrahydrofuran containing hydrogen bromide. Solvent 50 % Aq ethanol Hexane 85% Aq ethanol. O. Note that in this case selectivity moves with dielectric constant in opposite directions in protic and aprotic solvents.6 10.12. SOLVENTS 9 and (b) the charge on the species undergoing hydrogenation should not change.

REACTORS. One of the most common of competing systems is some sort of hydrogenation versus some sort of hydrogenolysis. The generality is that the hydrogenation product is favored by the less polar solvent.12.3.014 Hydrochloric acid 0.12. This latter single bit of data can be used to illustrate a good working generality.20 Acetic acid 0. Unrecognized traces of residual acids or bases in catalysts is one reason investigators have failed to duplicate the work of others (or their own). Note that hydrogenolysis with this catalyst can be prevented completely by traces of base. AND REACTION PARAMETERS nonpolar hexane. 1. benzylic.2. Acidity of a catalyst can be readily checked by slurring it in water and measuring the pH. and ring-substituted molecules versus loss of function by hydrogenolysis. The generality applies to a variety of competing reactions including saturation of vinylic. Reactive Solvents Solvents may enter into the reaction sequence transiently or permanently.008 Sodium hydroxide Maximum % phenylethanol 90 60 76 100 Other workers have obtained higher yields of phenylethanol is absolute methanol.10 1. with various additives present (83). the hydrogenolysis product by the more polar solvent. On the other hand. allylic. 1. this variable often has little or no influence. Well-known examples of the transient participation of solvent are the use of . Moles of additive per mole of acetophenone None 0. as illustrated above. Effect of Acidity In general. the hydrogenolysis product is also favored by an acidic medium. addition of base is often a useful means of preventing or minimizing unwanted hydrogenolysis in a variety of systems. as illustrated in the hydrogenation over 5% palladium-on-carbon of acetophenone to the hydrogenation product phenylethanol and to the hydrogenolysis product ethylbenzene. CATALYSTS. the 90% yield reported above was probably due to traces of residual acid remaining from the catalyst preparation.

hydrogenations will not detonate unless the substrate or solvent itself is explosive or undergoes extensive decomposition. With Ru-onC. followed by hydrogenolysis to 7. 1. For example 84% This ether formation arises from conversion of the phenol to a cyclohexanone.1. which undergoes intramolecular reductive alkylation with the carbonyl group. explosions and fires from mixtures of hydrogen in air. Excessive pressures can only come from overpressuring the reaction vessels and from pressures generated by large . Solvents sometimes participate in the reduction unexpectedly. the nitrile is reduced to an amine.13. oximes. None of these should cause concern. and. dust explosions. in the presence of ammonia reductive alkylation at the carbonyl group occurs to give the equatorial cyclohexylamine. Safety There are several sources of potential danger in catalytic hydrogenations. with finely divided carbon supports. Ammonia has been used to change stereochemistry as in reduction of 8 to either 7 or 9 (77). Unlike reactions such as certain oxidations and polymerizations. solvent fires.13. or anilines. SAFETY 11 ammonia to prevent secondary and tertiary amine formation in the hydrogenation of nitriles. which in turn reacts with the intermediate aldimine. for all may be avoided easily. the alcohol is formed solely (84). these are failure of equipment because of excessive pressures. and ketal formation catalyzed by Pd-H2 and hydrogenolysis. Ammonia enters the product permanently in other reactions such as reductive alkylations with aldehydes or ketones. In the absence of ammonia.

a poor practice in any case. or by failure of temperature controllers (94).13. Metal catalysts on finely divided carbons can undergo dust explosions just as can the carbon itself. are pyrophoric in themselves and will ignite when brought into contact with air. AND REACTION PARAMETERS exotherms. by stopping the agitation. Due care should be taken in handling them. It has been suggested. the catalyst concentration be kept below 5% (73). and/or by interrupting hydrogen flow to the vessel. stearic acid. with due allowance made for pressure increases caused by reaction exotherms.12 1. such as Raney nickel. argon is ideal if available.2. all catalysts containing adsorbed hydrogen may ignite when dried. fire will not occur. but this should not be relied on. 1. REACTORS. Catalysts Some catalysts. especially when they contain noble metals. Dioxane should never be used with any Raney nickel above 20O0C. Virgin noble-metal catalysts are nonpyrophoric and can be safely held in the hand. it may decompose almost explosively. or. for instance. filtered catalyst should be kept wet and out of contact with combustible vapors and solvents.13. A used. Once all of the catalyst has been wet with solvent. and in all cases due precaution should be taken. 1. Other solvents are ignited with much more difficulty and very rarely. flour. are particularly apt to ignite. The problem is circumvented easily by not dusting the catalyst. Compounds that are dehydrogenated readily. The solvent. exclusion of oxygen permits completely safe handling. Some workers put the catalyst in the reaction vessel and sweep air from the vessel with a gentle flow of nitrogen or carbon dioxide. Especially active catalysts should be used in smaller concentrations than less active ones to prevent excessive exotherms. that in using Raney nickel W-6 above 10O0C. For a catalyst-ignited fire to occur. Air can also be removed from the flask by . such as lower alcohols and cyclohexene. They are best kept wetted. CATALYSTS. After use. which may be cooled to diminish its flammability. Hydrogenations that are proceeding too rapidly are moderated conveniently by cooling. however. as recently happened.1. is then added. oxygen must be present. Loading a Catalyst Catalysts that in themselves are completely safe may catalyze combustion of hydrogen or of organic vapors or solvents. Pressure vessels should be charged only to pressures well below the manufacturer's rating.

11 was formed cleanly. At O0C in benzene. As with heterogeneous catalysis.14. Nonetheless. (4) where selective labeling is desired. Catalyst particles falling through organic vapor cannot be effectively cooled and may enter the liquid glowing. Many catalysts are sold as water-wet and are useful when water can be tolerated. (3) where disproportionation of incipient aromatic systems is possible. Stereoselectivity in hydrogenation of 10 to generate the axial methyl group over (Ph3P)3RhCl depended on both solvent and temperature. when solvent is added rapidly to the catalyst. selectivity fell (76). and (5) where asymmetric hydrogenation is sought (80). five areas have been identified where homogeneous catalysts may be superior. Catalysts can be wetted with safety with methylcellosolve (2-ethoxyethanol) before adding them to volatile solvents (40). HOMOGENEOUSCATALYSTS 13 application of vacuum. but in ethanol as solvent or cosolvent. (2) where heterogeneous catalysts are poisoned. On the other hand. any tendency of the catalyst to heat is limited by quenching with a massive amount of liquid. 1. or at higher temperature. Other workers do the opposite and add catalyst to the solvent (which again may be cooled) after first sweeping the flask with inert gas to remove air. These wetted catalysts are much less apt to start fires. Homogeneous Catalysts Homogeneous hydrogenation catalysts provide a welcome supplement to heterogeneous catalysts although their use has been relatively limited for a single important reason: the more easily handled heterogeneous catalysts are just as or more satisfactory in most cases.1. and solvent is added to the flask from a dropping funnel. selectivity in homogeneous catalysis depends on reaction conditions and solvent. These are (1) where some aspect of selectivity is involved. O OCPh (Ph 3 P) 3 RhCI \ ^ O ^s H2 OCH3 .14. It appears that if catalyst and solvent are mixed without removal of air (which is certainly not advised) fires are more likely to occur when catalyst is added to the solvent.

An effective catalyst must give both high regioselective and stereoselective yields. Chirality was introduced by treatment of the Raney nickel for 1 h at 10O0C with 178 ml water adjusted to pH 3. pyridine CH3 I CH 3 I THF. The mixture was kept at 10O0C for 1 h.S)-tartaric acid and 20 g NaBr. Chiral heterogeneous hydrogenations have been much studied. The method of Ito et al. The catalysts may be homogeneous.9 g Raney nickel alloy to 40 ml water containing 9 g NaOH. and asymmetric homogeneous or heterogeneous hydrogenation. AND REACTION PARAMETERS 1.2. CH3CCH2CCH3 O A 5.14. 10O C.4S)-2. Hydrogenation over this catalyst of acetylacetone (100 atm. (50) as applied by Bakos et al.2 with NaOH and containing 2 g (S. Ligand Synthesis Four general methods have been used for obtaining chiral ligands: resolution of a racemic mixture. The area is not without complication. use of a chiral naturally occurring product (33).4-pentanediol will serve to illustrate how a chiral heterogeneous catalyst has been used to prepare a chiral homogeneous ligand precursor. heterogeneous (98).6% optical purity).1 Asymmetric Hydrogenation One of the most interesting and useful developments in recent years is asymmetric hydrogenation in which chirality is introduced into prochiral molecules in the hydrogenation process through use of chiral catalysts. an anchored homogeneous complex (9.14. 100 atm CH-CH2-CH BDPOP I I OPPh2 OPPh2 The chiral catalyst was made from Raney nickel. and the modifying procedure was twice repeated. (12) to the reduction of acetylacetone to either (-)-(2R94R).or ( + )-(2S. Results vary widely and depend on a number of .10).5-tartaric acid — 0 » CH3CHCH2CHCH3 QJJ QJJ ' 2Ph 2 PCLO 0 C THF. and then washed 15 times with 40 ml water. CATALYSTS. REACTORS. 1.14 1. or a hybrid of the two. The solution was then decanted. which was prepared by addition in small portions of 3. 10O0C) in THF containing a small amount of acetic acid gave an isolated yield of chiral pentanediol of 44% (99.

is prepared from (S)-( + )-mandelic acid (76) by the following route: OH H2 lOOpsig MeOH. Optical yields also depend importantly on the ability of the substrate to coordinate at more than one point. Results may depend on minor variations in catalyst structure. Many results are spectacular. 1. An understanding of the factors affecting chiral reductions is unfolding. To use this type of catalyst as a tool. for instance. and it appears that a stereochemically rigid complex is necessary for the highest optical yields.1. Chiral Homogeneous Hydrogenations Published reports on homogeneous asymmetric hydrogenations are already voluminous despite the relative newness of the area. see. HOMOGENEOUSCATALYSTS 15 conditions. In general. the same advice just given for chiral heterogeneous catalysts is pertinent.14. the most reasonable approach would be to check the literature and then adapt the procedure that was successful for a close analogy. and with the present state of the art only by luck could a process be optimized without considerable effort. and they are less sensitive to reaction parameters. (55).14. To apply these catalysts in synthesis. (90). Scott et al. optical yields tend to be higher when using chiral homogeneous catalysts. The following procedure chosen here because of the interesting rhodiumcatalyzed aromatic ring hydrogenation.2-bis(diphenylphosphino)-l-cyclohexylethane. For leading references. and bidentate ligands accordingly usually give higher optical yields than do monodentate ligands. and Amma and Stille (6). dubbed (R)-cycphos.3. great success has been had in the asymmetric hydrogenation of a-(acylamino)acrylic acids (105). but compounds lacking either or both a carboxylic acid or an acetoamido group have given much lower optical yields (51). Koenig et al. The ligand (R)-l. illustrates the preparation and use of a chiral homogeneous catalyst from a naturally occurring product. rather than as a research area per se. Valentine et al (103). HOAc \ N OH / ' j \ >95% LiAlH4 H OH * (I)TsCUC6H5N (2) LiPPh 2 THF \ < / \ \ / V-C-CH22PPh2 « 2 PPh 2 ( / \ / V-C-CH2OH H i* (R)-cycphos .

4. The white crystals were filtered and dried in vacuo at 4O0C. The procedure is useful when hydrogen is unavailable or zoned against. [Rh(NBD)Cl]2 in acetone under a nitrogen blanket. reflux CH2CHCOQNHJ 2h CH2CHCOO- . The 70 ml abs EtOH 4OmIHOAc 3OmIC 6 HiQ 2. 250 ml cyclohexane was added. solid residue was dissolved in 1 1 of hot diethyl ether and filtered while hot.0 g of the Rh dimer. certain organic compounds can serve as the hydrogen source. More solvent is removed in vacuo. CATALYSTS. only simple equipment is required (18). The catalyst was removed by filtration through Celite. The catalyst {[Rh-(#)-cycphos] (NBD)} PF6 (NBD = norbornadiene) is typically prepared by adding 2. and. and the cyclohexane solution was stored for several hours in a refrigerator. small amounts have a marked accelerating effect (95) larger amounts promote hydrogenolysis of the benzyl oxygen. The yield of {[Rh-(#)-cycphos] (NBD))PF6 is 74%. Good reviews of asymmetric homogeneous hydrogenation catalysts and their syntheses are those of Caplar et al (28) and Vineyard et ai (106).15. on cooling. The remainder of the ether was removed. After reduction of the volume to 400 ml. and the methanol was removed in a rotary evaporator. AND REACTION PARAMETERS A solution of 76 g (S)-( + )-mandelic acid in 400 ml methanol and 5 ml acetic acid was reduced over 5% rhodium-on-alumina under 100 psig for 10 h.1 g of (K)-cycphos is slowly added. The white. which is washed with ether and dried in vacuo. To the hot solution. The use of small amounts of acetic acid is important.0g5%Pd-on-C 10O0C. The solution is reduced to 15 ml and filtered. the yield of (5)-( + )-hexahydromandelic acid was 71%. 50 ml CH3OH is added. 1. Many catalysts of this type are sensitive to oxygen and should be handled with rigid exclusion of oxygen. After filtration of the AgCl.2 g AgPF6 to 2. REACTORS.16 1. Hydrogen-Transfer Reductions In the presence of hydrogenation catalysts. an orange precipitate forms.

16. transfer reductions have no advantage over conventional hydrogenation. but occasionally superior results are obtained (37). after 1 min the reduction was 11.5-diene-2. A case in point is hydrogenolysis of the 1-phenyltetrazolyl ether of tyrosine. 99. respectively (97). and 99% complete. HYDROGENATION REACTORS 17 procedure can be carried out in a column (35). and cyclohexene (71. apart from convenience. Suitable donors include materials such as formic acid (73). The point is illustrated by selected data of Tabor et al (97) on the transfer hydrogenation of dimethyl bicyclo [2. In general. Hydrogenation Reactors All hydrogenation reactors serve the purpose of bringing hydrogen. catalyst.3-dicarboxylate. a-phellandrene. 1. d-limonene. and substrate together in the absence of oxygen. 1 -methylcyclohexene.19). ^^COOCH M^COOCH3 10%Pd-on-C ~ Donor % in product 64 36 78 12 The rate of transfer hydrogenation also varies markedly with donor structure. various olefinic hydrogen donors are not necessarily equivalent. For cyclohexene. Equipment for doing this comes in great variety. and l-methyl-4-r-butylcyclohexene as donor in the above hydrogenations.1.2. to phenylalanine (107). 1 -methyl-4-isopropylcyclohexene. 78.16. l]heptane-2. In hydrogen-transfer hydrogenations. COOCH3 3 ^^ /COOCH. ranging from microreactors to huge vessels and . neither in selectivity nor in rate.

92. 1.. After the desired . Illinois).104. Atmospheric Pressure Reactors Equipment for use at ambient pressures can be improvised easily in most laboratories. Moline. Specially made smaller bottles.70. Agitation can be provided by a stirrer of some sort. with agitation to ensure hydrogen reaching the catalyst. Low-Pressure Reactors Apparatus for carrying out hydrogenation at several atmospheres can be constructed readily (1. REACTORS. but there seems little point in this exercise since good commercial equipment is available.60. The bottle is then opened to the hydrogen reservoir.and 2000ml reactor bottles. the substrate. CATALYSTS. The most commonly used commercial low-pressure equipment is the Parr hydrogenator (manufactured by Parr Instrument Co. (38. Requirements for these reactors are more exacting because of the need to measure accurately small amounts of consumed hydrogen (22.16.46. Hydrogen absorption is measured readily with a buret and leveling bulb containing water or mercury There are many descriptions of various microreactors for hydrogenation.69. In operation. down to 50 ml. especially when the catalyst is very active.58). AND REACTION PARAMETERS suitable for operation with pressures ranging from atmospheric to thousands of pounds per square inch.78.111). and solvent (if any) are sealed in a reaction bottle and connected to a hydrogen reservoir. catalyst. by a flow of hydrogen. 1) has withstood the test of time. Shaker bottles should not be more than half full to ensure good mixing. a consideration in selection of bottle size. This equipment (Fig. Many workers use magnetic stirring.18 1. can be used also but require special holders to compensate for differences in bottle heights.16. 1. and with some means of measuring the amount of hydrogen consumed.36. Parr supplies both heating and cooling jackets.45.30. it was first described in 1922 and offered commercially in 1926. which is convenient and usually adequate. It comes in two sizes: one for 500-ml reactor bottles and one for 1000. or by shaking the reaction flask.93). The requirements are that it be provided with some means of removing oxygen from the system. Air is removed either by applying vacuum or by flushing with hydrogen. 49. and the bottle is shaken vigorously to initiate the reduction.31.1. but relatively ineffective for mixing.

Parr shaker bottles are made of borosilicate glass. Hydrogen absorption is determined from the pressure drop in the system.1. is incorporation of a pressure switch that stops agitation when a predetermined . Parr shakers are commonly operated in the open laboratory without additional barricade. HYDROGENATION REACTORS 19 Fig. 30-60 psig. Various workers have suggested modifications of this useful equipment (26.79). 1. A Parr shaker type reactor. which can be adopted to any reactor. depending on size. Additional safety requirements are necessary should bottle breakage release a toxic material. The relationship between pressure drop and moles of hydrogen consumed is determined by hydrogenation of a weighed amount of known compound that unambiguously gives a single product. the bottle is vented and the product and catalyst are recovered. and each is pressure tested at twice its specified maximum pressure. hydrogen absorption.16. One such modification. Some bottles can be furnished with a tough outer fiberglass coating that usually retains any broken glass and prevents loss of valuable materials should a mishap occur. but a glass safety screen is recommended nonetheless. In operation the bottle is surrounded by a screen to contain glass splinters should the bottle accidently break.

A major aim of any investigation in this area is to make certain that the phrase does not become an apt description.56. This device is useful when overhydrogenation is a possibility and allows operation without constant watching of the equipment (72).and overdesign.74.42. A number of workers have given general descriptions of high-pressure reactors and facilities together with various aspects of safety.16. High-pressure equipment is best bought from suppliers rather than made. can be a fertile source of useful publications.16. and control (3. design. Some companies design and build completely packaged units including instrumentation and containment areas.15. CATALYSTS. REACTORS. It is much easier to improve a less than satisfactory yield.41.63. a study of the rise and decline of various reaction products.3. 1.57.4-dichloronitrobenzene. A large-scale destructive. A useful device to have installed in a stirred autoclave is a liquid sampling tube by which liquid samples are withdrawn under pressure through a filter attached to the lower end of the tube. runaway reaction occurred for this reason during hydrogenation of impure 3.14. confinement of an unstable material under elevated temperatures. High-Pressure Reactors High-pressure processing requires specially constructed equipment.94). This device is especially useful for analysis of reaction progress and supplements information obtained from pressure-drop determinations. an unfortunate term indeed. which is available from a number of manufacturers. Serious accidents are most likely to happen not as part of the hydrogenation process but as a result of chemistry extrinsic to the hydrogenation. that is. AND REACTION PARAMETERS quantity of hydrogen has been absorbed.20 1. For this reason no space is taken here for detailed description of reactors since these are given gladly by equipment manufacturers on request. These and other references are well worth consulting before investing in extensive and expensive pressure facilities. caused by . It is not an area that lends itself easily to amateur work. 1. For academically orientated persons.16. to prevent both under. In this regard there is some danger in trying to force a hydrogenation to completion by increasing the reaction temperature excessively. as a function of reaction parameters and catalyst. safety High pressure reactors are frequently called bombs.75.3. if it can be determined what is going wrong and when.1.

particularly at higher temperatures. and hydrofluoric acid systems. hydrogen fluoride. Hastelloy C-276* was developed specifically for wet chlorine service. It is also excellent for sulfuric acid. Judging by spectrographic analysis of spent catalysts. Carpenter 20 Cb-3 is a registered trademark of Carpenter Technology Corp. Inconel 600* offers excellent resistance to caustics and many other materials. nitric. but sensitive to the presence of ferric or other oxidizing ions. Materials of Construction Reactors should not dissolve in the reaction medium. * Hastelloy is a registered trademark of the Cabot Corp. HYDROGENATION REACTORS 21 exothermic disproportionation of intermediate 3. Similarly. but other alloys may provide better resistance to specific corrosive agents. It may be a cause of catalyst failure. Stainless steel is much better except for use with caustics. but it is not intended for use with strong oxidizing acids. sulfuric. Type 316 stainless steel will handle most organic materials including organic acids. * Monel and Inconel are registered trademarks of the International Nickel Co. Parr Instrument Company (Moline. Zirconium offers usable resistance to hydrochloric. Carpenter 20 Cb-3f is an enriched grade of stainless steel designed specifically for use with dilute sulfuric acid. Carbon steel is generally used in laboratory apparatus mainly to duplicate available plant equipment. It rusts easily. Illinois) kindly provided the following general recommendations for this and other alloys. It can be used also with nitric and phosphoric acids.16.2. Reactors are commonly made of type 316 stainless steel. It is used also for aqua regia and other mixed acid applications. The operating pressure in a vessel should never exceed 70% of the range covered by the rupture disk. Most reactors are equipped with safety rupture disks to protect the operator and equipment from destructive pressures.16. It has perhaps the broadest general corrosion resistance of all commonly used alloys. 1. and offers excellent resistance to chloride ions.4-dichlorophenylhydroxylamine at its autodecomposition temperature (100). It is not recommended for strong mineral acids and is susceptible to stress corrosion cracking in caustic and chloride solutions. Monel 400* is good for most caustic and chloride solutions and excellent for most fluorine.. Titanium offers good resistance to nitric acid and other strong oxidizing acids.1. Inc. Nickel is used generally to handle strong caustic solutions. Hastelloy B-2* is about the only alloy with real resistance to hydrochloric acid systems. some attack of the reactor is more common than is generally supposed. and phosphoric acids as well as to caustics and many salt environments. f . gauges should not be stressed beyond about 70% of full-scale readings for safety and to ensure reliable readings.3.

quite usable. A commonly used base metal is some form of Raney nickel. W-6. nickel boride Pl (20). loss of activity does not occur with any of the catalysts. There are a number of variations that differ in the way the alloy is added.22 1. essentially the development of Hartung (47). for those who wish to make their own catalyst some comments seem in order. Many workers routinely use Raney nickel W-2. The Nishimuri catalyst (30% Pt. W-S (54).4 that hydrogenation catalysts be bought rather than made.102). a 5% palladium chloride-on-carbon reduced by alkaline formaldehyde. The hydrogen-reduced palladium chloride-on-carbon. nickel carbide (24). 70% Rh oxides) can be prepared by the same procedure as for platinum oxide or with variations from platinum and rhodium salts (64. and a hydrogen-reduced 10% palladium-on-carbon. and nickel catalysts. nickel-on-graphite (87. It is usually most useful when hydrogenolysis is to be avoided (67. in the washing. This catalyst has much merit. The well-known Adams' platinum oxide can be prepared conveniently by the procedure of Adams et al.43).85. nickel boride P2 (21). and W-7 are given in Organic Syntheses (13). provided they are kept in tightly closed bottles. W-5 (4). It is instructive to read comments on the wide variations in activity of samples of this simply prepared catalyst. W-6 and W-7 are very active catalysts. which in certain reactions can have an adverse effect.65. in alkali concentration.66).88). they differ in that W-7 is alkaline and is useful where alkali is beneficial. Nonetheless. These active catalysts are effective for . Urushibara nickel (61. Detailed procedures for Raney nickels W-2. platinum. Catalyst Preparation It was recommended in Section 1. made in one laboratory with constant ingredients (110). it is more active than W-I and has considerable stability. and Nic catalysts (complex nickel catalysts prepared from sodium hydride) (25. CATALYSTS. The sodium can be removed by washing with dilute acid (53). W-3. These catalysts have been compared in activity in the hydrogenation of /?-naphthol (5). Platinum oxides prepared in this way usually contain some traces of sodium. AND REACTION PARAMETERS 1. and in temperature and length of digestion. REACTORS. of course. nickelon-kieselguhr (32). (2). nickel boride (8P).17. all of which are. The catalyst is made by treating a nickel-alumina alloy with sodium hydroxide. In our experience. Other references to various nickel catalyst preparation are available for Raney nickel W-I and W-4 (71).86). Raney nickels W-3 through W-7 all lose their special activity rather rapidly when stored under water. The advantage of palladium chloride-on-carbon is said to be that there is no loss of activity on storing.99. gives a relatively low-activity catalyst. Mozingo (62) submitted therein preparations for 5% palladium-on-calcium carbonate or barium sulfate. Organic Syntheses describes a number of preparations of palladium.

Failure to operate within these limits has resulted in violent reactions. It is recommended there that the most active Raney nickel catalysts be used at temperatures lower than 10O0C or if at a higher temperature. and nitro compounds under mild conditions. which is often available for the asking. improved results are obtained by addition of ferric chloride or chromium chloride (68). Often purification of the feed can alleviate economically poisoning difficulties caused by extrinsic materials. alkynes. catalytic hydrogenation is the cheapest possible way to reduce a compound.1. The knowledge that a similar type of hydrogenation is already in industrial use should provide the research worker with assurance that a contemplated process is economically viable. aldehydes. and there is some advantage to using them. nitriles.1. Economics of Catalyst Use When hydrogenation reactions cease to be experimental and enter the stage of industrial development. Supply of large quantities of catalyst is ensured if needed. Purchased Catalysts Hydrogenation catalysts in great variety can be purchased from commercial suppliers. not all laboratory preprations of catalysts can be conveniently scaled up. The warnings of Organic Syntheses (13) are worth heeding. poisoning by the substrate is more difficult to correct. Raney nickel W-8 is a low-activity catalysts that has proved useful in deuteration experiments. ketones. .18. and a great many industrial processes are in operation.18. the cost of the hydrogenation process becomes important. Exceptions to this generality arise when the yield of hydrogenated product is not comparable to that obtained with other types of reduction or when poisoning of the catalyst causes excessive consumption and unacceptable space-time yields. It is a low-activity catalyst. Neither catalyst will retain its peak activity very long. Hydrogenation is a mature field. with a catalystto-hydrogen acceptor ratio of less than 5%. beyond the time and labor saved. Commercial catalysts are the end result of much empirical testing and represent the best of a type. oximes. Also some suppliers have experience and background in the choice and use of catalysts. Cobalt boride has been used for reducing unsaturated aldehydes to unsaturated alcohols.17. In general. 1. Some of the factors that enter into the determination of this cost are considered here. 1. ECONOMICS OF CATALYST USE 23 reduction of alkenes.

18. The price of bulk quantities can be obtained directly from manufacturers. and purification costs. some metal will be lost and must be replaced with fresh metal. that is. 1. 1.18. The number of greater significance is the cost of the catalyst in use. In . space-time yield. Eventually all catalysts become spent. In a loop system. the pure metal is converted to a suitable salt and again used for catalyst manufacture. the cost of using a catalyst is reduced to: cost of catalyst manufacture + cost of refining + cost of replacing lost metal The mistake is sometimes made of estimating catalyst cost based on the price of a small sample of catalyst. Considerable data are needed to make an accurate evaluation. noble-metal catalysts are always returned to a refiner. or returned to a refiner for recovery of metal values. is very much higher than the price of bulk quantities. which largely reflects the cost of handling.. the catalyst is destroyed and the noble metals are recovered and converted to high-purity metal. the reclaimed metal can be sold and the investment in it recovered.1. Among the factors entering into the determination are catalyst cost.24 1. At the refinery. If metal cost is considered a capital investment that will be later recovered. the pounds of product produced per pound of catalyst.2. For noble-metal catalysts. Cost of Catalyst The purchase price of an initial charge of catalyst is but one factor entering into the cost of using a catalyst. At this stage they can be discarded. i. In the entire loop. REACTORS. itself sometimes a problem. This price.e. which have high reclaim value. AND REACTION PARAMETERS Determination of the actual cost of a hydrogenation process is difficult. Catalyst Life An important determinant in the cost of using a hydrogenation catalyst is catalyst life. the cost of the catalyst when the value of reclaimed metal has been deducted. Refining is nowadays very efficient. CATALYSTS. The total cost of a catalyst used in a loop is accordingly given by: cost of metal + cost of catalyst manufacture + cost of refining + cost of replacing lost metal When the process is finally terminated. this price is in itself relatively unimportant. actual yield. cost of materials. capital investment. In commercial use. and most metal loss will occur in the process itself. catalyst life.

1.18. and J. 12. which is difficult to estimate without experiment. Org. G. 412 (1948). Org. Marko. Reuse may also influence selectivity. A variety of factors influence catalyst life. lower numbers may be tolerated. and R. Billica. Chem. 2960 (1981). Baker. J. R.. Soc.4. either favorably or adversely. J. 11. Am. Chem. 8. Org. J. 10. H. 70. 463 (1941). Synth. J. Chem. Chem. . Space-Time Yield Space-time yield refers to the quantity of product that can be produced in a reactor in a given time. Org. R.REFERENCES 25 some reactions the catalyst can be used only once. Coll VoL 1. R. J. W. Am. L. 46. Chem. of Wisconsin Press. Catalyst cost thus becomes a function of the demands put upon it. J. Adams. Org. Adkins and G. "Reactions of Hydrogen. Coll.. 46. V. 47. 46. Krsek. K. P. It is a function of both selectivity and activity. a high actual yield lowers purification costs and minimizes disposal problems. Acceptable catalyst life can be extended if space-time yield demands are not heavy. and L. L. 2954 (1981). H. J. F. 3. 2614 (1981). and J. Vol. Often the saving from a small improvement in yield effected by a change in catalyst completely overshadows the cost of the catalysts. in many it can be reused repeatedly with or without intervening regenerations. Synth. J. 4. Org. J. 7. The effective life of the catalyst can thus be limited by loss of activity or selectivity or both. S. Amma and J. G. Baker. R. S. but if production schedules are not full. L. 70. R. J. 6. and J. Org. 1937. catalyst activity declines somewhat with each reuse. Adams. 63 (1976). and V. 46. 5427 (1981). Augustine. 5. 46. 2. Voorhees. Madison. K. 61 (1932). 2960 (1981). Catai 25. Bakos. J. In general. K. Stille. Voorhees. Stille. L. Adkins. 9. Actual Yield High actual yields are always desirable. Adv. Fritschell. References 1. K.3. Fritschell. Toth. Org." Univ. Baker. 2. J. G. L. K. Chem. 468 (1982). 695 (1948). Soc. L. J. Chem. Stille. Adkins and H. Maximum efficiency is reached when this number is high. 1. Besides making efficient use of the starting material. Stille. Chem. Augustine and R. Stille. J. H. R. Shriner. Scott. Warner.18.

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and T. Org. A. Jr. A. Suzuki. F. T. Am. 847 (1952). J. 101.h. Nat/. Soc. 52 (1967). Emmett. G. J. J. Bachman. Weinkauff. Chem. Urushibara. Acad.Y. R. Vineyard. K. V. . and H. 18. Soc. M. Chem. M. Chem. 33. Knowles. Sd. Bull. Chem. Sabacky. Wiederhora. W. R. W. 34. J. 5946 (1977). Seagraves. 83rd. Chem. H.. 104. long. G. W. D. V. Prakt. J. Soc. 330(1937). Catal. Org. I. Toth. Vineyard. R. 159 (1983). D. REACTORS. 108. Viswanatha and V. 100. J. Werner.C. Vandenheuvel. Loss Prev. 799 (1961). J. Chem. and K. Wuesthoff and B. 2010 (1980). J. Jpn. 796. Y. Chem. Chem. 223 (1981). 45. J. Soc. Chem. Ito. Anal. D. 45. 1294 (1961). Young. MoI. 19. J. 24. Texas (1977). J. D. S. Sun. C. Am. Yao and P. N. Tsuji. S. Knowles. and M. 45. CATALYSTS. Daniels. and M.I. Sabacky. 107. 103. J. Org. C. H. 83. 112. Jpn. Symp. H. Snyder. 54. Chem. 102. 110. Young and H. S. 99. 149. Tai. B. J. R. A. Chem. and D. H. B. 3703 (1980). 227 (1953). L. Houston. Weygand and A. 1311 (1968). Org. AND REACTION PARAMETERS 98.-C. 3161 (1961). N. J. Hartung.E. 105. Org. Chem. Bu//.28 1. Taira. Shiota. Ann. J. 106. 2730 (1980). Richborn. Soc. Am. 109. Hrudy. and R. 145. Harada. W. 111. J. 99. Valentine. 83.

substrate. The extent of migration may be the key to success or failure. Often the course of reduction is influenced greatly by the catalyst. However. Mechanism of Olefin Hydrogenation The mechanisms of olefin hydrogenation are complex and many details are still unknown. Double-Bond Migration Double-bond migrations during hydrogenation of olefins are common and have a number of consequences (93).1. With active catalysts.105). It is influenced importantly by the catalyst. which correspond to one. two.or stereoselectivity. and by hydrogen availability at the catalyst surface. 2.-2Hydrogenation of Olefins Olefins are hydrogenated very easily.101. 2.68. 29 . since hydrogen can be consumed faster than it can be supplied to the catalyst surface. and reaction environment. Most problems connected with olefin hydrogenation involve some aspect of regio.20. the reaction is apt to be diffusion limited. by reaction variables. isomerization. Hydrogen is dissociatively adsorbed on two catalyst sites. a mechanism proposed long ago by Horiuti and Polanyi (51).1. over a variety of catalysts. and exchange (7. ledges (or steps) and kinks. These sites display differing activities toward saturation. provides a useful way of accounting for all aspects of olefin hydrogenation that are of interest to the synthetic organic chemist. A consideration of mechanisms of olefin hydrogenation will provide a rationale for the influence of these variables.1 f Recent work has defined more carefully the nature of active sites.103.1. Metal surfaces are thought to contain three main types of sites. terraces.104. unless highly hindered. indicated by an asterisk. Sites need not necessarily be on different atoms. and three coordinatively unsaturated sites of organometallic chemistry. while lacking insight into subtle problems of present thinking.

+ 2* If the half-hydrogenated state undergoes a configurational change before reverting to an olefin. that under conditions of low hydrogen availability on palladium the mechanism changes. . It has been suggested.+ 2* Addition of a second hydrogen atom forms the paraffin.+ H > -CH 2 CH 2 CH 2 CH 2 .*=* — CH-CH-CH2-CH2.+ 2* ?=* -CH2-CH-CH-CH2- A hydrogen atom adds to one carbon. -CH2-CH-CH2-CH2. —CH2-CH=CH-CH2. This last statement is supported by a huge body of experimental data but the reason for it is less certain. which is desorbed from the catalyst.30 2. that hydrogen is lost to give a syn or anti 7r-allyl species.+ H The extent of migration and isomerization is related to the rate at which the half-hydrogenated species reforms a diadsorbed species relative to the rate at which it adds a second hydrogen.H 2 *=* H + H I * I * and the olefin is diadsorbed on two adjacent sites. and supported with some data. Double-bond migration will occur if the half-hydrogenated state returns to a diadsorbed species different than the original. Migration and isomerization are favored by a low hydrogen concentration at the surface ("hydrogen-poor catalysts"). cis-trans isomerization may be effected. and that then through addition of hydrogen the initial 7i-species or an isomer is reformed. and diminished by high hydrogen availability at the surface ("hydrogen-rich catalysts"). the greater will be the rate of saturation relative to the rate of reversion. for instance. -CH2-CH-CH2-CH2. and the cycle is repeated. The greater the hydrogen concentration at the catalyst surface. often referred to as a half-hydrogenated state. HYDROGENATION OF OLEFINS 2* -I. leaving a monoabsorbed species. —CH2-CHCH2CH2. All steps except the last are reversible.

For example.2.125). Hydrogen availability refers to hydrogen concentration at the catalyst surface. Os (0. the experimental facts are clear. Effect of Hydrogen Availability Regardless of detail.124).3.2. they may also block sites with enhanced activity for migration (53). Ru. Palladium is used frequently when migration and isomerization are wanted.1. the ratio of isomerization to hydrogenation in isopropanol for various unsupported metals was Pd (2. Table 1 is a convenient summary of this concept. when they are to be avoided (2. the apparently straightforward saturation of 1 to give pupukeanone (2) could not be achieved by hydrogenation over Pd-on-C. The influence is a property of the metal itself and its structure and is little altered by the support (17. Catalysts Catalysts have a profound effect on the extent of double-bond migration.12).009) (82). process conditions that favor formation of hydrogen-poor catalysts favor migration and isomerization. At 20% conversion of 1-octene to octane. Ir (0. It is related to the relative tendencies of the halfhydrogenated states to reform an unadsorbed olefin.025). A decreasing ordering of metals for double-bond migration (46) is Pd > Ni » Rh » Ru ~ Os > Ir ~ Pt.025). Rh (0. Additives that retard the rate of reduction increase hydrogen availability and retard isomerization. Pt > Os > Ir (84).18). In examination of various disubstituted cyclic olefins.05).1. TABLE 1 Influence of Reaction Variables Increased variable Pressure Agitation Solvent Inhibitors Catalyst activity Temperature Metal concentration Catalyst concentration Effect on H 2 availability + + + + - Effect on migration Effect on isomerization + + + + — + + + + 2. DOUBLE-BOND MIGRATION 31 2. Pt (0. Ru (0. platinum. the following decreasing isomerization order was adduced Pd » Rh.1. .

the reaction proceeded in two stages. Most of 3 was probably formed by isomerization of an initially formed monoene. In this case.32 2. In some cases the tendency of double bond to migration rather than saturation is so large that even platinum does not prevent it. depending on whether or not the catalyst was prehydrogenated (92). Pupukeanone was obtained smoothly by saturation of 1 over platinum oxide (96).4-addition (3). depending on the catalysts. Minor . In these cases homogeneous catalysts may be useful. HYDROGENATION OF OLEFINS instead. hydrogen addition (5) followed by hydrogen elimination and migration (28). however. the product was that derived as if by 1. which affords either dihydrocoronopilin (8) or the isomerized product isocoronopilin (9). (Ph 3 P) 3 RhCl O (9) (7) Over platinum oxide the yield of isocoronopilin varied from 63 to 100%. (3) (1) (2) Conversion of 4 to 6 consumes no hydrogen and appears to be a consequence of double-bond migration. A case in point is coronopilin (7).

. OCH3 H2 SmIC 6 H 6 10mgRhCl(Ph 3 P)3 3h. DOUBLE-BOND MIGRATION 33 structural differences may alter the course of reaction and over RhH 2 Cl(Ph3P)3 [formed from RhCl(Ph 3 P) 3 by treatment with H 2 ] damsin (10) mainly is isomerized to isodamsin (11) rather than undergoing saturation (14).1. If the solvent were benzene-ethanol. Effect of Solvent Solvents can have a large influence on the extent of double-bond migration (6). depending on the system. 3-methylcyclohexene. O CH 3 The extent of double-bond isomerization over homogeneous catalysts is influenced by choice of solvent.1.30 mmol CH3O OCH3 CH3O 2. 5% Pt. Saturation of the double bond in 4-(4-methoxyphenyl)-3-(2-nitro-4-methoxyphenyl)-l-pentene was achieved smoothly by reduction over RhCl(Ph 3 P) 3 in benzene without any hydrogenation of the nitro function.4. isomerization of the double bond to a conjugated position also occurred. The factors involved are complex as shown in the hydrogenation of methylenecyclohexane. in pentane. and 4-methylcyclohexene to methylcyclohexane in benzene-ethanol. The amount of isomerized 2-methylcyclohexene was measured at 25% completion and.25°C 0. and in ethanol over 5% Pd. and 5% Rh-on-carbon. this styryl bond was inert to reduction under these conditions (77).2.

(14) Regardless of substrate and solvent. if at all. for unless tracers are employed. and. 2.14.2. isomerization fell with solvent in the order ethanol > pentane > 1:1 benzeneethanol. Selective removal of cis homoconjugated dienes and trienes in natural oils. isomerization fell in the order 12 » 13 . there may be no direct evidence remaining that migration has occurred. HYDROGENATION OF OLEFINS varied from 73. Substituted benzenes are less effective than benzene. Regardless of solvent and catalyst. Benzene proved to be a strong isomerization inhibitor. the fact that it does occur can have a number of important consequences. which can be hydrogenated only with difficulty.34 2. used to make edible hydrogenated fats. Nonetheless. A common consequence of migration in complex molecules is that tetrasubstituted olefins result.3 to 0%. It is easier to try to prevent hindered olefin formation than it is to correct it. 1:20 benzene-acetone showed marked inhibition. Attempted hydrogenation of the exocyclic methylene group in 15 proved difficult when using an aged 10% Pd-on-C catalyst. Benzene is effective as an isomerization inhibitor mixed with other solvents as well. depends mainly on prior isomerization of multiple unsaturation into conjugation under hydrogenation conditions (39). there was a . isomerization fell in the order 5% Pd-onC » 5% Rh-on-C > 5% Pt-on-C. regardless of substrate or catalyst. Consequences of Double-Bond Migration Double-bond migration often passes unnoticed.



complete isomerization of the exo double bond to the more hindered endocyclic position. The hydrogenation was achieved successfully with a large amount of 10% Pd-on-C in triethylamine containing a small amount of methanol. A quantitative yield of a mixture of epimeric methyl derivatives (16) was obtained in 85:15 ratio. The major isomer had the secondary methyl function in the equatorial (/?) configuration; hydrogen had added from the less hindered face (95).

^\^%>*CH3 XOCH3
!drop CH3OH >p 750 tng!prereduced prereduced 10%Pd-on ; Pd-on-C 0 3O C , l a t m C, k ^K. / y * ^^ ^

»* W

f/ \


Compounds that have no easily hydrogenolyzable function may lose that function, nonetheless, as a consequence of its becoming allylic or vinylic during the hydrogenation. Carene-3, which contains a nonconjugated cyclopropyl ring, gives mainly 1,1,4-trimethylcycloheptane on reduction over palladium, a result of isomerization to the conjugated 2-carene. Platinum, which has a low isomerization activity, gives high yields of carane (29).

Another example is the hydrogenation of the homoallylic compound 4methyl-3-cyclohexenyl ethyl ether to a mixture of 4-methylcyclohexyl ethyl ether and methylcyclohexane. The extent of hydrogenolysis depends on both the isomerizing and the hydrogenolyzing tendencies of the catalysts. With unsupported metals in ethanol, the percent hydrogenolysis decreased in the order palladium (62.6%), rhodium (23.6%), platinum (7.1%), iridium (3.9%), ruthenium (3.0%) (83).
OC 2 H 5 OC 2 H 5 +



The cis ether was always formed in greater amounts than the trans, but the cis-trans ratio varied considerably with the metal [Pd (2.0), Ru (3.0), Rh (4.0), Ir (4.4), Pt (5.2)]. Unsaturated alcohols may be converted to saturated carbonyl compounds as a result of migration (75). When migration relative to saturation is high, the isomerization gains synthetic utility (9,49). Olefins contained in an incipient aromatic system may be especially prone to migration, aromatization providing the driving force (87,109). Aromatization may occur even if a carbon-oxygen (27) or a carbon-carbon bond (8,76) need be broken in the process. Disproportionation is a special form of migration in which, in essence, a double bond migrates from one molecule to another, producing an aromatic and a hydroaromatic compound from the same olefinic substrate. Palladium is probably always the catalyst of choice when aromatization is wanted (26,54). Homogeneous catalysts, (Ph3P)3RhCl, are useful when aromatization is to be avoided (11).

2.3. Selective Reductions of Olefins
Most problems concerned with olefin hydrogenation involve the competitive hydrogenation of a double bond in the presence of another double bond or other function. There is usually a way of achieving the desired selectivity. 2.3.1. Dienes and Polyenes Several generalities can be formulated regarding selective reduction of polyolefins. Usually the least hindered double bond is hydrogenated preferentially (123), and, with steric hindrance about equal, the most strained bond will be reduced first. Exocyclic olefins are reduced more easily than those in the ring. (R)-( + )-Limonene, 190 g, was shaken with W-4 Raney nickel (12 g) under hydrogen at atmospheric pressure. After 31.9 1 of hydrogen had been absorbed, the solution was filtered. Essentially, pure (R)-( + )-carvomenthene was obtained in 96% yield (58).
W-4 Ra-Ni



In judging hindrance, it is useful to view the molecule in its threedimensional, folded configuration. For instance, 17 can be reduced without undue difficulty, whereas 18 requires extreme conditions (Raney Ni, 20O0C, 200 atm) (1), a difference not expected from planar representations of the molecule. Saturation of A9ao-octalin (17) may largely go through a prior isomerization to A lf9 -octalin, despite an unfavorable equilibrium (121).


Selectivity depends importantly on the catalytic metal. A number of selectivity series have been determined for simple olefins, and the presumption is that the sequence holds for more complex polyenes as well. Selectivity for the reduction of allene to propylene declined with metal in the order palladium > rhodium ^ platinum > ruthenium > osmium » iridium(17). Allenes with terminal bonds are selectively reduced in the terminal position (37,45). Selective reduction of conjugated diolefins, such as 1,3-pentadiene, falls with metal in the sequence palladium > rhodium > ruthenium > platinum > iridium (18). Selective reduction of homoconjugated diolefins, such as found in naturally occurring fatty acids, falls with metal in the order palladium > rhodium > platinum > ruthenium > iridium (125). This latter sequence results as a combination of the relative tendencies of metals to induce conjugation through double-bond migration, and of the selectivity order for conjugated dienes. In reductions of dienes to monoenes, it is important to monitor the hydrogen consumed and to stop the reduction at the stoichiometric point; few reductions will stop spontaneously. Tricarbonylchromium complexes are useful for 1,4-addition of hydrogen to 1,3-dienes to afford monoenes selectively (40,42,43,44). With 1,4-dienes, isomerization into conjugation precedes hydrogenation. Isolated double



bonds are untouched as illustrated in the synthesis of citronellol from isoprene (50). Methyl benzoate-Cr(CO)3, prepared according to King (62), was used under elevated pressures (30 atm) and temperatures (~ 15O0C). To minimize decomposition of the catalyst, it is important to flush the system with nitrogen and to purge the autoclave repeatedly with hydrogen before heating (41). Appropriate choice of catalyst permitted formation of either of two dihydro derivatives of mevinolin in high yield (67). Hydrogenation of mevinolin over platinum oxide in ethyl acetate gave the tetrahydro derivative as a 1:3 mixture of cis- and tr0ns-decalin isomers.

Catalyst and solvent (Ph3P)3RhCl, PhCH3 5% Pd-On-CaCO3, EtOH

90% minor

10% major or exclusive

Dienes can sometimes be completely saturated under conditions where a monoene is not reduced, as illustrated by the data of Reuvers and deGroot (91). In fact, the monoene was still inert at 1200 psig, whereas the diene could be reduced at 28 psig.

as illustrated by selected examples (91).3. SELECTIVE REDUCTIONS OF OLEFINS O 39 R . OAc cis-trans 1:1 RhCl(Ph 3 P) 3 -C 6 H 6 .2.and stereochemistry are markedly influenced by relatively small pressure changes.H . HO CH3O HO HO CH3O Pressure (psi) 24 60 150 230 37 87 70 30 63 13 20 40 10 30 . CH3OH 1200psig O In this series both regio.

102 g 22 and 0.CHO CHO CHO (19) (21) Homogeneous catalysts are useful in this type problem. whereas 13. or a vinylogous aryl carbonyl.4-androstadiene-3.17-dione to 4-androsten-3.07 g (Ph3P)RhCl was stirred in 15 ml benzene for 8 h under 1 atm hydrogen. Sometimes conditions can be adjusted so that either or both double bonds can be reduced at will. at a level of about one atom of iron per atom of palladium. Yield of 24 was 94%.2. such as in cinnamaldehyde is employed. Quantitative yields of either 19 or 21 could be obtained by hydrogenation of 20 with appropriate use of modifiers (114).17dione was achieved with (Ph 3 P) 3 RuCl 2 (81). Selective conversion of l. Unsaturated Carbonyl Compounds Reduction of unsaturated carbonyl compounds to the saturated carbonyl is achieved readily and in high yield. The conjugated double bond of eremophilone (22) was reduced preferentially over a variety of heterogeneous palladium catalysts to (23). Carbonyl reduction can be diminished or stopped completely by addition of small amounts of potassium acetate (35) to palladium catalysts. Of greater challenge is the selective hydrogenation of those carbonyl compounds having two or more double bonds. Pd-on-C 25OmICH 3 OH 0. Homogeneous catalysts are not very effective in hydrogenation of unsaturated aldehydes because of the tendencies of these catalysts to promote decarbonylation. prepared by refluxing ruthenium . HYDROGENATION OF OLEFINS 2. such as ferrous sulfate. A solution of 0. If an aryl carbonyl compound.40 2.3. Over palladium the reduction will come to a near halt except under vigorous conditions (73). Other effective inhibitors are ferrous salts. The ferrous salt can be simply added to the hydrogenation solution (94). some reduction of the carbonyl may occur as well.Ig(C 2 Hs) 3 N sulfur—quinoline . 14-dihydroeremophilone (24) was obtained on reduction with (Ph3P)3RhCl (23).

when used in the presence of base (84).2. VINYLIC AND ALLYLIC FUNCTIONS 41 chloride hydrate in ethanol with triphenylphosphine (107). 10% palladium-on-carbon (119) and prereduced ruthenium dioxide (111) are also effective in these selective reductions. It is an excellent solvent for steroids and permits hydrogenation to be done at high concentrations (115). by nonpolar solvents and low temperatures. In dienes of this type. acid.106). The use of 4-methoxypyridine has given excellent results whenever low yields were obtained in other solvents. selectivity is influenced by the structure as a whole. hydrogenation. or preferably. The ratio of olefin saturation to hydrogenolysis depends importantly on catalyst.34).5). After a comparison with other bases. acetic acid. temperature. Hydrogenolysis of allylic functions over palladium may (82). Other selective homogeneous reductions of 3-oxo-l.72. In both classes of compounds.59.17-dione varied with pressure ranging from 66% at 10 atm to 92% at 162 atm. In general. hydrogenolysis is favored by polar solvents. tetrahydrofuran with hydrobromic acid have favored formation of 5/?-compounds. and pH. Solvent effects are also influenced by substituents remote from the unsaturation (85). substituents at position 11 may interfere with coordination of the catalysts to the 1. . is an important factor in determining 5/J-content (115). hydrogenolysis of vinylic compounds is favored by platinum and hydrogenation by ruthenium and rhodium (31. and elevated temperatures. pyridine. Palladium catalysts are usually used. lower alcohols with potassium hydroxide.55. In the reduction of 4-methyl-l-cyclohexenyl ether. Vinylic and Allylic Functions Reduction of vinylic and allylic compounds without hydrogenolysis may present a problem. the authors concluded that the nucleophilicity of nitrogen bases.4-diene steroids is a convenient and widely used route to 5/?-steroids (4. the order of decreasing hydrogenolysis to give methylcyclohexane was established as Pt » Ir > Rh > Os » Ru ^ Pd The order for decreasing hydrogenolysis of allylic functions appears to be Pd > Pt » Rh ^ Ru.4.4-diene steroids have used (Ph 3 P) 3 RhCl (15.32. Ligands carrying p-methoxy and p-methyl substituents greatly enhance activity. Selective hydrogenation of 3-oxo-4-ene and -1. Reaction virtually ceases after absorption of 1 mol of hydrogen. For instance. rather than their p/Cas. Stereoselectivity depends on the reaction solvent. Selectivity to 4androsten-3.2 double bond and sharply lessen discrimination (122).4. but even it has given poor results. Pyridine has been generally the most useful. solvent. Heterogeneous catalysts. 2.

Attempted saturation of 25 over PtO2 or Pd-on-C in acetic acid. NaNO 2 ).CH 2 CH 2 OH CH3 CH 3 (30) CH 3 (31) R = (CH 3 J 2 C=CHCH 2 R=(CH 3 J 2 CHCH 2 CH 2 . hydrogenolysis of the allylic oxygens was extensive (70). Reduction of zoapatanol (30) over PtO 2 -NaNO 2 gave 31. OAc OGIu(Ac)4 (29) A difficult reduction was achieved smoothly over an unusual system (PtO 2 . but over 5% Rhon-C in ethyl acetate a 1:1 mixture of 26 and 27 was obtained in 95% combined yield (12). after many other catalysts had failed (69). ethanol.3O0C and raising the temperature slowly to O0C over 3 h. whereas over Pd-on-C. 29 was obtained quantitatively. O O HO. . OAc OAc OAc O OAc OGIu(Ac)4 (25) OAc OGIu(Ac)4 OAc (26) (27) Hydrogenolysis can be diminished by reduction at low temperature. Hydrogenation of asperuloside tetraacetate (28) over 5% Rh-on-C in ethyl acetate at 250C gave mainly 29 accompanied by several hydrogenolysis products. following Dart and Henbest (33). or dioxane-water gave extensive hydrogenolysis of the allylic acetate groups. HYDROGENATION OF OLEFINS occur through formation of a 7r-allyl complex (3). The catalyst was reusable at least three times (13). but by starting at .42 2. ethyl acetate.

4cycloaddition of a. cyanide. Steric hindrance around an allylic function will diminish its hydrogenolysis as access of the function to the catalyst surface is impeded. and dihydrothebaine (16)./?-unsaturated carbonyl compounds with isocyanides. but in the following such a bond was readily reduced even though it contained a vinylic oxygen. If hydrolysis precedes hydrogenation. dihydrothebainone. to afford unsaturated N-substituted iminolactones. whereas reduction of thebaine itself is less clean and gives dihydrothebainol. HOAc Pd H2 O O . catalyzed by diethylaluminum chloride.2. or hydroxide added later. VINYLIC AND ALLYLIC FUNCTIONS 43 Dart and Henbest (33) demonstrated that the amount of salts remaining in platinum oxide catalysts had an important bearing on the hydrogenationhydrogenolysis ratio of allylic functions. Hydrogenolysis is inhibited by salts remaining from the catalyst preparation or by salts such as sodium nitrite. These are stereoselectively hydrogenated by palladium-oncarbon and then acid hydrolyzed. (33) (32) Tetrasubstituted double bonds frequently are difficult to reduce. + CH 3 NC Et 2 AlCl NCH 3 10%Pd-on-C 10atmH 2 5O0C. NCH. NCH 3 CH3O O CH3O O OCH3 OCH. the resulting unsaturated lactone is very difficult to reduce (57).4. A general stereoselective synthesis of y-butyrolactones involves 1. Reduction of 5methylthebaine (32) proceeds smoothly over Pd-on-C in ethanol at 1 atm to afford 5-methyldihydrothebaine (33).

A remarkably effective reduction of a complex vinyl sulfide was achieved (65) in a synthesis leading to the antibiotic alkaloid chuangxinmycin.5. The double bond is tetrasubstituted and is a vinylogous amide. Palladium-on-carbon gave the desulfurized indole (38).80.4-addition. Indeed. a variety of catalysts and reducing agents failed to give any 37. Under mild conditions. Olefins with divalent sulfur can be reduced satisfactorily but will require high catalyst loading and lengthy reduction times. Olefinic Sulfur Compounds Olefins containing divalent sulfur can be expected to be reduced slowly. oxidized sulfur is not. However.88. structures known to be difficult to reduce. have often proved effective when hydrogenolysis was to be avoided. this catalyst has low activity at best. HYDROGENATION OF OLEFINS Similar lactones (34) have been reduced over Pd-On-BaSO4 to the dihydro derivative (35) in high yield (36). This catalyst. H3C O H3C 50 ml EtOH I g 5% Pd-On-BaSO4 1 atm.98JlO). success was achieved with 5% PdSx-On-C producing a single product. Usually palladium-on-carbon is employed in these reductions (71. as well as PtSxon-C and RhSx-On-C. 250C O O O (35) 2. and materials such as sulfuric acid and dimethyl sulfoxide can be excellent solvents for hydrogenation. On the other hand.44 2. and very high catalyst loadings and patience were required for success. Compound 36 would be expected to be converted to 37 only with great difficulty. perhaps facilitated by 1. The sulfur atom would be expected to inhibit the catalyst and the compound is susceptible to hydrogenolysis. since divalent sulfur is a strong inhibitor for hydrogenation catalysts.89. COOCH3 5% PdSx-On-C EtOH 70psigH 2 (38) (36) .

sometimes to a marked degree. solvent.6.6. STEREOCHEMISTRY 45 2.19. Experimentally. The phenomenon appears general for related 3. Hydrogenation of a stereoisomeric mixture of dehydro alkaloids over PtO2 in acetic acid produced only a single alkaloid. Double-bond isomerization frequently occurs.COOR COOR O O O R = K R = CH 3 100% 61% O 25% Stereochemistry can be influenced strongly by both catalyst and nonbonded interaction between an oxygen lone pair and nonadjacent n electrons. it is expedient. as illustrated by selected data of Ishiyama et al. stereochemistry has been found to vary. with olefin purity. Generalizing. among which is the difficulty of determining which side of the molecule is the least hindered. and catalyst (30JOO). Stork and Kahne (108) have demonstrated remarkable stereochemical control in the hydrogenation of a series of cyclohexenols containing allylic .113).74.5-dialkyl-A3'4dehydroindolizidine alkaloids. reaction parameters. has been observed by many investigators (10. This anchoring effect. (56) (Table 2). and the hydrogenation product is the resultant of a number of competing reactions. But there are many exceptions and complications (97). when unwanted products arise as a result of prior isomerization.COOR 10%Pd-on-C > SOpsig EtOAc . Stereochemistry The stereoisomers of olefin saturation are often those derived by cis addition of hydrogen to the least hindered side of the molecule (99). Involvement of a center remote from the point of saturation has also been demonstrated in another connection.78. An example of GuIa and Spencer (47) illustrates how the anchoring tendencies of a function remote from the point of saturation may influence the stereochemistry.90. .2. to avoid those catalysts and conditions that are known to favor isomerization. dubbed haptophilicity (112.120). Some olefinic molecules have a second function that anchors itself on the catalyst surface in such a way so as to enforce addition of hydrogen to its own side of the molecule.

cy = cyclohexyl.0 Catalyst Raney Co Raney Ni Ru-on-C Rh-on-C Pd-on-C Ir-on-C Pt-on-C PtO2 73 89 88 87 90 76 84 98 37 45 77 61 26 66 64 64 and homoallylic double bonds. A further example of the stereochemical influence that may be exerted by proper choice of catalyst and solvent is shown in the hydrogenation of a complex enamine.5-cyclooctadiene. py = pyridine. a result characteristic of indenones.* This catalyst was chosen because it has two sites available for coordination with a bidentate substrate and because it was known to reduce trisubstituted double bonds. Reduction of 40 over 5% Pd-on-C gave the ds-indanone 39 almost exclusively. whereas in reduction over Ir(cod)py(Pcy3)PF6 the trans-indanone 41 formed in high yield. By proper choice of conditions high yields of either the cis or trans product could be obtained.46 TABLE 2 2. OH OH lr(cod)py(cy3)PF 6 OH O H (39) (40) (41) Solvents and pH may have a marked effect on stereochemistry as was illustrated in Chapter 1. HYDROGENATION OF OLEFINS Percentage cis Isomer Resulting from Hydrogenation CH 2 . using Ir(cod)py(Pcy3)PF6. ' cod = 1. Selected results are shown below (52) (data used with permission). a result attributable to the oppositely placed hydroxy group. and the generality given there is useful. .

such as in DIOP and BPPM (61.116). STEREOCHEMISTRY 47 CH 2 N(CH 3 ) Ratio (%) Catalyst 5% Pd-on-C 5% Pd-on-C PtO2 PtO2 PtO2 PtO2 Solvent Benzene Ethanol Benzene Ethanol Ethyl Acetate Isopropanol cis trans O 100 O 100 O 100 92 8 95 5 98 2 Isolated yields of amines (%) 99 99 — 59 38 39 This was the first investigation of stereoselective formation of geometric isomers of tertiary amines. Wide variations in stereoselectivity are possible between the E and Z isomers (79). The medically important compound. chiral rhodium-phosphorus complex. In hydrogenation of several (E).38.2. Usually the best optical yields are obtained with a chelating diphosphine ligand.116). but in all cases the S enantiomer was formed in greater excess (117). the optical yield is decreased with increasing pressure.and (Z)-a-acylaminocinnamic acid derivatives.22. such as DIPAMP.1.6. the Z isomers gave greater enantiomeric excesses at 15-100 times the rate of reduction of the E isomer. In general. Asymmetric Hydrogenation of Olefins Asymmetric hydrogenation of olefins has not been highly stereoselective except in the synthesis of amino acids and closely related compounds (21. Stereoselectivity may be influenced strongly by both temperature and pressure. where chirality may reside in the coordinating phosphorus atom. The greater effectiveness of Z-olefins is general (118). an area in which enantiomeric excesses approaching 100% have been obtained.60.64. or in a substituent or backbone carbon.63.24.6. and at high pressures (50 atm) the predominant product chirality actually has been . The authors suggested most enamine systems should be subject to considerable stereochemical control. L-Dopa (3.4dihydroxyphenylalanine) is so obtained by hydrogenation over a homogeneous. 2.

\_/ OCH3 /PCH 2 CH 2 P DIOP DIPAMP BPPM reversed (86). optical yields may fall with decreasing temperature and increase with increasing temperature (48). reached the opposite conclusion. (Z)-2-Benzamide(acetamido)-3-(2-thienyl)-2propenoic acid was reduced in 100% yield and 78% enantiomeric excesses over Rh(I)-DIOP catalysts (25). which frequently does not accumulate in sufficient concentration to be detected. The origin of the remarkable stereoselectivities displayed by chiral homogeneous catalysts has occasioned much interest and speculation. less stable diastereomer of the olefin-catalyst adduct. Homogeneous catalysts may also be effective in the hydrogenation of sulfur-containing compounds. Halpren (48) on the basis of considerable evidence. the predominant product enantiomer arises from the minor. in one case. using a lock-and-key concept. It has been generally assumed. The predominant adduct is in essence a "dead-end" complex for it hydrogenates at a much slower rate than does the minor adduct. . Perhaps running counter to intuition. optical yield rose from O to 60% in going from O to 10O0C (102). HYDROGENATION OF OLEFINS V/ CH3O.48 2. that the major product enantiomer arose from a rigid preferred initial binding of the prochiral olefin with the chiral catalyst.

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and barium sulfate are frequently used supports. Acetylenes are. Examples of some differences are noted later. very largely sequential. see Ref. may prove more useful (35. Carbon. it will occupy most of the catalyst sites and be reduced preferentially. over selective metals.1. and hydrogenation of the triple bond occurs in many reaction sequences (1). and hydrogen availability at the catalyst surface.87) have compared various metals for the selective hydrogenation of lower acetylenes to olefins.65). regardless of the relative rates of the acetylene and olefin hydrogenation when not in competition for sites.-3Hydrogenation of Acetylenes Acetylenes have high synthetic utility. 53 . Experimentally. reaction conditions. which usually can be achieved in very high yields (for an exception. substrate. and as long as the acetylene is present. solvent. The reduction acetylene » olefin » paraffin is. 10). Despite these complexities. and it was always found that palladium was by far the most selective. Often the goal of this reduction is formation of the cis olefin. This conclusion concurs with the usual synthetic experience. The catalyst support may also have an influence (21. The term molecular queuing has been used to describe the operation of a hierarchy of adsorbabilities (19). calcium carbonate. but under special circumstances other metals.6. 3. both the relative and absolute rates of acetylene and olefin hydrogenation have been found to depend on the catalyst. much more strongly adsorbed than the corresponding olefin.7. such as platinum. in general. high yields of desired product usually can be obtained without difficulty. Catalysts Many workers (5.63). Continued reduction gives the paraffin.

RhH 2 (O 2 COH)[P(I-Pr) 3 J 2 (88). For instance. but workable systems have been described (78). A remarkable trans hydrogenation of alkynes has been achieved with the homogeneous catalyst.6. 6gHaNCH2CH2NH2 ' 25 ml C 2 H 5 OH. but when the HOCH1CH2(^CCH2CsC(CIUoCH. The catalyst is prepared by reduction of nickel acetate in ethanol with sodium borohydride (9).9-heneicosatriynol. PhC=CPh O H3COCC=CCOCH3 Il Il » H3COC H/ H c=c S0CH3 O 0 0 .55. the use of nickel is relatively infrequent (51).9-heneicosatrienol smoothly (34).6-diynol over P-2 nickel gave the corresponding (Z. but the classical Lindlar catalyst (45) gave (Z. Palladium-on-barium sulfate in methanol containing quinoline (16). or palladium-on-calcium carbonate in hexane containing triethylamine (14) gave almost the same results as P-2 nickel.58.54 3. 3. selectivity was poor. Pd-On-CaCO3 HO(CH2)2C=CCH2C^CCH2C^C(CH2)10CH3 HOx A A A /(CH 2 J 10 CH 3 Homogeneous catalysts rarely are used for hydrogenation of acetylenes.Z. HYDROGENATION OF ACETYLENES Highly stereospecific hydrogenations of acetylenes to cis olefins have been achieved also with nickel (P-2) catalysts in the presence of ethylenediamine as prontoter (37.72).Z)-3. An a priori choice of an optimum acetylene hydrogenation catalyst is not always easy. 250C /CH2J10CH3 catalyst system was applied to hydrogenation of the similar 3. Despite successes (44).Z)-dienol satisfactorily (37).38. the reduction product contained at least four components in comparable amounts.6. hydrogenation of octadeca-3.93 g 3 . A solution of PdCl2 in CH2Cl2 containing polyethylene glycol was more selective in hydrogenation of diphenylethyne to diphenylethylene than 10% Pd-on-C.



Heretofore, most homogeneous and all heterogeneous catalysts have given cis hydrogenation. 3.1.1. Catalyst Modifiers A variety of modifiers have been used in hydrogenation of acetylenes to improve selectivity (4). The modifiers have been incorporated during preparation of the catalyst and also added subsequently to preformed catalysts at the time of use. Among the metal salts used for this purpose are those of zinc, cadmium, zirconium, ruthenium, gold, silver, lead, and tin. A function that many modifiers may have in common is to increase hydrogen availability at the catalyst surface, by decreasing the rate of hydrogen consumption relative to the rate of hydrogen supply. They may also cause rearrangement of the palladium surface (46,47)- The best known of these promoted catalysts is the Lindlar catalyst, palladium-lead-on-calcium carbonate (45), which has been used successfully by many workers (17,25,26,32,36,53,54,66,77,79,80,83,85) with and without additional modifiers. Selective hydrogenation of alkynes over Lindlar catalysts has proved very useful in syntheses of pheromones (67) and prostaglandins (15,76). A general route to synthetically useful a-vinyl carbonyl compounds involves semihydrogenation of the corresponding a-chloroethynyl compounds, over Pd-Pb-CaCO3 (Lindlar catalyst) in 10:1 ethyl acetate rtriethylamine at atmospheric pressure. Yields are uniformly in the high nineties (41).

EtOAc=Et 3 N 1 atmHi 250C Pd-Pb-CaCO3


>C> + HCl

Hydrogenations with Lindlar catalysts frequently slow down or stop after absorption of 1 mol of hydrogen. Reduction of 4-hydroxydodec-2-ynoic acid stopped spontaneously when about 95% of the theoretical hydrogen had been absorbed (39).
150 mg Pd-Pb-On-CaCO3 15OmIEtOAc

6.3 g




However, this behavior cannot be depended on. It is safer to monitor hydrogen uptake. Reduction of 4-oxo-trans,trans-7,10-dodecadiene-2ynamide (1) to 2 neither stopped nor slowed down at the ethylene stage; although in other compounds, the same catalyst did give spontaneously selective reductions.

7 drops quinoline H2


Beside metal salts, a variety of other modifiers, which include amines, chlorobenzene, hydroxides (82,820), and sulfur compounds, have been used. Among amines used are quinoline (8,20,57,84), pyridine (29,33,50,60,64), piperidine, aniline, and diethylaniline. The reduction may be quite sensitive to these modifiers; for instance, one drop of quinoline was sufficient to cause hydrogenation to come to an abrupt stop after absorption of 1 mol of hydrogen (2a).

3.2. Solvents
Many solvents have been used successfully. Some workers have expressed preference for nonpolar solvents, such as pentane or hexane, over alcohols


Amines (7aJ2d), especially pyridine (73), have also been used as solvents in the hydrogenation of acetylenes. Hydrogenation of 3 over 5% Pd-On-BaSO4 in pyridine gave d/-ds-jasmanate (4) quantitatively (40). The authors comment that this combination for reduction of acetylenes was superior to the Lindlar catalyst in all cases examined. (See also Refs. 12 and 24 for similar conclusions.)

1OmIC 6 H 5 N 25 C, 1 atmH 2 5% Pd-On-BaSO4



A convenient synthesis of 5-(methoxymethoxy)-2-pentenal was accomplished by selective reduction of 5 to 6, followed by oxidation with pyridinium chlorochromate (59).

" lequivH2




13.3 g

A useful self-terminating catalyst system (11), employs a Pd catalyst [prepared from Pd(OAc)2, NaH, and r-AmOH in THF]. The solvent required for the hydrogenation depends on the acetylene structure; monosubstituted acetylenes require solvents such as hexane or octane, whereas disubstituted acetylenes need ethanol, ethanol-hydrocarbon, or ethanol-THF mixtures. In all cases it was necessary to use quinoline as a catalyst modifier. The authors consider this system one of the best for achieving both high yield and stereoselectivity.

3.3. Influence of Reaction Variables
Selectivity of acetylene hydrogenation to the cis olefin has been found to depend on temperature, catalyst loading (21,260), catalyst support (21), agitation (220), modifiers, and solvent. Many of these effects can be rationalized by the influence the variable has on hydrogen availability at the catalyst surface. Over palladium, the metal most often used, double-bond migration and cis-trans isomerization tend to be faster than saturation, especially so, as the catalyst becomes hydrogen poor. Hydrogenations proceeding beyond 1 mol of hydrogen absorbed will result, therefore, in the loss of more initially formed cis isomer than calculated from the stoichiometry of the excess absorption. It is sometimes advisable to stop the hydrogenation before stoichiometric hydrogen is absorbed (2,78). High thermodynamic selectivity (7) demands that the initially formed cis olefin be displaced rapidly relative to its saturation or to its isomerization. As the reaction nears completion and the acetylene concentration diminishes, its effectiveness in displacing olefin will diminish and selectivity will fall. Displacement by acetylene is also impeded through depletion of acetylene in the vicinity of the catalyst owing to intra- or interpartile diffusion resistance (53d). A change in a reaction parameter thus can have different influences



depending on whether or not the reaction is at the transition into the range of external mass transfer (12b). Support has been shown to influence selectivity and some workers have obtained higher yields of cis isomer over palladium-on-calcium carbonate or palladium-on-barium sulfate (21), whereas others find carbon satisfactory. In general, carbon support makes the more active catalyst and it is, therefore, more prone to become hydrogen poor. Choice of catalyst and solvent allowed considerable flexibility in hydrogenation of 8. With calcium carbonate in ethanol-pyridine, the sole product was the trans isomer 9, but with barium sulfate in pure pyridine the reaction came to a virtual halt after absorption of 2 equiv of hydrogen and trans-2-[6cyanohex-2(Z)-enyl]-3-(methoxycarbonyl)cyclopentanone (7) was obtained in 90% yield together with 10% of the dihydro compound. When palladiumon-carbon was used in ethyl acetate, a 1:1 mixture of cis and trans 9 was obtained on exhaustive hydrogenation (86). It is noteworthy that in preparation of 7 debenzylation took precedence over double-bond saturation.

Pd-on-C, EtOAc Pd-On-CaCO3, EtOH-C6H5N




3.4. Functionalized Acetylenes
A frequent problem is selective reduction of an acetylene to the olefin in the presence of other easily reducible functions. Usually the reaction can be done without difficulty because of the relatively strong and preferential adsorption of the acetylenic function on the catalyst. Functions adjacent to the triple bond may cause special problems if the resulting allylic compound is itself susceptible to facile hydrogenolysis (78,23). The product composition is, as expected, sensitive to steric effects (82).

as well as. All are hydrogenolysis products arising from the initially formed 2. cyclization to furans (82a).5-dimethyl-3-hexene 11. (14) (15) .5-diacetoxy-2. but it remains complex. They are often hydrogenated to either the olefinic or paraffinic hydroxy compounds. 2. Hydrogenation of acetylenic carbinols is sometimes accompanied by isomerization to the ketone. and Esters Acetylenic carbinols and glycols appear frequently in synthetic work. usually without difficulty. FUNCTIONALIZED ACETYLENES 59 3.68). One of these. Seven different products are formed together with acetic acid.3. Another technique for minimizing hydrogenolysis (8a) and cis-trans isomerization is to operate at subambient temperature (32.4. Hydrogenation of 2. A good technique for full or partial hydrogenation of hydroxyacetylenes is use of palladium promoted with small amounts of potassium hydroxide (82b). the isomerization to 15 was most pronounced when hydrogenations proceeded very slowly as when impure 13 was used (39). The preferred metal usually is palladium.4. Acetylenic Carbinols.5-diacetoxy-2. Glycols. for they undergo hydrogenolysis more readily. CH3 CH 3 CH 3 CH3 CH3 AcOCC=CCOAc I l CH3 CH3 (10) » AcOCCH=CHCOAc I l CH3 CH 3 (11) * /C=CHCH2COAc U33C^ CH3 (12) The authors suggested a concerted addition of hydrogen via a six-centered transition state that would produce 12 directly from the olefin (11) (61). In the case of 13. Reduction of acetylenic glycols and carbinols in general seems less stereospecific than that of nonsubstituted acetylenes (42).1.5-dimethyl-3-hexyne 10 over 10% palladium-on-carbon is exceptionally complex.5dimethyl-2-acetoxy-4-hexene 12 forms in as much as 48% yield. Large amounts of alkali may promote cis-trans isomerization (460). in the presence of acids. The glycols are more sensitive to catalysts and conditions than are the carbinols. Addition of pyridine or quinoline alters the reaction.

other metals have at times given an equal or better performance. Hydrogenation ceased spontaneously.2-epoxydec-4-ene in 95% yield (69). HYDROGENATION OF ACETYLENES Although palladium is usually the catalyst of choice. . Acetylenic Epoxides Acetylenic epoxides are reduced readily to the olefinic epoxide. followed by hydrogenation and acidcatalyzed deprotection and cyclization. In the latter case. Platinum oxide. provided the resulting epoxide is not allylic (27). one might surmise that hydrogenolysis could best be avoided by use of rhodium in a neutral nonpolar solvent (81) or a Lindlar catalyst (13).2-epoxydec-4-yne over Lindlar catalyst gave (Z)-l. Commercially available 3-nonyn-l-ol was converted to its phosphorane (16) and Wittig-coupled with the unsaturated aldehyde (17) to afford 18.2. which was reduced over Lindlar catalyst to give 19.4. (1) IaUnH 2 CH3OH Rh-On-Al 2 O 3 (2) H + " 3. light petroleum 1Og Another example of this preference is found in the enantiospecific syntheses of tritium-labeled leukotrienes (13).60 3.5]decanes can be prepared conveniently by reaction of the lithium salts of protected alkynols with equimolar amounts of lactones. Rhodium-on-carbon has been used effectively in similar reductions (75). and Rh-onAl 2 O 3 were compared as hydrogenation catalysts and Rh-On-Al2O3 was found to give the cleanest reaction and most reproducible yields (62). Pd-on-C. A variety of 1.6-dioxaspiro[4. Reduction of l.4]nonanes and l. Nickel (P-2) is said to saturate propargylic hydroxy compounds without hydrogenolysis (9).6dioxaspiro[4.

which may be intramolecular (74) or intermolecular (28). Considerable control can be exercised over the reaction course by appropriate choice of catalyst and conditions as illustrated by hydrogenation of 21. In absolute ethanol over palladium.4.48.3. . Other examples of carbon-carbon bond formation. The extent of hydrogenolysis is sensitive to substrate structure (310). FUNCTIONALIZED ACETYLENES 61 COOCH3 The unlabeled ester is made conveniently by reducing the C9 acetylene to the olefin before coupling. —^ H-C5H11CH-CHCH2CH2OH 96.4. Tn-C5H11C=CCH2CH2OH u 0.3 ml synthetic quinohne SOmlhexane 250C. whereas over W-2 Raney nickel the saturated product 22 was obtained in 72% yield.3. the cyclized products 23 and 24 formed. have been reported in the hydrogenation of acetylenes. Propagargylamines Hydrogenolysis may be an important side reaction accompanying reduction of propagargylamines.56). H 2 . . Hydrogenolysis has been minimized by employing platinum instead of palladium and by reduction of an amine salt instead of the free amine (22.49.4% 5-lg 3. In related problems. when potassium hydroxide was added to suppress hydrogenolysis (43). Reduction of 21 over platinum oxide in a variety of solvents or over palladium in aprotic solvents gave the hydrogenolysis product 20 in high yield. potassium hydroxide was found to be less of a rate inhibitor than sodium hydroxide (82).

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and an ordering of catalyst activities usually applies to both functions. and the platinum metals group have been used successfully in carbonyl reduction. this latter group has a low strength of adsorption on palladium relative to other metals (72. an excellent catalyst for hydrogenation of aromatic carbonyls is relatively ineffective for aliphatic carbonyls. N(CHJ6COOCH3 40m . unless special structural features are present. and preferred catalysts differ. 4. nickel.25°C 35atmH 2 0. as illustrated by the difficult-to-reduce vinylogous amide 1 to 2 (9). Catalysts A variety of catalysts including copper. but with aryl carbonyls either reduction to the alcohol or loss of the hydroxy group can be achieved at will. But the difference between aliphatic and aromatic carbonyls is marked. cobalt.1.Hydrogenation of Aldehydes and Ketones Aldehydes and ketones are similar in their response to hydrogenation catalysis.cH30H N(CH 2 J 6 COOCH 3 OH C*H 12h. palladium can be used very well with aliphatic carbonyls with sufficient patience. Hydrogen was added stereoselectively to the least hindered side of L-ascorbic acid (3) to give L-gulono-l.4-lactone (4) 66 .2g5%Pd-on-C C 6 H 13 (2) In ketones existing largely as the enol.91). In hydrogenation of aliphatic carbonyls. palladium may prove effective in minimizing hydrogenolysis. Nonetheless. Palladium. hydrogenolysis seldom occurs.

2. This type of promoter can also sharply curtail hydrogenolysis if it is a troublesome reaction (Rylander and Starrick. and it. Rhodium has given excellent results under mild conditions when other catalysts have failed (4. high selectivity can only be obtained through prereduction of the catalyst just before use.2glO%Pd-on-C 5O0C.23. as well as nickel. Platinum oxide. Osmium makes a sluggish carbonyl hydrogenation catalyst but has the unusual property of reducing a. Nickel usually requires vigorous conditions unless large amounts of catalyst are used (11. Solvents Solvents have a marked effect on the rate of reduction of carbonyls (16).15. SOLVENTS 67 quantitatively. Raney nickel was inactive under mild conditions and platinum oxide gave a mixture of products (7). Copper chromite is always used at elevated temperatures and pressures and may be useful if aromatic-ring saturation is to be avoided.82).27. 1966).75. it frequently is worth resorting to. Platinum. especially platinum oxide. The usefulness of this regenerative technique transcends aldehyde reductions./?-unsaturated aldehydes to the unsaturated alcohol in good yield (85). It is useful in reduction of aliphatic carbonyls in molecules susceptible to hydrogenolysis.4. 50 psigH 2 HO (3) 23 g OH (4) Ruthenium is excellent for hydrogenation of aliphatic carbonyl compounds (92). The system has proved erratic.60). 4.37. when used with aldehydes is apt to be deactivated before reduction is completed.8.29. Deactivation is inhibited by small amounts of ferrous or stannous chlorides (59.100).5. is used industrially for conversion of glucose to sorbitol (14. Deactivated systems can often be regenerated by shaking the reaction mixture with air (2.66).2. has been used by many investigators (5).96).21. 17OmIH 2 O 2.20. such as W-6 Raney nickel (6). or the catalyst is very active. in .

but it is also a property of the hydrogenation catalyst itself.53). but hydrogenolysis of an aromatic carbonyl will occur easily. 89. (68) emphasize how strongly ether formation depends on the catalyst. HYDROGENATION OF ALDEHYDES AND KETONES Small quantities of acid or base may have major effects on both rate and product. 4.79. Hydrogenolysis Hydrogenolysis of aliphatic carbonyls usually does not occur readily unless certain types of structures prevail (78).3. Many reasons have been advanced to account for these promotional effects (65).97). 4.32. mostly via an intermediate benzyl alcohol. 69.41. and many examples have been cited (31. The effects of pH are very worthwhile exploring in reductions that somehow are less than satisfactory. The reaction has been made the basis of certain ether syntheses (45.2. Reaction of alcohols with carbonyls may be promoted by trace contamination.0% cis 100%. Catalysts themselves may contain sufficient acid or base to alter the course of reduction (25). So strong is the tendency of palladium-hydrogen to promote acetal formation that acetals may form even in basic media (61). such as iron in platinum oxide (22.8% cis 74.3% cis 70.0% cis Hydrogenation of the constrained 4-f-butylcyclohexanone gives 99% ether (97% cis) in ethanol over palladium (68). Alcohol Solvents Hydrogenation of carbonyls.and 5/?-cholestan-3-ones in methanol over palladium. High yields of methyl ethers are formed by reduction of 5a.1%. The data of Nishimura et al.80). . H•»3C-< \ >=O + C2H5 OH 2 5 Pd Pt Rh Ru > H3C^f 3 \ V-OC2 H 5 -^H33 C-X 2 5 \ >—OH / catalyst / / 96. 83.1. in lower alcohol solvents may result in the formation of ethers.68 4. The ether arises through formation of acetals or ketals with subsequent hydrogenolysis. or incipient carbonyls such as phenols (86).6%. 83.7%.

OCH3 /COOC 2 H 5 125 ml 95% EtOH 2-nlHC.62.3. a fact that effectively rules out the alcohol as a major intermediate in deoxygenation. indeed.4.3-dicarbethoxy-5.3. . jS-keto amides (48). The rearranged by-product was shown to arise from attack of acid on the amino alcohol (50).3. If hydrogenolysis is desired. compounds such as jS-keto esters (83.4. and.8-dimethoxy-ltetralone (5) over 5% Pd-on-C gave 6 quantitatively (54) when hydrogen absorption ceased spontaneously.84).98). Aromatic Carbonyls Hydrogenolysis of aromatic carbonyls occurs mainly by conversion to the benzyl alcohol and its subsequent loss. In certain cases the ability to enolize has been shown to be a prerequisite for hydrogenolysis (48).83. It is difficult to formulate generalities from available data. Resistance to hydrogenolysis is characteristic of /?-amino aromatic alcohols (56).and 1. because of their tendency to cyclize. and jS-diketones (84. The influence of reaction variables and catalyst is complex (19. Certain /?-amino ketones also undergo extensive hydrogenolysis in acidic media (78). a rapid absorption of 1 mol of hydrogen at 380C to give the amino alcohol. 5 % Pd-on-C OCH3 (6) An unusual by-product was obtained in small yield in palladium-catalyzed reduction of 2-amino-4. The reduction was done in two stages: first. and then a much slower reduction in the presence of HClO4 at 7O0C. For instance. suffice it to note that much can be done to alter the extent of hydrogenolysis in compounds susceptible to this reaction. Hydrogenolysis is facilitated by polar solvent and by acid (58). HYDROGENOLYSIS 69 4.5-dimethoxyindanone hydrochloride. 4. hydrogenation of may undergo extensive hydrogenolysis. the usual catalyst is palladium (38). Hydrogenolysis occurs also with 1. a fact that makes reduction of aromatic oximino ketones to amino benzyl alcohols a useful synthetic reaction. Aliphatic Carbonyls The stability of aliphatic alcohols to hydrogenolysis is demonstrated by their widespread use as hydrogenation solvents.5-diketones.

COOC2H. In compounds of this type. HYDROGENATION OF ALDEHYDES AND KETONES :H3O 100 ml HOAc CH3O 0. COOC2H5 4. deoxygenation may occur via an intermediate allylic alcohol (51). the olefinic function. . these side reactions could be curtailed.18). Some industrial processes that can tolerate a mixture use nickel. In general. and carbonyl reduction by platinum or ruthenium. is easily reduced preferentially if the olefin is not hindered (3. 3atmH 2 NH 2 add 3 ml HQO4 7o°C. toluene and 50% aq ethanol.16. By use of a two-phase system. The preferred catalyst is palladium if carbonyl reduction is to be minimal.6glO%Pd-on-C 380C. the catalyst plays a large role in shaping product composition.4. In conjugated systems.5. Carbonyl reduction begins to compete with olefin saturation when the double bond is hindered or the carbonyl is aromatic or an aromatic vinylog. Apparently the desired product was removed effectively from the aqueous layer into the toluene as soon as it was formed (26). Distillation of available data suggests that olefin reduction is favored by palladium.3atmH 2 3g CH3O CH3O NH2-H CH3O A special technique was necessary to obtain good yields of ethyl pyrrole-3acetate from ethyl pyrrole-3-glyoxalate. Reduction over W-7 Raney Ni in 50% aq ethanol was accompanied by major ring reduction and tarring. whether conjugated or not.70 OCH3 CH3O 4. Unsaturated Carbonyls Either or both functions in an unsaturated carbonyl compound may be reduced. the products depending in large measure on substrate structure and catalyst.

In cyclohexane solvent. nickel-cobalt-iron (42-44). such as unsupported (96). l a t m H 2 O CH1OC Ketones contained in easily aromatized systems are apt to be converted to phenols on hydrogenation (46). None of these catalysts appears to reduce an a. 5% Ir-on-C (95%)./?-unsaturated ketonic carbonyl selectively. probably because of the less hindered nature of the aldehydic function. 5% Ru-on-C (92%). from 1. 5% Ru-on-C (35%).5. Diketones Diketones can be reduced usually in high selectivity to either an intermediate ketol or the diol (12). or supported (81) platinum-iron-zinc. rhenium heptoxide (74). A variety of special catalysts. platinum-nickeliron (47). . osmium (85). DIKETONES 71 Q 5%Pd-on-C 25 C. Generalizing from these data. 5% Pt-on-C (27%) (86). or iridium-on-carbon (49).05 g 5% Pd-on-C 25 C.4-cyclohexanedione in isopropanol initial selectivity to the ketol fell in the sequence 5% Pd-onSiO2 (96%).4. from acetylacetone the descending order was 5% Pd-on-C (86%). 4. have been developed for selective hydrogenation of the carbonyl group in unsaturated aldehydes. l a t m H 2 Reduction of unsaturated aldehydes seems more influenced by the catalyst than is that of unsaturated ketones. platinum-cobalt (90). 5% Rh-on-C (92%). 5% Ru-on-C (63%).5. it appears palladium is a good first choice to achieve maximal selectivity. 5% Rh-on-C (60%). Selectivity to the ketol depends in large measure on both catalyst and solvent. the maximal yield of ketol obtained on partial hydrogenation of biacetyl fell in the order 5% Pd-onC (99%). 15 ml EtOAc 0. 5% Pt-on-C (88%). 5% Pt-on-C (67%) (13).

a compound obtained otherwise with difficulty. Catalytic hydrogenation of 5a-cholestan-3one over palladium gives the equatorial 3/?-ol in high yield. H 2 . a preferential adsorption not shown by other metals. and it serves as a complement to other reducing systems (76).72 4.89. EtOAc Li(J-Bu) 3 BH 40 psig 26% 95% 74% 5% Various rules have been devised with partial success (10. HYDROGENATION OF ALDEHYDES AND KETONES A convenient synthesis of 3. to a strong adsorption of the a face of the steroids on palladium. rr O COOH O PtO 2 .30.5-dimethyl-l.3-dimethylcyclohexenone (24).64. and haptophilic effects (77). but it is difficult to formulate encompassing generalities in a reaction subject to the influence of so many reaction parameters. whereas 5/?cholestan-3-one gives high yields of the axial 3/?-ol. The reduction is believed to go through 3. substrate structure. solvent (63).3-dimethylcyclohexanone. Platinum shows this selectivity to a much smaller extent and other noble metals give the same mixture of isomers from both ketones (70).65.99). The extraordinary and unique selectivity exhibited by palladium has been attributed.6. A remarkable example of haptophilicity and effect of metal has been reported by Nishimura et al (72). Stereochemistry A great deal of control can be exerted over the stereochemistry of ketone hydrogenation. involves hydrogenolysis of 5.94). Hydrogenation virtually ceases after absorption of 2 mol of hydrogen.3cyclohexanedione (88). 5g5%Pd-on-C 250 ml CH3CH2COOH 5 ml coned H 2 SO 4 80 C. The stereochemistry can be affected importantly by the catalyst (35. 60 psig 4. Haptophilic effects .36. The same explanation has been advanced to account for the unusually high reactivities of A 5 steroids in palladium-catalyzed hydrogenation (73).77. on the basis of competition experiments.

platinum oxide the least (65. STEREOCHEMISTRY 73 have been invoked previously by many investigators but heretofore always involving a preferential adsorption of a functional group. Nishimura et al (72) represented interaction of the a faces of 5a. Reduction .6. the direction of change being itself a function of the catalyst.and 5/?-cholestan-3-ones as follows: Palladium surface HO H CH 3 C8H1 Palladium surface CH 3 HO 4. A useful method for the synthesis of axial alcohols from unhindered cyclohexanones is by hydrogenation over rhodium in THF-HCl. Solvents too may have a large influence (69Jl).1.94).4. Traces of alkali may produce marked changes in the percentage of axial alcohol. Axial Alcohols The conclusion was reached in a study of hydrogenation of alkylcyclohexanone that rhodium-on-carbon is generally the most effective for producing axial alcohols.6.

55.5% yield.28.57). Reduction of 5a-cholestan-3-one (7) in the same system gives the axial alcohol 8 in 97. Iridium-catalyzed hydrogen transfer from aqueous phosphite esters or phosphorous acid is an effective way of producing axial alcohols 4. A single example of each type must suffice to illustrate the area.2.3% cis isomer (70Jl).6%. HYDROGENATION OF ALDEHYDES AND KETONES of 4-f-butylcyclohexanone gives the cyclohexanol quantitatively with 99.40. Reduction of 7 over platinum in r-butanol give predominantly the equatorial alcohol 5a-cholestan-3/J-ol (69). Epinephrine hydrochloride (10) was obtained from 9 in 95% enantioselectivity (39).93.34.95).33. I a I m H 2 (7) (17. Similarly 5/?-cholestan-3-one is reduced to the corresponding 3/J-ol in 96. C8H1 Rh THF-HCl 25 C C.6. Asymmetric Hydrogenation Asymmetric hydrogenation of ketones by chiral homogeneous catalysts and by heterogeneous catalysts modified by chiral additives has been the subject of much interest (1. Excellent optical yields of H0 HO-C 7 \ \ / I ^ V-CHCH 2 NHCH 3 OH N / V-CCH 2 NHCH 3 HCl -^l^U HO-/ I l A f\°f^ \ (10) 100% yield 95% ee . High optical yields of 2-amino-l-arylethanol have been achieved by asymmetric hydrogenation employing (R)-(S)BPPFOH rhodium complex. The chiral ligand is (#)-[(£)-l'.74 4.2-bis(diphenylphosphino)ferrocenyl]ethyl alcohol.

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5. 5. anhydrides. Rh 2 O 3 becomes a useful catalyst for carboxylic acid hydrogenation (13).12.24). High pressures (5. Strongly synergistic effects were found on substituting half of the Re 2 O 7 with ruthenium-on-carbon. Yields of alcohol tend to be less than perfect because of esterification of the alcohol. Near quantitative yields of alcohol can be obtained by mixing ruthenium and copper chromite catalysts so as to reduce the ester as formed. This fractional reduction is without utility but it is sufficient to cause errors in absorption measurements when a carboxylic acid is used as a solvent.4.-5Hydrogenation of Acids. Ruthenium dioxide or ruthenium-on-carbon are effective catalysts for hydrogenation of mono. RCOOH+ 2 H 2 RCH 2 OH-^RCOOH Ru > RCH 2 OH-HH 2 O » RCH 2 OCOR-HH 2 O RCH 2 OCOR + 2 H 2 -^+ 2RCH 2 OH Rhenium oxides are also useful in reduction of carboxylic acids (~ 17O0C. and excellent results can be obtained at 78 . Acids Acids require vigorous conditions for successful reductions on a synthetic scale. Anhydrides. None is reduced easily and often vigorous conditions are required.and dicarboxylic acids to the alcohol or glycol.000 psig) and elevated temperatures (130-2250C) have been used in these hydrogenations (8.000-10. and Esters Acids. At 15O0C and 2000 psig.6). and esters are considered together because of their structural similarities and common characteristics on catalytic hydrogenation. Aromatic acids can be reduced to alcohols without ring saturation (3. but they can be reduced to the alcohol in small yield over rhodium even at ambient conditions. 3500 psig).1.

Rhodium or palladium with rhenium also shows synergistic effects (27). tetrahydrofuran. McAlees and McCrindle (20) established the following increasing order of difficulty for various carbonyls: acid chlorides > aldehydes. If 1.4butanediol. ketones > anhydrides > esters > carboxylic acids > amides. Tetrahydrofuran can be obtained in 98% selectivity from vapor-phase hydrogenation of maleic anhydride over Cu-Cr-Zn-On-Al2O3 (23O0C. ANHYDRIDES 79 part attributable to competition of substrate.20). and solvent (11. reaction conditions.25). any of which may be made the major product of reduction. The necessary temperature is sufficiently higher than that required for esters to permit selective reduction of half-acid esters to the hydroxy acid (23). 5. This homogeneous catalyst will reduce acids and anhydrides. Products vary with substrate structure. A catalyst made from Re2O7 and Pd(NO3)2-on-carbon gave a 97% yield of 1. 20O0C and 600 psig.5. (CH3CO)2O -^^ CH3CH(OCOCH3)2 The course of reduction of a variety of anhydrides with platinum and palladium under mild conditions have been discussed in detail (16. hydrogen.200. At 1 atm and 27O0C.1-diesters are formed by acylation (26).2. favoring the diol. as in the presence of strong protic acids over palladium. The reverse selectivity can be achieved by reduction over H4Ru4(CO)8(PBu3)4 at 100-20O0C and 1500-3000 psig.2. Hydrocarbon by-products increase if the catalyst is reused and with increased temperature but decrease with increased pressure.2-addition of hydrogen or by cleavage of an oxygen-carbonyl bond.17) have been used for acid reductions but very high temperatures (30O0C) are required. 1. 25 atm) (21). and solvent for catalyst sites (52).4-butanediol depends markedly on pressure. Anhydrides Anhydrides are reduced with relative ease. Copper chromite (14) and barium-promoted copper chromite (15. Unsymmetrical anhydrides are reduced preferentially at the carbonyl group having the least . butyrolactone is highly favored. at 300 atmospheres the ratio is 6:94. The equilibrium ratio of butyrolactone and 1. Reduction may proceed by 1.2-addition to the carbonyl occurs. and 1. but not esters (2).6-hexanediol from adipic acid (10). The most studied reaction of this type is hydrogenation of maleic and succinic anhydrides as precursors of butyrolactone.

2 g 4 ml J^Ta?. L.Y. N. J. AND ESTERS 5. Details for the preparation of this catalyst (17) and a detailed procedure for hydrogenation of ethyl adipate to hexamethylene glycol (18) are given in Organic Syntheses. The hydrogenation of esters to alcohols is a reversible reaction with alcohol formation favored at high pressure. A. 2343 (1963). 5. F. 3. 4. perhaps by elimination with formation of an intermediate olefin. Acad. Organomet. Hager. C. T. J. the product composition seems to depend largely on the structure of the substrate. S. Soc. E. H. Chem. 24. Menchi. G. Hartley. S. Broadbent. or hydrocarbons.3766(1955). or allyl.80 5. HYDROGENATION OF ACIDS. Burke. ethers. J. Soc.19) form acids and undergo facile denomination. Faraday Soc. F. Chem. F. Grisby. ester at low pressure (1). Gresham. H. acids. S. References 1. 77. Hartley. Dixon. V. J. R. Org. Chem. 2. J. Campbell. S. 7. 28. E. H. 194 (1970).. 1847 (1959). Copper chromite is usually the catalyst of choice. H. Matteoli. J. Broadbent and T. 2345 (1963). Am. Bianchi. Org. Org. . Francalanci. and C. Kemball. 109-119(1980). perhaps arising through an intermediate alkene (22). 2583 (1963). S. G. 59. Certain bromo esters (7. P. Carnahan. Esters Hydrogenation of esters may give alcohols. Trans. H. 28. J. Chem. Broadbent and W. and J. Fiacenti.9. F. W. Chem. G. H. W. 188. ANHYDRIDES. The reaction might be useful in selectively removing a tertiary oxygen in a polyfunctional molecule or removal of a f-butyl protecting group from an ether or ester. Mylroie. Sd. W. Jr. Adkins and R. Chem. Tertiary alcohols also undergo facile hydrogenolysis in trifluoroacetic acid. vinyl. 6. M. Campbell and C. 70. and G. Am. J. 172. J. Broadbent. Selin. probably through conversion to the trifluoroacetate. J. U. Ann. 8. E. Tertiary esters in the presence of a strong acid also undergo hydrogenolysis readily with formation of a carboxylic acid. Botieghi. Acids are expected to form when an R—O bond has been weakened as when R = benzyl.3. Johnson. Frediani. and W.!^ > (CH 3 ) 3 CH + H 2 O Alcohols are the most frequently formed products of ester hydrogenolysis. 4174 (1948). Ford. CH3 H3CCOH + F3CCOOH CH 3 0.

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Cyclic ketones tend to alkylate ammonia or amines to a further extent than do linear ketones of comparable carbon number (36). Product distribution is influenced also by the catalyst and by steric hindrance with the amount of higher alkylate formed being inversely proportional to the steric hindrance in the neighborhood of the function (60. Reductive alkylation is a two-step process. or a primary or secondary amine by means of an aldehyde or ketone in the presence of a reducing agent (16).6 Reductive Alkylation 6. RCHNHR' I OH It R'NH 2 + RCHO ^ 2 RCH 2 NHR'+ H 2 O RCH=NR' Primary or secondary amines arising from this reaction are themselves suitable reactants that may undergo further alkylation. The work of Greenfield and MaIz (25) on the preparation of arylamines illustrates the sensitivity of yield to hindrance and an influence of catalyst. RCH 2 NHR' + RCHO » (RCH 2 J 2 NR' + H 2 O Product composition can be controlled to a considerable extent by the molar ratio of reactants. Introduction Reductive alkylation is the term applied to the process of introducing alkyl groups to ammonia. 82 . alkylation tends to become more extensive as the molar ratio of carbonyl to amine increases. The carbonyl compound and amine first undergo an addition reaction to give an intermediate that can undergo hydrogenolysis directly or dehydration to an imine that is then reduced. The term is also applied to those compounds that are not amines or carbonyls per se but that are converted to them in the course of the reaction.62).1.

more primary amine was formed over Ru and Rh and more secondary amine over Pd and Pt. 280-495 psig 5% RhSx-On-C (10% loading). Catalysts may have a marked influence.5 mol 20 81 2 14 5% PtSx-On-C (10% loading) 8O0C.5 mol 0.5 mol 0. 345-505 psi 5% RhSx-On-C (10% loading) 8O0C. Isolation of the Schiff's base was necessary in the following sequence for it was desired to acetylate the alkylated product as formed. Alkylation to yield a tertiary amine may occur easily if the formation involves cyclization (53). 0. refluxed 1.63). . 445-565 psi 58 41 40 12 Platinum was more efficient than rhodium in these experiments. 320-545 psig NHCH 3 O NHCH 3 N-CH3 O OH 0. 25 C.1.5 mol 0 ~98% 5% PtSx-On-C (10% loading). A solution of 50 mmol of an aromatic aldehyde (1) and 50 mmol of aminoacetaldehyde dimethylacetal (2). gave after distillation nearly quantitative yields of the Schiff's base 3 (56).5 h in toluene under nitrogen. 8O0C. Sometimes the intermediate imine is isolated.6. These catalysts give excellent yields of tertiary amines in reductive alkylation of aliphatic secondary amines with ketones (46). Reduction of the ketone to an alcohol is an important side reaction over ruthenium. In reductive alkylation of ammonia with cyclohexanones. INTRODUCTION 83 Sulfided catalysts are used to minimize reduction of the carbonyl to an alcohol. but generally it is not and may even be inferior to direct alkylation (54.

but the temperature is inconvenient on a large scale. Some workers allow the amine and carbonyl compound to stand together some time before hydrogenation (3.PhCHO NH 2 (4) NCH 2 Ph 5 % Pd-on-C /NH (7) Cyclization of 4 at 258 C in boiling Dowtherm A gives isoquinuclidone in 81-84% yield (55). For similar entries into a variety of tetrahydroisoquinolines. REDUCTIVE ALKYLATION + H 2 NCH 2 CH(OCH 3 J 2 CHO (2) IT "V CH-NCH 2 CH(OCH 3 ) 2 R 45mmol3 90 mmol (CH3CO)2O 100 ml EtOAc AlCl 3 NCCH 3 N—CCH. Bobbitt and Moore (6).59). Gensler et al (24). The delay technique is illustrated by reductive alkylation of ethyl-4-aminocyclohexane carboxylate (4) with benzaldehyde to 5. but this procedure is not always necessary nor even desirable (33). By 0 . a route that permitted an important improvement in the production of isoquinuclidine (8) (59). and Coomes et al (12).84 6. Bobbitt and Shibuya (7). O r CH(OCH3). see Bobbitt et al (8). OC2H5 -I.

acetic acid. enalapril maleate. Palladium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-Lproline in a synthesis of the antihypertensive. SchiflPs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. CH3 10% Pd-on-C PhCH2CH2CCOOC2H5 + H 2 N .54 g ethyl 2-oxo-4-phenylbutanoate and 1. The yield was 77% with a diastereomeric ratio of 62:38 (SSS: RSS) (68). To a solution of 4. CH3 I a I m H 2 . and the mixture is hydrogenated at ambient conditions to afford 5 in quantitative yield. reductive alkylation of (S)-a-methylbenzylamine with (#)-tetrahydrofuran-2-carboxaldehyde over PtO2 to give 11 was achieved without significant racemization. and ethanol. The mixture was hydrogenated for 15 hr at room temperature and 40 psig H 2 .6.86g L-alanyl-Lproline was added 16 g 4A molecular sieve and 1. cyclization occurs readily in refluxing tetrahydrofuran containing sodium f-butoxide. In a further example. Both cis and trans isomers are useable. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The reductive alkylation of 4 is carried out in a solution of triethylamine. which has stood for 2 h. A mixture of 9 and 10 in methanol containing a few drops of acetic acid was let stand at room temperature before PtO2 was added (5). A 10% loading of 5% Pd-on-C is added.1. INTRODUCTION 85 first making the benzyl derivative 5.0 g 10% Pd-on-C. 25 0 C (9) 265 mg (10) 322 mg (11) Some workers avoid delay.

regardless of catalyst. for economical use. acidic carbons. A variety of catalysts have been used for the condensation. They are more resistant to poisoning than are nonsulfided catalysts. have little tendency to reduce the carbonyl to an alcohol. are used at elevated temperatures and pressures to maximize space-time yields and for most economical use of catalysts. Solvents A variety of solvents have been used in reductive alkylations. In industrial practice. Sulfided catalysts are very much less active than nonsulfided and require. 50-18O0C). acids such as hydrochloric (1) or acetic (61). platinum. Platinum is the most used by far (16). NH2HC1 + CH3CCH3 V-^ 0. . can be catalyzed. but as the molecular weight increases. Acids catalyze also the hydrogenation step by neutralizing the inhibiting effects of the more strongly basic amine products (22). including basic materials such as tertiary amines (32) or pyrrolidine (63).11 mol NaOAc lglO%Pd-on-C 10OmICH 3 OH 13. elevated temperatures and pressures (300-2000 psig. Both steps of the reductive alkylation. such as acetone.3. and are effective for avoidance of dehydrohalogenation in reductive alkylation of chloronitroaromatics and chloroanilines (14. and Raney cobalt (43) have all been used successfully in reductive alkylations. Platinum oxide may show induction periods (13) in reductive alkylation and prereduction has been recommended (37.86 6.2. platinum is apt to be more effective (30). 6. but it is not always necessary (19).. imine formation and the hydrogenation per se. i. palladium. REDUCTIVE ALKYLATION 6.47). With small carbonyl molecules.15).3 g 5ml CH3O^f V-N NCH(CH 3 ) 2 Platinum and rhodium sulfided catalysts are very effective for reductive alkylation. Catalysts Nickel. rhodium. palladium is about as effective as platinum. excess carbonyl compound is often used as both reactant and solvent. Most industrial reductive alkylations. and drying agents (31).e.

and.2 g 180ml (12) (13) (14) The solubility of the resulting product may dictate the choice of solvent. and many others. when n = 4 or 5. making catalyst separation difficult.6. further hydrogenation of which gives the unwanted isomer 17 by attack at the convex face. SOLVENTS 87 This common technique. 6 g 5 % Pd-on-C 2 60 psig 250C " 13. The problem was circumvented by using glacial acetic acid as solvent (38). Campbell and Lavagnino (10) obtained satisfactory results only with an excess of aniline serving as both reactant and solvent. in an unusual variation. However. Normal procedures were satisfactory when the more basic cyclohexylamine was the reactant. The purpose of the strongly acid system was to prevent cyclization of the deblocked amino ketone to 16. failed in reductive alkylation of 13 by 12 to 14.3. . Reductive alkylation of norepinephrine with a series of keto acids proceeded smoothly over platinum oxide in methanol-acetic acid mixtures. OH O I Il HO ^r^ CHCH 2 NH 2 + CH3C(CH2X1COOH OH CH3 CHCH 2 NHCH(CH 2 J n COOH An unusual solvent system was chosen for the intramolecular reductive alkylation of the masked amino ketone (15). The desired opposite isomer can be obtained by reduction of 16 with LiAlH4 (52). the product tended to precipitate from solution.

8. In a synthesis leading to methoxatin. azo. Alkylations using masked functions have been successful at times when use of unmasked functions have failed (2).7.2 ml 5% HCl 60 mg 5 % Pd-on-C 1 atm Hz CH3O .24.4. nitro and nitroso compounds. REDUCTIVE ALKYLATION OCH2OCH3 12.41.SmIF 3 CCOOH OCH2OCH3 CH=CHCCH2CH2 CT 1. phenols. 250C 1 atm (16) Pd-on-C. hydrazo. or hydrazones serve as carbonyls (6.17. acetals. and hydroxylamines serve as amines.12.42. a key 3SmICH 3 OH 0. but which are transformed during the hydrogenation to suitable functions. ketals.58).H2 EtOAc OCH2OCH 6. Azides. Amine and Carbonyl Precursors Reductive alkylations have been carried out successfully with compounds that are not carbonyls or amines.6. pyridines.9.5glO%Pd-on-C ElOAc. oximes.

The reaction with aliphatic alcohols is thought to go through a carbonyl intermediate. Reductive alkylation has been used to prepare a-amino acids suitable for lactam formation and further elaboration. In a single step a carbobenzyloxy group was removed. In a variation. as it . 10%Pd-on-C 5OmICH 3 OH 3SmIH 2 O + /NHCOCH 2 Ph ' Il O (HO)2CHCOOH ^gp* 6. the reaction appears to be an amination. the source of hydrogen being aromatization of the cyclohexanone (66). and alkylation with glyoxylic acid hydrate was achieved (18).7 g 6 n= 1. an aromatic nitro compound acts as both an amine precursor and a hydrogen acceptor (64). AMINE AND CARBONYL PRECURSORS 89 step involved a ring closure between a hydrazone and a nitro function (23).4.2 Hg H /(CH2U Boc \ /COOH N H C-OH Il O •'^/O Cyclohexanones may serve as precursors to aromatic amines in a reductive alkylation. CH 3 N °2 1/3 theoretical H 2 p-cymene " 5%Pd-on-C Alcohols also may serve as carbonyl precursors.6. but since no hydrogen is actually consumed.

REDUCTIVE ALKYLATION must be in the industrial production of aniline from phenol and ammonia. All0i x 24O0C > Ph(CH2I11N(CH3I2 + H 2 O 3 4 mm cylinders Reductive alkylation by alcohol solvents may occur as an unwanted side reaction (22. interesting use was made of a reductive alkylation of a nitro function. accompanied by loss of a diazonium group. No further use of this combined reaction seems to have been made. and the entire solution was mixed with 10% palladium-on-carbon and reduced under hydrogen.Af-dicyclohexylcarbodiimide gave a mixture of 19 and 20 with the major product being the N-ethyl derivative (49. and a number of alkylated anilines are made industrially starting with the appropriate nitroaromatic in the ketone as solvent. By carrying out the reduction in acetic acid. o Il H PhCH 2 OC^ H . y .60psig (2) DCC Ph (18) HO 0 / 1 Ii L I HO T H H COOC2H5 (19) (20) Nitro functions are easily reductively alkylated. followed by cyclization with N.39).^ B . Ph(CHAOH + HN(CH 3 J 2 40%c . When diazotization was complete. Reduction of 18 in ethanol over 10% palladium-on-carbon to an amino acid. The addition reaction can occur at the hydroxylamine intermediate as well as the aniline. and it is to avoid this reaction that Freifelder (20) recommends ruthenium instead of nickel in pyridine hydrogenation.90 6. A process step is saved by beginning with the nitro compound. The sequence provides a clever way of utilizing the unwanted 9-nitro isomer that arises from nitration of 6-demethyl-6-deoxytetracycline (11). In a synthesis of minocycline.^^ /O~| \ O _J (D 500mglO%Pd-on-C 15 ml EtOH 25°C.50). 20 was obtained as the sole cyclized product (40). Alkylation by alcohols may occur with surprising ease (67). This type of reaction is illustrated by Baiker and Richarz (4). urea and 40% aqueous formaldehyde were added. .

47. Wills.35). Chem. Lape. 7. Chem. Org. 33. and M. M. Can. Bobbitt and T. Williams. 5. Org. J. S. Jr. 10%Pd-on-C I H2 N=N CH3OH H2SO4.5. Shibuya. Chem.00C C4H9ONO NO2 OH OH 6. Belanger and H. Moore.48. J.29. J. 8. J. J. Ando and S. Bull. Stereochemistry Reductive alkylation with chiral substrates may afford new chiral centers. O.28.REFERENCES OH O2N HO OH O CNH 2 H2N OH H2N N(CH3). Richarz. 27 (1978). 501 (1974). Unser. The degree of induced asymmetry is influenced by substrate. Am. Commun. Synth.27. C. Chem. G. M. A. 2. 79. Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine. R. T. 5783 (1957). 2958 (1968). M. Chem. Emoto. 35. Hoppe. Soc. Org. 4. 1181 (1970). . Bobbitt and S.51. 61. Lewis. J. and temperature (26. Asymmetry also has been obtained by reduction of prochiral imines. References 1.. Baiker and W. Archer. Soc. 33. J. A. solvent. Jpn. 2123 (1968). 1383 (1983). J. R. not the hydroxyamino addition compound. P. E. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety (34.65). 6. J. using a chiral catalyst (44). W. 3. and H. Chem. T. and that the catalyst approaches the least hindered side (57). Anderson. M.

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RCH=NH + H 2 O > RCHO + NH 3 "2 > RCH 2 OH The aldehyde may be also a source of a secondary amine. followed by saturation.-7Hydrogenation of Nitrites and Oximes Nitriles and oximes are considered together because of common features. The extent of coupling is sensitive to environment. Both functions are reduced to primary amines. RCHO-HRCH2NH2 "2 * (RCH 2 J 2 NH + H 2 O 94 . RCH=NH + RCH 2 NH 2 -» RCHNHCH 2 R -» (RCH 2 ) 2 NH NH 2 -NH3 In aqueous media.H R C H = N H -» RCH 2 NH 2 further reduced to an amine. an imine. The imine is RCH=NOH -H 2 O > RCH=NH < RC=N H 2 . both undergo coupling reactions to secondary amines. These similarities arise from a common intermediate. or direct hydrogenolysis. the intermediate imine can undergo a reductive hydrolysis. increasing with increasing temperature and decreasing with increasing pressure. and the amine and imine can give an addition product that undergoes either elimination of water to an imine. resulting in a secondary amine. and both are subject to reductive hydrolysis. Tertiary amines are formed similarly by further reaction of secondary amines.

81).1.34. .74).1 mol) O-(ethoxycarbonyl)-3-methoxymandelonitrile (4) in 300 ml absolute ethanol was added dropwise (0.13 mol) concentrated sulfuric acid as hydrogen gas was bubbled through the solution. A solution of 23.7.1. unsymmetrical amines would result (48).1-0]isoindol-6(2H)-one (2) (84).1. 2-(w-methoxyphenylethylamine) (5) was obtained in 92% yield (47) (procedure used with permission). For example. RCN + R'NH 2 —^-» RCH 2 NHR' + NH 3 The amine and nitrile can be in the same molecule. the products changing with scale. stirring and bubbling continued for 8 h. Nitriles The above scheme to account for products of nitrile hydrogenation was proposed sixty years ago (80). (I) 7.5 g 10% Pd-on-C and 12.5 drop/sec) to a mechanically stirred solution of 300 ml absolute ethanol containing 1. It might be expected from the foregoing that. and indeed the reaction provides an excellent way of preparing these amines (49. hydrogenation of mandelonitrile provides a good route to /?phenylethylamines. as illustrated by the reductive coupling and cyclization of 1 to give tetrahydropyrazino [2. and with minor variations (28.23. After addition was complete. and many workers have used such solutions for this purpose with success (14. if a nitrile were reduced in the presence of an amine. Solvents Both acidic and basic media are effective in suppressing coupling reactions. NITRILES 95 7.45.86) has withstood the test of time.5 g (0.75. After filtration and extraction. The procedure was resorted to when hydrogenation of the jS-nitrostyrene 3 proved fickle.9 g (0.1. Strongly acidic. solutions prevent further reaction of the initially formed primary amine by formation of an ammonium salt.

Anhydrous ammonia is preferred to prevent hydrolysis reactions. also suppress formation of coupled products.96 CH3O CHO 7. and hydroxides (20.23. NH 2 RCH 2 NH 2 + NH 3 The above equation adequately accounts for the action of ammonia. HYDROGENATION OF NITRILES AND OXIMES CH 3 O CH 3 NO 2 CH^CHNO 2 (3) O Il OCOC2H5 CH3O "CN H2 CH3O NH 2 (4) (5) Inter.59. carbonates (46). A common technique for minimizing secondary amine formation is to carry out the hydrogenation in the presence of ammonia (21. RCN H2 RCH=NH NH 3 -NH3 RCHNH. .30. This technique is especially useful if the acetylated amine is the desired product (17. but it may function in other ways as well.42). The solvent for ammonia may have an important influence. such as tertiary amines. Ammonia is thought to compete with the primary amine in attack on the intermediate imine. CN CH 2 NH 2 CN CH 3 OH HCl 5%Pd-on-C CH 2 OH HO Jk^CH2OH HO H3C HO H2 H3C 70% H 3 C^N^ 77% Another effective way of preventing coupling reactions is to acetylate the primary amine as formed by carrying out the reduction in an anhydride solvent.77). ammonia-r-butanol proved the preferred system. In reduction of C10 unsaturated dinitriles to primary amines over ruthenium-on-alumina. Greenfield (28) suggested that bases may function by suppressing the hydrogenolysis reaction leading to secondary and tertiary amines.32). normal alcohols gave poor rates and secondary alcohols produced N-alkylated products (18). for a variety of bases.and intramolecular amine coupling was prevented by the use of hydrogen chloride in a synthesis of pyridoxine (33).

rhodium. Cobalt is used similarly but mainly under even more vigorous conditions. dibenzylamine (74). The reaction is done at elevated temperatures and pressures (~ 10O0C. nonreactive media. Aromatic nitriles form only primary and secondary amines. The differences among palladium. platinum. or ruthenium in the presence of ammonia (4. nickel boride.6 g) in 100 ml of ethanol containing 4 g. more water encouraged hydrolysis products. Nitriles containing a benzylamine can be reduced over Raney nickel to an amine without hydrogenolysis of the benzyl group (7).11. in neutral. compounds that undergo extensive hydrogenolysis under conditions necessary for base-metal catalysis.67. A solution of N-[N-(Ibutoxycarbonyl)-3-aminopropyl]-N-(3-cyanopropyl)benzylamine (13.7. 1000 psig) unless massive amounts of nickel are used.0 g Raney nickel at 40 psig for 28 h. gives on hydrogenation over rhodium-on-carbon high yields of dipropylamine. In hydrogenation of benzonitrile. palladium. Good yields of primary aliphatic amines can be obtained by use of cobalt. Catalysts Nickel in the presence of ammonia is often used for reduction of nitriles to primary amines. rhodium and platinum. Greenfield (29) used platinum-on-carbon effectively for hydrogenation of neat benzonitrile to dibenzylamine in a system containing one-half equivalent of water to prevent catalyst poisoning. whereas high yields of tripropylamine arise from palladium or platinum-catalyzed reductions (71). NITRILES 97 7. Freifelder (23) considers rhodium-ammonia the system of choice when reducing /?-amino nitriles and certain /?-cyano ethers. palladium tends to form benzylamines. The yield of N4-benzyl-N1-(t-butoxycarbonyl)spermidine was 95% (7). Il (CH ) NHCOC(CH ) 2 3 O O (CH 2 ) 3 NHCOC(CH 3 ) 3 » PhCH 2 N^ (CH 2 ) 3 NH 2 Il 3 3 PhCH 2 N^ (CH 2 ) 3 CN Platinum. nickel. Propionitrile. Catalysts show remarkable product variation in hydrogenation of simple nitriles.1. whereas palladium is much different.69). and rhodium will function well under milder conditions and are especially useful when other reducible functions are present.68.1. and rhodium cited above for simple aliphatic nitriles do not apply to aromatic nitriles.2. and in this regard platinum and rhodium are alike. Parallel results were later found for butyronitrile (28) and valeronitrile (74) but not for long-chain nitriles. NaOH was reduced over 3. The cyano group in aromatic nitriles can be converted directly to a methyl group in vapor phase over 30% Ni-On-Al 2 O 3 prereduced by hydrogen in situ .

CH 3 1 at m H 2 'CN 150 C 30% Ni-On-Al 2 O 3 + NH 3 The above technique is limited to compounds of sufficient volatility and thermal stability.98 7.10. Cyclizations A variety of ring systems have been prepared by reduction of nitriles containing a suitable second function. I a I m H 2 O O COC2H5 I! HN N I C=O Ph H2O (7) NH (8) .79. Cyclization itself may be an important factor in preventing secondary amines and can serve as a trapping reaction for synthesis of the primary amine. making success in the cyclization dependent largely on prevention of secondary amine formation during nitrile reduction. These functions are all reduced with relative difficulty. The reaction can be made more general by the use of palladium (44).3. There is some evidence that benzylamine is not an intermediate in this synthesis (31).87).1.9. Cyclization may occur as a step subsequent to the hydrogenation proper. as in reduction of a nitrile to an amine.41. or amide (5. which will reduce an intermediate benzylamine. Reaction of 6 in acetic COOC2H5 satddryNH 3 3OmIEtOH 50 mg Pd black 20 mg PtOz 250C. followed by ring closure through interaction of the amine with an acid. HYDROGENATION OF NITRILES AND OXIMES at 40O0C (3). 7. ester. The nitrile 6 was reduced to porphobilinogen (8) with difficulty.51.

but under these conditions it is apt to promote extensive . The catalyst has more influence on nitrile cyclizations in which the second function is itself easily reducible. which in essence changes the functions undergoing cyclization (64). Rhodium (16.24. 7. Catalysts Both base and noble-metal catalysts have been used with success in the hydrogenation of oximes.64) have each given excellent results in the hydrogenation of cyano ketones. the product will be an amino or cyano alcohol. Oximes Hydrogenation of oximes to primary amines usually can be made to proceed smoothly despite the potential complications cited earlier.56. For instance.63). Noble-metal catalysts can be used under mild conditions. hydrolysis of 7 gave 8 (17). unlike nitriles.2. Base metals. OXIMES 99 anhydride over platinum oxide was foiled by accompanying ring reduction.73) has given excellent results.53.61. and under these conditions runaway reactions have occurred with easily reduced compounds. are used at elevated temperatures and pressures (~ 80-10O0C.2. if the ketone is reduced first. The stereochemistry of cyclization has been altered by the presence of ammonia. Many of the same considerations applicable to control of nitrile reductions hold for oxime reductions as well. 1. but over platinum the product is the amino alcohol. Ruthenium functions best in aqueous media. Rhodium seems especially useful when other catalysts give excessive secondary amine. such as nickel (1. Reduction of 2-(/?-cyanoethyl)cyclohexanone in methanol over palladium or rhodium gives high yields of decahydroquinoline.2.1. and cyclization will not occur. can be reduced to hydroxylamines. only the double bonds were reduced. 100 atm). The sequence of functional group reduction can markedly alter the products. The primary amine could be trapped successfully as the lactam ester 7 by reduction in ethanolammonia over palladium black-platinum oxide.13. over 10% Pd-on-C. Oximes.79) and palladium (55. Due caution must be exercised by limiting the catalyst or hydrogen or by sufficient dilution with solvent (22).76) or cobalt (26. cyclization of cyano ketones presumably goes through a normal reductive alkylation after preferential reduction of the nitrile to an amine. Raney nickel (10.7.50.

65). which stopped spontaneously at the 2-amino-l-indanol stage under similar conditions (43). Primary amines can be trapped also as amides by use of an anhydride solvent (2. This latter result accords with the general experience in reduction of aromatic /?-oximino ketones (35.34. Acidic solvents prevent the formation of secondary amines through salt formation with the initially formed primary amine.78.57). Unless the ammonia is anhydrous hydrolysis reactions may also occur.73).83). . aromatic oximes give amines. Palladium has been used often (52).82).58. Best yields are obtained from oximes of aliphatic carbonyls. HYDROGENATION OF NITRILES AND OXIMES hydrolysis reactions (72.25. but acids cannot always be used interchangeably (43). Solvents Solvents influence the hydrogenation of oximes in much the same way as they do hydrogenation of nitriles. Oximes can form either an imine or a hydroxylamine. A variety of acids have been used for this purpose (66).2. H 2 O + RCH=NH H2 RCH=NOH RCHNHOH !mines are easily reduced and rarely accumulate (62. Ammonia prevents secondary amine formation through competition of ammonia with the primary amine in reaction with the intermediate imine.40).15.39.100 7. 7.38.5-dimethoxy-2-aminoindan (10) (R = OCH3) occurred over 5% Pd-on-C in H2SO4-HOAc (12). The amino function usually severely inhibits hydrogenolysis of the alcohol. NOH 75 ml HOAc 5 ml coned H2SO4 2 g 5% Pd-on-C 50psigH2 » (10) This result stands in contrast to hydrogenation of 2-oximino-l-indanone (R = H). Hydroxylamines are reduced relatively slowly and can be obtained in good yield.5-dimethoxy-2-oximino-l-indanone (9) to 4. platinum in acidic media appears to be the preferred system (6. and these in turn can be reduced to an amine. Smooth hydrogenolysis and hydrogenation of 4. especially in acidic media (79.

Chem. Smith. of Wisconsin Press.2415 (1983). Borch. 1937. J. 2. Andrade. G. 2386 (1960). J. Chem. Garlich. Carothers and G. J. J. B. 802 (1980). 68. J. T. Org. J. B. H. lnd. Drake. W. Med. Chem. Lamborg. 22. Chem.2.. Butte. Benington. E. R. R. 1141 (1972). P. Bhatnager. Demopoulos. Chem. The reduction is carried out usually in acid to prevent formation of secondary amines and dihydropyrazines. Fishburn. 2079 (1945). Clark. Univ. 70. C. R. Mitchell. 10. Weber. 75. 3243 (1953). J. M. Ginsburg. J. Linn. Cook. Morin. New York. and R. A. 1971. Chem. L. J. Dolan. Archer." p. J. Am. 2065 (1963). Jr. Deana. 580 (1983). B. 2. and N. and F. Will. C.3. 8. J. 1442(1982). W. Hartung. Murtaugh. Wiley. Maier. Kissinger. L. R. Bullitt. Barnett. 14. 17. Chem. L. . Stokker. Soc. Barr and J. Am. and W. A. Cannon. 92. W. O. Perez. 100 (1965). E. Freifelder. 20. Res.. 8. and I. Am. Eng. W. A. W. A. Chem. J. 49. Schleyer. 1150(1948). E. Chem. M. Med. Anderson. Soc. J. J. Bull. Semeniuk. Chem. A. 22 (1944). C. Soc. Absorption of only 2 mol of hydrogen invariably leads to the amino ketone (8. H. 6. 37. Bergeron. J. D. Duschinsky and L. J. W. Zapf. 67. Marwil.1222(1946). A. Fluchaire and F. 5. Eng. R. J. Patent Appl. Chem. and L. Chim. Dev. H. 83(1982). 19. v. Soc. 3051 (1925). 82. J. Chem. Am. R. M. and S. G. Am. Grudzinskas. Even small amounts (1%) of platinum or rhodium show beneficial effects (60). 16. R. J. W. F. J. R. 47.529A (1980). M. 21. R. Jones. Chem. 11. Cash. 8.5 7. 12. F. Campbell.042. C." p. J. 7.580). S. W. Prod. W. Soc. H. References 1. 61. 145 (1969). F. Soc. Watson. Faber. V. Soc. 9. 2997 (1984). Shtolowich. H. D. 26. Carmack. Hydrogenation of a-oximino ketones usually gives the amino alcohol as a single diastereoisomeric racemate. K. M. Am.. Can. J. Chem. B. Oximino Ketones Hydrogenation of a-oximino ketones provides a facile route to amino ketones and amino alcohols. and K. W. 999 (1956). Sharabi. Equal weights of palladium and platinum together have been claimed to give superior results (85). Long. Br. Adkins. S. Schultz. N. 15. Jr. Org. J. and I. Med. A. F. Fr. S. F. W. Bien and D. J. Dev.. D. Chambert. C. A. Process. J. H. M. 3. J. Jr. J. J. Loader. A. Vanderveen. Russo. H. 4. 18. 262. V. Cragoe. "Reactions of Hydrogen. 438 (1945). Freifelder. Peterson. E. and S. and L. although alkaline reductions are satisfactory also (36). C. 21. Chem. G. 25.. F. Synthesis. "Practical Catalytic Hydrogenation. Org.REFERENCES 101 7. L. and M. King. Soc. Tullar. Soc. J. J. 13. Palladium is often used in these reductions. P. and P. D. W. Von. Chem. O'Grady. Handrick. Chem. Boekelheide. R. F. Madison. Albertson. E.

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although their transient presence may appreciably influence the course of reaction. Moder and Leonard (65) stressed the importance of rigid exclusion of air during reduction of a nitro compound to a complex air-sensitive diamine in order to maximize the yield. Hydrogenation of 1 over 5% Pd-on-C was nonselective with hydrogenolysis of the benzyl ethers competing with nitro hydrogenation. It is accordingly easy to use inadvertently more catalyst than is actually necessary. nitro compounds often contain other reducible functions that are to be either maintained or reduced as well.1. nitroso compounds never accumulate. Aliphatic nitro compounds are reduced much more slowly than are aromatic. but at times the reduction is arrested at the intermediate hydroxylamine or oxime stage. Usually the goal of reduction is the amine. Hydrogenations have been carried out successfully under a wide range of conditions including vapor phase (89). 8.-8Hydrogenation of Nitro Compounds Aromatic nitro compounds are hydrogenated very easily. are the metals usually used in nitro-group reductions. platinum. or nickel. aliphatic nitro compounds considerably more slowly. The choice of catalyst often depends on what other functions are present and on the products desired. In practice.11) or relatively lengthy reduction times may be 104 . Platinum may be more useful than palladium in reduction of nitro compounds containing functions easily reduced by palladium. supported or unsupported. and higher catalyst loadings (6. Hydrogenation of aromatic nitro compounds is very fast. but over PtO2 in ethanol 2 was obtained in 96% yield (4). Catalysts Palladium. Reduction of aromatic nitro compounds may give products sensitive to air. It is quite likely that in these cases the oxidation products will have an adverse influence on catalyst life. and the rate is limited often by the rate of hydrogen transfer to the catalyst.

Reduction over palladium-on-carbon gave pure.95).91.60.9. where small amounts of . will react with the amine as formed.73). Basic solvents cause the formation of azo.59. can alter the course of reduction by arresting the reaction at an intermediate product or by causing the formation of coupled products (94.8. 63. The work of Kosak (56) on o-nitroanisole is instructive in this regard. 8.8. These deviations can range from only a small yield loss to the formation of a major product. CH 3 NO 2 -HHCCOH » OO COOH O2N 4OmICH 3 OH 40 mg 10%Pd-on-C 2.7atm. such as acetic anhydride.NX 85°/ /COOH OH 100 mg OH 8.3. azoxy. Nonetheless. present by accident or design. Solvents A great variety of solvents has been used with success. the reduction is very useful (7. Palladium proved especially useful in the hydrogenation of 2-hydroxy-3nitropropanoic acid. whereas platinum failed to reduce the nitro function under neutral or acidic conditions.2. paralleling chemical reductions (39. and hydrazo compounds. INFLUENCE OF IMPURITIES 105 OH PhCH 2 O PhCH 2 O NH2Cl 100mgPtO2 2SmIEtOH IaImH 2 .3. reduction over Raney nickel gave a bright green powder (96). 250C H.69).72.99). powdery isoserine.90. notably for synthesis of amino sugars. Influence of Impurities Various materials. Reactive solvents. 250C PhCH2O PhCH 2 O NH2Cl NH 2 (2) required (48.

Hydrogen chloride had a marked depressing effect on rate but not on product quality.87% pure 94-97% 82-85% 3-1% 14-12% Catalyst: 0. 8. Palladium gave a high quality 0-anisidine when starting with high-purity o-nitroanisole.o'-dichloroazobenzene > o-chloronitrobenzene » o-nitrophenol ~ o. aromatic hydroxylamines can be formed in 90% yield under mild conditions. 50psiH 2 100 g . 0.0'-hydrazoanisole formation are in declining effectiveness: o. complete poisoning occurs at a mole ratio of only 0.03 g 4.4. With hydrogen gas as a reductant and platinum-on-carbon or -onalumina and about 1 wt % of DMSO based on nitro compound as a modifier.5% Pd. may come to opposite conclusions regarding the relative effectiveness of catalysts. Palladium-on-carbon catalysts were shown to be more sensitive to the above modifiers than were platinum catalysts (56). HYDROGENATION OF NITRO COMPOUNDS impurities were shown to exert an appreciable influence on the rate and quality of reduction. 250C. This conclusion illustrates one reason why different investigators.042. with the Pd-Pt-Fe catalyst. Aromatic Hydroxylamines Hydroxylamines ordinarily do not accumulate in the reduction of aromatic nitro compounds for.106 8. OCH3 NH 2 OCH3 J\ /NHNH. The reduction slows markedly after absorption of the second mole of hydrogen and should be stopped at this stage (80).82% pure 98. Nonetheless. systems have been found that afford the intermediate aromatic hydroxylamine in excellent yield. 5% Fe-on-carbon per mole of nitroanisole Impurities identified as having an influence on promoting 0.o'-azoxyanisole. doing ostensibly the same thing. with some exceptions. most systems in competition will reduce the hydroxylamine function preferentially. OCH3 + I 99. but platinum catalysts were clearly superior when the starting material was less pure.5% Pt.

1. and the electrophilicity of the carbonyl (27. Sometimes hydroxylamines are formed in systems where the amino compound would have been expected. 8. 250C 85-90% combined yield If the hydrogenation is carried out in hydrochloric instead of sulfuric acid. This occurs usually in compounds containing either sulfur or basic nitrogen. One uses 5% palladium-on-carbon in aqueous tetrahydrofuran with phosphinic acid or its sodium salt as hydrogen donor. The reductions cannot be followed by pressure drop. while in hydrofluoric acid.68).12.4.86). chloroaniline is formed (20).50.98).8. the catalyst. Industrial routes to this compound have been developed in which phenylhydroxylamine. impurities may have had an influence also (1.67. Cyclic Products During hydrogenation.17. These systems are complementary and which is the better may depend on the substrate (36).29. The cyclized product may or may not maintain the N—OH bond. AROMATIC HYDROXYLAMINES 107 Two hydrogen-transfer systems have been developed that also give good yields of hydroxylamines. fluoroaniline is produced (37). the other uses 5% rhodium-on-carbon in aqueous tetrahydrofuran and hydrazine as donor. DMSO 25 %ag H2SO4 I a I m H 2 .32. and both require analysis of the product to determine when the reduction should be terminated.81).4. Phenylhydroxylamine rearranges in sulfuric acid to give mainly paminophenol. is rearranged as it is formed. . An easy way to obtain a favorable rate ratio is to carry out the reduction with about 1% DMSO present in the sulfuric acid (79. or carbonyl derivative. intermediate aromatic hydroxylamines may undergo various cyclization reactions in molecules containing a suitably disposed carbonyl group. depending on the solvent. Conditions are adjusted so that the rate of rearrangement is high relative to the rate of hydrogenation of hydroxylamine to aniline (15. formed by hydrogenation of nitrobenzene in sulfuric acid over platinum-on-carbon.28. such as an oxime (13).46.

more so than Af-methylmorpholine > W-ethylmorpholine > 3. Elevated temperatures and pressures are necessary to achieve reasonable rates (33. At one time a difficult task.5g A variety of inorganic (31. amount of catalyst. but ethanolamine and ethylenediamine are poisons. .34). Dehydrohalogenation relative to nitro group reduction is favored by hydrogen-poor catalysts and retarded by hydrogen-rich catalysts. the reaction is now practiced industrially on a large scale. overall structure. 8. Bifunctional Molecules A frequently occurring problem is the full or partial reduction of a nitro function in the presence of other reducible functions.5-dimethylmorpholine (55). HYDROGENATION OF NITRO COMPOUNDS 8.87) and organic bases have been added to the catalyst to improve selectivity. Preferential hydrogenation of an aromatic nitro group can usually be achieved for it is very easily reduced. Newark. These catalysts [manufactured by Engelhard Industries. Morpholine is an effective inhibitor. Piperazine is effective. and catalyst activity have been related in part by the influence these variables exert on hydrogenation availability at the catalyst surface. amount of catalyst. temperature.0g5%PtS x -on-C 103. The effectiveness of organic bases is very sensitive to structure. catalyst support.5. 850C 800-500 psig 1. Halonitro Aromatics A problem of both academic and industrial interest is the hydrogenation of a halonitro aromatic to the haloaniline (89).25h 23OmICH 3 OH 3. catalytic metal. In general. agitation. with or without modifiers. The extent of dehalogenation may depend on the halogen present. New Jersey (51)] have a high intrinsic selectivity for this type of reduction and have given excellent results under a wide range of conditions.1. The influence of pressure. Excellent results have been obtained by use of supported noble-metal sulfides (47).108 8. and reaction conditions.5. combined with a fast rate of reduction of the nitro function. platinum. makes the best catalyst for minimizing dehalogenation.

Cobalt polysulfide and ruthenium sulfide catalysts have been used similarly. At low pressure (< 50 psi) complete displacement of halogen by morpholine occurs to give p-(N-morpholino)mtrobenzene. especially when excess morpholine is used.40.76. BIFUNCTIONAL MOLECULES 109 Many other systems have been disclosed (85a). 8.25. are more likely to be hydrogenated preferentially at the nitro group (70. Acetylenic and Olefinic Nitro Compounds Aliphatic. Both platinum and palladium have been used. (92) obtained a good yield of /?-phenylethylamines from hydrogenation of nitrostyrenes over 5% Pd-on-C in dil aq HCl at 50-8O0C and 500-1000 psig.21).85). either or both may be reduced. Ruthenium. Nitronitriles The nitro group is reduced easily in preference to a nitrile (23.360. 25-70 atm) (71). In molecules containing both an acetylenic and a nitro function. on the other hand. 8. Catalyst life is prolonged by protection of the acetylenic function (70).3. above 200 psi. Wagner et al.44). The reverse selectivity seems not to have been reported. Preferential reduction of the acetylenic function is best achieved with palladium (42. but more vigorous conditions are required (10O0C. such as sulfurichydrochloric acid (26). . or dilute aqueous hydrochloric acid (22). better yields are obtained in acidic media (83).8.5.3-diphenylbutane derivatives (54. nonconjugated nitroolefins can be reduced to the saturated nitro compound without difficulty (30.76). Over 5% Rh-On-Al2O3 in ethanol-acetic acid-ethyl acetate.19. Reduction of /?nitrostyrenes in neutral medium result in products derived through coupling of two molecules at the a carbons to give 2. Conjugated nitroolefins may afford a variety of products through partial or complete reduction as well as products arising by reductive hydrolysis. but the reverse preference has been seen (100) in certain aliphatic molecules.84) especially if the nitro group is aromatic and the groups are unable to interact.j?unsaturated nitro compounds. on the other hand. the product is pchloroaniline (55). The technique gives yields of only about 60% when applied to aliphatic a.5. high yields of (3aminophenyl)acetylene were obtained from the corresponding nitro compound.45. Pressure has a marked effect on the course of this reduction.5.2. favors selective reduction of an aromatic nitro function. 2-/?-dinitrostyrenes are converted to 2-nitrophenylacetaldehyde oximes (13).75). Coupling is avoided in strong acid media. Unsaturated aromatic nitro compounds. Excellent yields of the oximes of phenylacetaldehydes are obtained by reduction of jS-nitrostyrenes over Pd-on-C in a pyridine solvent (74.

110 CH. H3C DMF H1C CH3O NO2 CN (3) NH 2 R (4) R = CN 43% (5) R = CONH2 13% (6) R = H 17% CH3O 8. Nitroaldehydes and Nitroketones There is little difficulty in reducing a nitro function in preference to a carbonyl (38) unless the functions are spatially proximate. The nitrile function is lost before formation of the amine. as well as 6. Hydrogenation of o-nitrobenzonitrile over either palladium or platinum gave o-aminobenzamide (78).4. for 4 resists reduction. the amide (5). Hydrogenation of 3 over 10% Pd-on-C led to the expected cyanoamine (4). with the amide oxygen transferred from the nitro group (66). On the other hand. 8. in which the nitrile carbon is lost (58). HYDROGENATION OF NITRO COMPOUNDS CH3 O2N I g 5% Ru-On-Al2O3 200ml 7O0C C^CH O2N ^C=CCOH I CH3 20. A somewhat different distribution is obtained over PtO2.93). and accords with the tendency of platinum to produce more intermediate hydroxylamine (82). but the amino nitrile over palladium (82). the lactam (7).5g H2N H2N C=CH Reductions of nitronitriles situated to favor interaction are apt to involve both functions (84. as expected. l-amino-2cyanonaphthalene gave the amino amide on reduction over PtO2. A .5. in which case the tendency to ring closure provides an easy entry into a variety of systems.

10 ml of 50% H2SO4. Azaindoles are correspondingly prepared from nitropyridines (97). I \^ 400 mg 10% Pd-on-C 25OmIEtOAc 5O0C. Lazer et al. Similarly. The hydrogenation is stopped at .2benzenediamine (12) (2) or to 2-nitro-l. hydrogenation of y-nitroketones gives pyrrolidines in good yields (52) and a-nitroketones give a mixture of pyrazines and piperazines (35).5.3 I g (8) (9) A similar synthesis starting with l-(2-nitrobenzyl)pyrrol-2-aldehyde used ethanol-ethyl acetate as solvent (62). and 350 mg 5% Pt-on-C at 850C and 30 psig.5. A case in point is the hydrogenation of 2. 60 ml HOAc. Very large volumes of diaminotoluene. presents no problem. V. a precursor to toluene diisocyanate. BIFUNCTIONAL MOLECULES 111 facile synthesis of the tricyclic compound 9 was achieved by reductive cyclization of the nitroaldehyde 8 (88).4-benzenediamine (10). (61). favor preferential reduction of the less hindered 4-nitro group. 4 aim H 2 2. 8. which are unable to interact intramolecularly. /^. Selective hydrogenation of one or the other of two nitro groups is much more of a challenge. if they show selectivity at all. selectively prepared 10 from 27 mmol 11. but a number of outstanding successes have been recorded.4-dinitroaniline (11) to 4-nitro-l. NO2 N .5. are produced by hydrogenation of dinitrotoluene over either nickel or palladium-on-carbon. Indoles are prepared in excellent yield by hydrogenation of o-nitrobenzyl ketones over Pd-on-C (3). In the aliphatic series.8. Most catalyst systems. hydrogenation of 11 over Pt-onC in acidic alcohol affords 10 in 70% yield (24). Dinitro Compounds Formation of diamines from dinitro compounds.

as expected.3 mol) is stirred for 10 min at 28-3O0C in 1:1 (v/v) ethanol:l. Platinum oxide in ammonical DMF showed fair selectivity.. but Pd-on-C none. v J^\ VOH —— C H OH 2 3 Ra-Ni N2H4 ClCH2CH2Cl NO 2 92% Typically a mixture of dinitroarene (0.4-dinitroanisole. Selectivity in the reverse sense. For example. i. HYDROGENATION OF NITRO COMPOUNDS absorption of 3 mol.e. the main product is derived by reduction of the more hindered nitro function. 0. with steric hindrance of the alkyl substituent. reduction of the more hindered nitro group in dinitroalkylbenzenes can be achieved with the homogeneous catalyst. In a typical experiment. Reduction of 2.4-dinitroalkylbenzenes tend to favor selective reduction at the least hindered nitro group.2-dichloroethane (10 ml . In general.4-dinitro-l-(JV-piperidyl)benzene gave 4-amino-2-nitro-l-(JVpiperidyl)benzene in 99% yield (49). Yields were lower in ethanol. These reductions were carried out at 15O0C and 200 psig with xylene solvent and a catalyst loading of 50% based on substrate.4dinitrophenol or 2. of many catalysts tested.3 mol of hydrogen were absorbed (2). but only Raney copper.1 mol) and hydrazine hydrate (0. RuCl2(Ph3P)3 (53).7 g 5% Rh-On-Al 2 O 3 was reduced at 40 psig until 0. Reductions of 2. Selective reduction of 11 to 12 is achieved in high yield by the use of 5% Rh-on-C in DMF containing NH4OH.1 mol of 11 in 250 ml DMF containing 3 ml 28% NH4OH solution and 0. This exceptionally high catalyst loading is of little economic consequence since the catalyst could be reused repeatedly. 3 8OaUnH 2 N NO2 NH 2 conversion 42% selectivity 96% Dinitroarenes containing substituents such as hydroxyl or amino groups are reduced with 3 mol equiv of hydrazine hydrate in the presence of Raney nickel to afford selectively a compound in which only one nitro group is reduced. The same reduction is nonselective when applied to 2. Reduction essentially stops after absorption of 3 mol of hydrogen. ^ . gave very high selectivity. Selectivity for reduction of the 4-nitro group increases.112 8.

6. whereas at 600 and 2000 psig the results were erratic.47).77). Hydrogenations of 2-jS-dinitrostyrenes over palladium provides a general way into the indole system (14. The catalyst is filtered and the product recovered (5).5. NH 2 NH 2 NO2 NO.4g5%Pd-on-C COOCH3 7. Stirring is continued for 3-8 hr at 50-6O0C. Reduction of 2. and a number of products were formed.5.3 g Ra Ni is added in three portions. .2'-dinitrobiphenyls gives a mixture of cinnolines and diaminobiphenyls in ratios that are influenced by the relative amounts of cis and trans configuration in the adsorbed substrate complex (18. Over a period of 40 min 0.Og In a similar system. Interestingly. Nitro groups disposed toward cyclization may do so on reduction.43. N=N 8. high yields of 2. Melhado and Leonard (64) obtained better results if the enamine (13) were first converted to a semicarbazone (14) before hydrogenation and cyclization to the indole (15). The temperature rises. Nitroenamines An excellent method for producing methyl indole-4-carboxylate from commercially available 3-nitro-2-methylbenzoic acid involves reduction of an intermediate nitroenamine (57).8.2'-diaminobiphenyl could be obtained over W-2 Raney Ni at 50 psig (1:3 ethanol-ethyl acetate). COOH (I)CH3LNaHCO3 (2) (CH 3 ) 2 NCH(OCH 3 ) 2 * COOCH3 N(CH 3 ) 2 14OmIC 6 H 6 50psigH 2 1. BIFUNCTIONAL MOLECULES 113 per g nitroarene). but it is not allowed to go above 6O0C.

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in agreement with others. nonetheless.1. and of rosin to perhydrorosin (26). such as conversion of benzoic acid to hexahydrobenzoic acid. 9. it was found impossible to reduce the doublebond in (1) over Pd-On-CaCO3 without some reduction of the aromatic ring as well (7). Ring saturation may occur with exceptional ease over palladium if the ring is activated by strain. a nylon-6 intermediate (44). The relatively slow rate of ring saturation over palladium often makes this the preferred catalyst for reduction of other functions without ring attack in mononuclear aromatics. established a declining rate of activity in hydrogenation of benzene and isobutylbenzene as Rh > Ru » Pt » Pd > Ni > Co. and control of stereochemistry. control of regioselectivity in polycyclic aromatics.Hydrogenation of Carbocyclic Aromatic Compounds Aromatic rings can be reduced without difficulty. palladium is used industrially in several important aromatic hydrogenations. COOCH3 COOCH3 (1) A surprising use of palladium hydroxide-on-carbon in the hydrogenation of (K)-a-phenylglycine to (K)-a-cyclohexylglycine was described by Tamura 117 . Major problems connected with these reductions concern maintenence of other functions. a different order applies in fused systems. Catalysts Greenfield (14). For instance.

2.118 9.45psigH 2 66% Rhodium (21) and ruthenium are excellent catalysts for the reduction of aromatic rings. as well as by double-bond migration in the . on the other hand. Phenylcyclohexane has been obtained in good yield from benzene by this technique (40).49). Platinum. which is unique in ruthenium catalysis (36). other isomers are accounted for by desorption and readsorption in a new orientation of intermediate olefins. If this catalyst contains residual alkali. HYDROGENATION OF CARBOCYCLIC AROMATIC COMPOUNDS and Harada (43).42. where 1. as in acetophenone. NH 2 CHCOOH Pd( °. unless especially active. especially as platinum oxide.4and 1. Water has a powerful promoting effect.20°n-C » (ViHCOOH + (^CH2COOH ^ ' \=/ 20°C. but their formation.3.18..13. the product is phenylacetic acid (15). The hydrogenation was very slow. In the presence of an acidic catalyst.41.10. Under mild conditions.35. and rhodium or ruthenium would likely have proved more effective and selective. Hydrogenation of aromatics under mild conditions gives mainly the all-cis isomer as if hydrogen addition takes place from only one side of the molecule (23. has been used by many investigators. Hydrogenolysis increased with increasing temperature. gives ethylbenzene quantitatively. 9. the intermediate olefin can be trapped by alkylation.1P) or unless the compound also contains a carbonyl group. Nickel.24).29. for this type of catalyst is used frequently for hydrogenolysis of benzylamines without ring reduction.37. Reductions under more vigorous conditions may give other isomers by isomerization of the initially formed all-cis product. Surprising. in varying amounts.48.52). requires vigorous conditions—conditions that may promote side reactions. Rhodium (41) and ruthenium (45) each reduced methylphenylcarbinol to methylcyclohexylcarbinol in high yield. In aqueous alkaline solution over Pd(OH)2-On-C. It is with these catalysts that the best chance resides for preservation of other reducible functions (2. it is apt to be ineffective for aromatic ring reduction unless an acidic solvent is used (1. as might be expected. Palladium. lacks synthetic utility.6-addition are possible (46). Olefin Intermediates Olefins have often been shown to be intermediates in the saturation of aromatics (6.

naphthalene. unless the substituents introduce exceptional strain.39). (Palladium was also most selective in partial hydrogenation of diphenylmethane.32.3. rates decrease as substitution by alkyl groups increases (47). Ethylbenzene and toluene are hydrogenated faster than benzene over CuZnO.3. In other cases. In general. rhodium.38. temperature. the surface concentration of which increases with the increasing electron-donating ability of the system (50). Rhodium tends to produce the greatest amount of isolatable olefin (30). or ruthenium (34).25.9. EFFECT OF SUBSTRATE STRUCTURE 119 olefin (16. Effect of Substrate Structure The rate of aromatic hydrogenation is influenced by both steric and electronic factors (20. the trend may be general). contrary to the general rule.53). support. and bipyridyl. the reaction essentially stopping at absorption of 3 mol of hydrogen (4.33). CAMP 9. Such behavior is evidence for a rc-bonded intermediate. Selectivity in hydrogenation of biphenyl to phenylcyclohexane was found to be influenced by catalyst. Strained aromatic systems will undergo facile saturation even over palladium under mild conditions (31.3. Palladium was much more selective than were platinum. selectivity is influenced strongly by catalyst and reaction parameters. 9. Selectivity . A synthesis of CAMP depends on the selective hydrogenation of the least substituted of two aromatic rings in PAMPO (51). Success in this endeavor is dependent heavily on substrate structure and in some molecules is achieved easily.54).1. Polycyclic Systems A frequently occurring problem is the saturation of only one aromatic ring in a molecule containing several. Catalysts may differ appreciably in their tendency to release adsorbed olefin and consequently give products of quite different stereochemical composition.9. and solvent.

3. and perhaps running contrary to expectations. the rate constants.71. Naphthalenes substituted in the 2-position are reduced preferentially at the unsubstituted ring. maximal selectivity to phenylcyclohexane (5O0C) varied appreciably with solvent. The above generalities apply particularly to palladium. Naphthalenes carrying 1. A great deal of control can nowadays be exerted over the products obtained on partial hydrogenation of fused aromatic systems. This trend might be expected to be general in reactions of the type A -> B -> C. cyclohexane (59%). For example. unlike mononuclear aromatics. in acetic acid at 5O0C and 1 atm.4). For example.2.42. less on an alumina support.120 9.024. Pt (18. k x 106 in mol sec"1 g catalyst"1. whereas the reverse is true for 1-alkyl substitution.8-substituents are hydrogenated preferentially at the ring carrying the larger substituent (31). Reduction of 1-f-butylnaphthalene over platinum. 1-f-butylnaphthalene (28) and 1. respectively.8-diisopropy!naphthalene) Pd (142). the steric interaction of the 1-alkyl group with the 8hydrogen atom or 8-alkyl group. rhodium. Hydrogenation over platinum or rhodium are far less sensitive to the influence of steric crowding. ethyl acetate (66%). Selectivity was highest on unsupported palladium. with selectivity to B falling as pore structure develops. and Rh (7. Over 5% Rh-on-C. methanol (50%). tetrahydrofuran (78%). 0.4-di-t-butylnaphthalene (8) are hydrogenated only at the substituted ring and at relatively high rates. the greater the selectivity toward reduction of the substituted ring. Fused Rings Either ring of an alkyl-substituted naphthalene may be reduced and the rate ratio (kl/k2) depends both on the position of R and its size (28). Selectivity depends on . the larger the 1-substituent.1) (28). Also. f-butanol (57%). and palladium resulted in values of kl/k2 of 0. 9. HYDROGENATION OF CARBOCYCLIC AROMATIC COMPOUNDS increased with increasing temperature in the range 25-1250C and was almost independent of pressure. were (for 1. palladium reduces substituted naphthalenes at substantially higher rates than does either platinum or rhodium. ethanol (49%). These results have been explained in terms of release of peri strain. and 0. and less still on carbon.

References 1. D. Outlaw. Chem. Org. Patent No. J. whereas reduction over platinum gave (2) in 95% yield. A. E. Fu and R. B. R. Doecke. Cowen and E. Yanagi. 11. P. 7. and A. 3. R. 50. Mylroie and Stenberg (27) reported interesting differences between Ru-on-C and RuO 2 . Chem. H. Chem. Cozort. 4190 (1983). hydrogenation of benz[a]anthracene (3) in the presence of Pd-on-C at 20 psig and 250C gave (4) in 97% yield. Marshall. F. Zahier. Still water.D. D. . and R. but over RuO2 extensive hydrogenolysis of the hydroxy groups occurred as well. Org. M. J. Arnold. W. Eisenbraun. Siegel. Org. Thesis of K. Hawkins. Shahriari-Zavareh. Unpublished Ph. Chem. E. Baltzly. Am. Adams and J.. Chem. J. M. (2) (3) (4) Hydrogenation of 4. 1977. G. U. J.555. 2. M. Freifelder and G. These and many other highly regioselective results (22) contrast with the complex mixture reported earlier when more strenuous conditions were employed. Am. K. J. Soc. Russell. P. Brooks. Schuetz. 5270 (1958). R P. J. Baker and R. 811 (1968). Am. Steinberg. Cowen. 29. Soc. H. whereas over platinum reduction takes place regiospecifically on terminal rings to give tetrahydroarenes. 10. 9. and S. 26. 6. J. Franck and K. B. 3669 (1961). D. 48. Chem. Hydrogenation of 9. J. Mehta. J. For example. 1412 (1984). H. Grivsky. 5. Harvey. R. Org. 4.5-dihydropyrene (2g) over 10% Pd-on-C (500 mg) in 20 ml of EtOAc at 50 psig afforded tetrahydropyrene quantitatively (17).. C.. J. 1970 (1928). Org. 8. J. J. 69. 15O0C. R. Oklahoma State Univ. M. Tetrahedron Lett. Stone. R.S.10-hydroxymethyltriptycene over either Pd-on-C or Ru-on-C (4000 psig. J. 80. Chem. R. Chem. W. Soc.912 (1951). Garratt. 415 (1977).REFERENCES 121 the substrate structure and the catalyst (5). Jr. Freifelder. 2. 49. 979 (1964). Fu and Harvey (77) and Fu et al (12) found that hydrogenation of polynuclear systems over palladium afforded regiospecifically the corresponding /c-region dihydroarenes. R. EtOH) gave high yields of the perhydro compound. R. W. 33.1250 (1947). N.

F. 13. 31. Levine. Chem. Keenan. Soc. Swett. Steele. Congr. R. 709 (1982). W. S. Patent No. J. 14. R. 35. Steele. J. 44. 87. Bull. Chem. Wu. Roth. 159 (1983). 8. S. . P. Rapoport and G. 13. 3136(1962). 32. Yoneda. Rapoport and J. Hydrocarbon Process. P. A. S. Chem. 2044 (1974). Soc. Taverna and M. 48. Soc. Konieczny. Catal. Buurmans. 229 (1954). J. U.. Pays-Bas 88. 16. and K. and W. J. M. J. L. M. Sd. 752(1962). Res. 214. J. Feldkamp. Gould. 29. R. J. C. Davis. E. 1790 (1967). Chem. Y. V. Chem. V. 39. Drossier. and R. Chem. Jpn. Vaflor. 82. Vineyard. Siegel. and H. Med. M. K. Bellinger. 145 (1968). H. L. Ku. R. 9. R. Org. Michaels. H. Am. N. J. A. Acad. Trahanovsky and D.4186 (1983). Soc. lnd. Bull. J. Halpren. Bull. Lee and R. 54. Meet. Lee. 29. 47. 255 (1973). 385 (1969). 2. Pataki. J. 49. Hirsch and G. H. Rakoncza. Chem. Chem. Org. Freifelder. 47. Jr. N. W. Tech. 77. Whetstone. Soc. J. 2192 (1972). (Nov. and W. Vickery. H. 76. Slaugh and J. J. Chem. Org. Am. Rec. 29. Chem. 404 (1973). J. G. J. Catal. 319 (1963). G. A. 629 (1982). 214. Smith. P. L. H. Chem.122 12. J. H. Gleen.S. Stocker.1676 (1954). 37. W. Siegel. W. 48. van Bekkum. Yoshida. G. Smolinsky. 42. Smith. Catal. 2797 (1980). J. Proc. 48. Chim. M. J. Dmuchovsky. Engelhard lnd. J. and A. N. Schwartzkopf. L. 2930 (1983). Can. and J. 22. Stenberg. Soc. I. N. Org. Knowles. G. Levine. 1964. R. Am. Kieboom. B. 19. Galantay. Taya. Thomas. Ber. 80. J. F. Int. 11. 23. Tetrahedron 19. K. 38. 2590 (1982). Soc. A.) 62(4). B. 19. Leclere. 1208 (1965). D. J. Theilacker and H. O. Northeast Reg. 47.387. 37. J. 24. E. A. Schwartz. Linstead. Catal. P. 27. P. G. and J. Dubbell. Gieseman. N. Trav. 33. 28. 43. A. Siegel. 2288 (1962). 50. J. and E. Chem. 233 (1973). J. Chem. Cozort. and S. S. and J. I. J. 6th (1974). Org. Harvey. W. Stocker. H. Harada. Chem. Chem. 50. H. R. Greenfield. Synth. R. Vedage and K. Siegel. H. and M. 79 (1963). Inst. Lobeck. Org. 17. Whetstone. 39. G. Am. 27. J. 3rd.Y. 558 (1982). Phys. V. 51. 2. Rylander. G. Glasebrook. Soc. Halpren. E. Chem. Zwietering. Bohlen. Ann. Chem. 26. Catal. Catal. 2. S.1171 (1960). Soc. F. Am. 331 (1976). 45. Am. 32. 137 (1970). 2014 (1942). M. 64. Chem. Chem. Adv. N. H. P. Decker. Mylroie and J. and R. H. Am. Chem. HYDROGENATION OF CARBOCYCLIC AROMATIC COMPOUNDS P. 123 (1966). 46. R. van Minnen-Pathuis.Y. Am. J. Thigpen. Harvey. J. D. 5. 41. W. Chem. Chem. E. 2763 (1958).. J. Klier. 183 (1968). Outlaw. Eisenbraun. 49. S. Chem. Sd. R. Pettit and E. Med. N. Sd. P. Weston. 3. B. 78. 40. 779 (1969). R. G. Org. van Bekkum. Hiramoto. J. Z. and B. G. Ann. J. Klapwijk. 3593 (1964). Hoffmann. T. Gasti. Catal. N. J. Hartog and P. B. W. T. R. Org. Chem. Sabacky. Chem. Nieuwstad.1985(1942). Mochida and Y. Acad. Tarnura and K. 36. J. and R. 95 (1963). 25. G. A. 313(1958). Wepster. P. 60. M. Rylander and X. Org. W.. Pap. Stone. (Jpn. 18. Pourahmody. 16. G. 345 (1978). H.048 (1968). N. and M. H. B. 2061 (1974). Soc.. 30. W. 4364 (1982). Fu and H. G. Pasky. 84. 4. 64. P. R. MoI. Catal. Commun. Eng. Hirota. van Bekkum. J. G. Harada. Leonard. Jpn. Zaugg. 53. 15. and P. J. 47. J. Rylander and D. J. A. H. N.). Doering. 25. M. J. 45. M. A. R. Org. H. 52. Linstead. J. Chita. Chem. 20. Jr. 34. Catal. 21. Harvey. 348 (1963). 3788 (1956). Montgomery. H.

iridium. platinum. The major features of aniline hydrogenations are accounted for by formation of partially saturated rings to afford vinylic and allylic amino derivatives. Currently. cobalt. ruthenium. Phenols. 10. reductive cyclization. whereas noble metals can be used under much milder conditions. The reduction may be accompanied by several side reactions.1. susceptible to hydrolysis and to reductive coupling (22). Anilines Anilines are saturated easily. and Derivatives Many of the considerations discussed in the previous chapter apply to anilines and phenols. preferred catalysts in both laboratory or industrial practice are rhodium at lower pressures and ruthenium at higher pressures. including palladium. for both display high activity and relatively little tendency toward either coupling or hydrogenolysis. rhodium. through isomerization to imines. Base metals require high temperatures and pressures (76). in certain compounds.10Hydrogenation of Anilines. including loss of the nitrogen atom by hydrogenolysis (2) and by reductive hydrolysis. and nickel. and. and. 10. coupling to secondary amines.1. but the presence of amino and hydroxy groups introduce new problems and opportunities. 123 .1. susceptible to hydrogenolysis. (54). Catalysts Anilines have been reduced successfully over a variety of supported and unsupported metals.

124 10. from the catalyst. a coprecipitated 3% Pd. At 20% catalyst loadings at least 10 batches of benzocaine could be reduced without loss in activity with intermediate catalyst regeneration.50) or as physical mixtures of separate catalysts (59). PHENOLS AND DERIVATIVES A variety of mixed metal catalysts. HYDROGENATION OF ANILINES. Catalyst Reactivation A general problem in the economical use of catalysts is to maximize the pounds of product obtained per pound of catalyst. either as fused oxides (42. a general observation supported by many experiments.4 11.4 11. but at 5% and 10% loadings the rate of hydrogenation fell rapidly with reuse.7 10.0 2. even with repeated regeneration. Lower catalyst loadings are less costly than are higher loadings on a once-through basis.9 Reduction done in 3A Ethanol (a denatured ethanol) with 85% H3PO4 at 60 psig.0 2. 2% Rh-on-C 3% Pd. In the hydrogenation of ethyl p-aminobenzoate. These data show hydrogenolysis to increase with temperature. 10. 2% Rh-on-C proved superior to 5% Rh-on-C.4 16. inasmuch as hydrogenolysis to ethyl cyclohexanecarboxylate was less (67) (Table 1).1. Time to 90% completion. formed in hydrogenolysis of benzocaine. An example of this is hydrogenation of ethyl p-aminobenzoate (benzocaine) over 5% Rh-on-C in ethanol containing phosphoric acid.57. 2% Rh-on-C 13.0 19. 2% Rh-on-C 3% Pd.0 3.2. but on reuse the lower loading may decline in activity more rapidly than higher loadings.58) or coprecipitated on supports (25.2 6. Regeneration was based on removing ammonium dihydrogen phosphate. commensurate with acceptable space-time yields.2 2. Here the influence of temperature is less with the mixed-metal catalysts. TABLE 1 Hydrogenation of Ethyl p-Aminobenzoatea Reduction time (h)" 3. The catalyst was . have been tested in aniline reductions.0 Catalyst and loading 10% of 10% of 5% of 10% of 10% of 5% of a b Temperature 0 (Q 60 80 80 60 80 80 Hydrogenolysis Conversion (%) 100 100 100 10 100 100 5% Rh-on-C 5% Rh-on-C 5% Rh-on-C 3% Pd.

In the hydrogenation of aniline over ruthenium oxide. Basic additives such as alkali-metal and alkaline-earth hydroxides and carbonates. additives. then with 6 N phosphoric acid.1. followed by drying at 9O0C (16) or by washing with acetic acid. 10.29). Carboxylic acid solvents increase the amount of coupling (42). oxygenated products form (22. The inhibiting effects of ammonia and amines. The ratio of these products is influenced by temperature. A rhodium-on-alumina catalyst deactivated in bis-(4-aminophenyl)methane saturation (1150C. The amount of coupled product was found to depend importantly on the catalytic metal. catalytic metal. and ammonia are useful in suppressing formation of coupled products (4. can be alleviated by venting and repressuring the reactor (5). It is possible to exert substantial control over the product composition. 100 psig) was regenerated by two washings with aqueous ammonia at 650C.10. Aqueous ammonia is less inhibiting than anhydrous ammonia. the amount of dicyclohexylamine was found to decrease in the order carbon > barium carbonate > alumina > barium sulfate > calcium carbonate. Control of Coupling Hydrogenation of anilines normally gives cyclohexylamines and varying amounts of the coupled products.3. The extent of coupling is also influenced by the solvent. probably owing to the inhibiting effect of greater concentrations of ammonia (44). Plain carbon added to rhodium-on-alumina-catalyzed reactions was found to cause an increase in the amount of dicyclohexylamine. dicyclohexylamines. but in aqueous solution.1. The rate was also lower in the lower alcohols. Lithium hydroxide specifically seems especially effective in promoting reductions over ruthenium oxide catalysts (46). coupling decreased with solvent in the order methanol > ethanol > isopropanol > r-butanol. and finally with ethanol while being kept free from air (67). In a study on the influence of supports on rhodium. ANILINES 125 first washed with water. .37). suggesting that carbon catalyzes the formation of the intermediate addition product (59). amines. Coupled products increase with increasing temperature (23). support. a sequence that reflects one reason for the industrial preference for rhodium and ruthenium in hydrogenation of anilines. and solvent. a sequence for increased coupling to dicyclohexylamine was found to be Ru < Rh « Pd ~ Pt (59). Amines suppress coupled products but at the expense of rate. formed in hydrogenolysis of aniline and JV-alkylanilines.

Synthetic Applications An excellent route to cyclohexylamines is by hydrogenation of the corresponding aniline over rhodium or ruthenium (17. Palladium is the preferred catalyst (33).77).61. which may occur as an unwanted side reaction when anilines are reduced in aqueous media. 10. The extent of hydrogenol ysis occurring in saturation of alkoxyanilines depends also on the solvent. . 10.2. the extent of this reaction again depending mainly on the catalyst. Reductive cleavage is facilitated by substitution on the nitrogen and by acidic media.19. In lower-alcohol solvents.1.and tricyclic systems. the oxygen is lost preferentially.64). PHENOLS AND DERIVATIVES 10.1. can be turned to synthetic advantage. Hydrogenolysis occurs more readily than hydrogenolysis of the nitrogen atom in anilines. Hydrogenolysis of the oxygen atom may be a major side reaction.1. Partial Hydrogenation of Phenols to Cyclohexanones An important industrial synthesis of cyclohexanone is by partial hydrogenation of phenol over palladium. HYDROGENATION OF ANILINES. carried out in either liquid or vapor phase.36.18.32. ester. or carbonyl functions provides a convenient entry to bi. and in molecules containing both functions.5. Phenols and Derivatives Phenols are reduced easily to either the corresponding cyclic ketone or to the alcohol. the major product of a phenol hydrogenation might be an alkyl cyclohexyl ether.126 10. Reduction of anilines containing acid. depending in large measure on the catalyst.4.2. Reductive hydrolysis of substituted anilines carrying chiral N-substituents gives chiral cyclohexanones (34).2.63. cyclization occurring once the rigidity of the aromatic ring has been lost through saturation (1. Reductive Hydrolysis Reductive hydrolysis of anilines. Rhodium has proved especially useful in saturation of alkoxyanilines with minimal hydrogenolysis of the alkoxy function (45). Hydrogenolysis of p-methoxyaniline over Ru(OH)2 fell with alcohol solvent in the order methanol (35%) > ethanol (30%) > propanol (26%) > butanol (22%) > isopropanol (16%) > t-butanol (8%) (43). 10.

The extent of hydrogenolysis depends very much on structure. phenylisocyanate. 1 -phenyl-5-chlorotetrazole. A 77% yield of the dione was obtained by alkaline hydrogenation of 3. many catalysts have been examined with variations in metal distribution.8-dihydroxynaphthalene to 8-hydroxy-l-tetralone (30).6-di-r-butylphenol to 2. rhodium.2. Hydrogenolysis is enhanced by the presence of acids. Deoxygenation with Ring Saturation Hydrogenolysis on saturation of aromatic phenols or phenyl ethers may range from a trivial to a major side reaction. and 2. of the carbon-oxygen bond in phenols cannot be depended on. Deoxygenation without Ring Reduction Hydrogenolysis. 10. Palladium may not be preferred for dihydric aromatics. Rhodium and ruthenium are especially useful if the phenol as phenyl ether also contains a benzyl substituent that is to be preserved. and a sharp decrease in the rate of absorption occurs at about 2 mol of consumed hydrogen. ruthenium. 250C) with loss of halogen (24). platinum and iridium tend to favor deoxygenation and are suggested if this reaction is desired. It is influenced also strongly by reaction parameters. and by polar solvents. PHENOLS AND DERIVATIVES 127 Because of the industrial magnitude of these processes. . and alkalinity. Palladium has a relatively low tendency to reduce aliphatic ketones.2.6-di-t-butylcyclohexanone (750 psig. Nickel may also be used but overhydrogenation is more apt to occur.3. it is diminished by nonpolar solvents and increased pressure (35).2. In most synthetic work where catalyst life and small variations in yield are not of great importance.2.4-dimethylcyclohexanone (27). and palladium at higher pressures are suggested when hydrogenolysis is to be avoided. Dihydroresorcinol was obtained in 87% yield by alkaline hydrogenation of resorcinol over 5% Rh-on-C (65) and in only 50-60% yield over Pd-on-C (15). 1. pore size. such as is formed by interaction of the phenol with 2-chlorobenzoxazole.4dimethylphenol to 2.5-dihydroxyphenylacetic acid over a 10% loading of 5% Rh-On-Al2O3 at 550C and 55 psig (39a). 10. without ring reduction. most palladium-on-carbon or -on-alumina powder catalysts will be found satisfactory for conversion of phenols to cyclohexanones.10. Examples of palladium-catalyzed reduction are 4-chloro-2. The extent of hydrogenolysis is influenced strongly also by the catalyst. but by conversion of the phenol to a better leaving group. by elevated temperatures.

70. The usual catalyst is palladium-on-carbon. Ring Saturation without Hydrogenolysis Hydrogenation of phenols to the corresponding saturated alcohols usually can be accomplished cleanly if appropriate conditions and catalysts are chosen.67). NCH 3 1. HYDROGENATION OF ANILINES. ethyl orsellinate OH 10% Pd-on-C H 3 C^ "V^ X)H COOC2H5 ~u °H H 2 O 5 KOH latmH2 25C H 3 C' OH COOC2H5 COOC2H5 Hydrogenolysis of 2-phenyltetrazolyl ethers has been accomplished cleanly.73).60.62'. using Pd-on-C and hydrazine or sodium phosphinate (13).4. but etherification to give 2 (R = CH3) permitted slow formation of 3.40. palladium was the preferred catalyst for achieving this reaction.Og (1) R = H (2) R = CH 3 (3) R = CH 3 T = 1-phenyltetrazolyl (44 Hydrogenolysis of 1-phenyltetrazolyl ether has been applied to deoxygenation of several heavily substituted phenols. hydrogenolysis could not be effected either directly or by catalytic hydrogen transfer (13). When R = H (1). 10.4. The mild conditions of hydrogenation were required to avoid racemization at the 6a-position. the reaction acquires synthetic utility (3J 1.77. PHENOLS AND DERIVATIVES or 2.128 10.35. An unusual sensitivity of this reaction to structure was reported by Ram and Neumeyer (51).2. At one time.6-trichloro-s-triazines.1 g 5 % Pd-on-C 45psigH 2 90 ml HOAc 25 0 C 11 days NCH 3 1. .49. for example. both elevated pressures (1000-2000 psig) and temperatures (801750C) usually being used (9. Hydrogenolysis is usually much more facile than is indicated by this example.

If pressure is available.o'-biphenol to o-(2-hydroxycyclohexyl)phenol (55). except that the catalyst was stored under water.68.26. direct oxidation of the reaction mixture with ruthenium trichloride and sodium hypochlorite via ruthenium tetroxide (78). An alternative to cyclohexanones from phenols involves ring saturation to the alcohol. hydrogenolysis rose with metal in the order Pd < Ru « Rh < Ir < Pt (47). Nowadays.52. The use of water as solvent permitted.69. Palladium may also show exceptional selectivities.20. as well as decreases whatever hydrogenolysis might occur at lower pressure. The ratio R of .45.39. the main product is not 4-cyclohexylcyclohexanol.28. as in the conversion of o. PHENOLS AND DERIVATIVES 129 In saturation of ethyl p-tolyl ether in ethanol solvent.8.69.72. using W-T Raney nickel as prepared by Billica and Adkins (6).38. If this latter reduction is continued in methanol solvent.74) are especially advantageous in reductions of sensitive phenols and phenyl ethers that undergo extensive hydrogenolysis over catalysts such as platinum oxide. after filtration of the catalyst. Hydroquinone can be reduced to the diol over 5% Rh-on-C at ambient conditions quantitatively (20). 16OmIH 2 O 10 gW-7 Ra-Ni 0. for increased pressure makes more efficient use of the catalyst. followed by oxidation (14). Rhodium (7.21.12. Rhodium can be used under mild conditions. 700psigH 2 14Og Hydrogenation of 2-naphthol can proceed at either ring with the general tendency to reduce the unsubstituted ring preferentially.65. whereas ruthenium needs elevated pressures.10. PtO2 HOAc 50 psigH 2 OH The sequence has been applied to the synthesis of 1.4-cyclohexanedione from hydroquinone (10).35 ml 50% ag NaOH 70 C. rhodium or ruthenium are often the preferred catalysts.68.75) and ruthenium (18. The various complex factors contributing to this ordering are discussed at length in this reference. but rather 4cyclohexylcyclohexyl methyl ether (84%) (56).2. it might as well be used even with rhodium.66. or p-phenylphenol to pcyclohexylphenol (90%).

Chem. 3. J. . Simpson. R. Synth. 7. W. S. Gogek. S. R. D. J. R. H. E. E. Grua. Org. 4747 (1980). J. 29. L. A. For example.0 8. 13. Soc. J. Chem. 34. Purves. Chem. Org. W. Webb. W. J. R. W. J. E. Y.C. and T. Billica and H. J.. Chem. Holker. 2. 12. 911 (1951). Sd. Tarbell. Chem. J. J.5 3. Jr. 2902 (1964). Gregonis. Bauer. Chem. Org. References R. J. again illustrating the efficiency of elevated pressures in decreasing hydrogenolysis. 48. H. Entwistle.130 10.3 Nishimura (41) developed a binary catalyst (30% Pt. OrQ. Chem. 204 (1973). E. Am.S. Chem. J. Cantor and D. 6. 11. C. Can. M. C. Barkdoll. W. 5. Barfnecht. 82. 47. Pierson. D. Acad. Hussey. Much higher yields of dicyclohexyl ether are formed over the binary catalyst at elevated pressures (42). 4. and over platinum oxide none of this product formed (53). Perkin Trans. Kirk. 70% Rh oxide) prepared by fusion of platinum and rhodium salts with sodium nitrate in the manner of the well-known preparation of Adams' PtO2 catalyst (31). V. J. U. E. and V. 10. C. W. Org. W. L. 2235 (1969). 1156(1953). N.2 9. PHENOLS AND DERIVATIVES unsubstituted ring saturation to phenolic ring saturation varies with the metal (48). 2138 (1970). R. Ann. 9. 7. O'Brien. Soc. 75. A. J. L. Tetrahedron Lett. Am. Epstein. R. 14. J. and G. 5466 (1960). E. 1366 (1983).S. A. 28. A. Brett. 21. Chem. Soc. Weaver. J. Chem. 667 (1983). and C. Burnham. England. J. Gray. B. Smith. Whitman. 1923 (1963). and T. 1.8 13. E. G. J. and D. C. Johnston. B. Reif. 86. I. Catalyst R Ru Rh Pd-on-C Os Ir Pt 7.341 (1968). J. 214. J. 8. R. 3. J. Dicyclohexyl ether can be obtained in 90% yield from diphenyl ether by saturation over 5% Pd-on-C in an ethanol solvent at 68 atm (43). Bithos. Can. 4a. hydrogenation of diphenyl ether over 30% Pt-70% Rh oxide at lower pressure gave dicyclohexyl ether in 50% yield. W. J.1074 (1975). A. J.376. D. Burgstahler and Z. VoI 3 176 (1955). Vag. 1070. Augustine and W. Adkins. whereas over rhodium oxide the yield was only 20%. 48. Bartlett. S. V. Coll. Christian. Augustine and L. Eisenbraun. 40. 1128 (1982). Am. Patent No. Eliel and T. R. J. Crawford. Org. E. This particular composition has been recommended when hydrogenolysis is to be avoided.3 9. HYDROGENATION OF ANILINES.

Coll. Keenan. Chem. P. J. 28. 216 (1972). Chem. Ann. Musliner and J. Khim. V. F. K. 39. S. Chem. Org. Chem. Soc. Freifelder and G. 129 (1951). Bychkova. Chem.93(\961). 3427 (1964). J. 132163 (1970). 7. Chem. N. Meyers and K. Am. Soc. Chem. Kalina and J. Engelhard Ind. R. S. 4271 (1966). Am. Jr. Jpn. R. Haas. Hart and F. P. Chem. 1267 (1951). S. Garcia-Munoz. R. Rylander and D. Hasbrouck. 49. and M. 42. Soc. 23. C. Nishimura. 54. O. Hara. 22. 28.. A. Kaspenko. J. Neumeyer. Z. C. N. 25. CA 72. L. S. E. J. 30. Soc. Catai 9. 14 (1968). 36. 27. L. Tech. S. Tech. Freidlin. Chem. 16. 36. 21. J. Suzuki. F. W. Soc. C. Hasbrouck and I.. 1. R. Engelhard Ind. 39. Org. N. Karpenko. R. Schiess. Soedin. 329 (1966). 44. 854 (1973). Sd. Greenfield. 19 (1962). C. Meet. F. and Y. W. Org. H. Chem. Soc. G. Bull. Chem. V. T. 44. 100 (1973). 2485 (1965). Jr. 34. Steele. A. Kirby. 670 (1969). I. Rylander. Yakubenok. J. Rylander and D. CA 79. J. C. 42. 2. Vysokomol. Cohn. Soc. Akad. N. 26. Tech. 37. W. 32. Bull. W. 325 (1971). H. Heterocycl. 43. 203 (1964). R. W. Rylander and M. J. 9. 58. E. Jpn. Kinet. A. G. 611. S. Katal. Haas. A. 29. Ger. K. R.Y. I. 38. Org. Pivonenkova. Soc. F. W. S. 33. Nishimura. A. Synth. Christy. Pharm.926 (1952). Org. 45. Matthew. Engelhard Ind. 86. R. 40. Chem. K. Frunze. Soc. Otsuki. Vaflor. Romanova. 566 (1960). V. Cassis.Y. Novello and M. Org. Nishimura.Bull. Am. Rylander and X. B. Giudici and T. Ed. 873 (1963). M. J. J. Offen 1. Kono. Rogier. K. G. Hindin. Hindin. 24. L. 5. and H. F. H. Northeast Reg. J. Jpn. H. Meyers. Jr. M. 240 (1971). 499 (1969). 3179 (1951). 18. I. Soc. S. Vol. 29.*. 78 (1968). Helgren. S. Assoc. 28. 718. 153 (1967). Chem. Chem. 59. Jpn. Am. Jpn. Ng. Patent No. 35. Takagi. 41. Kheifets. and H. 29. P.948. V. Chem. Acad. N. and A. Nishimura and H. Uramoto. Pond. 233 (1973). J. 49. Ackerman. 46. Kaye and R. Carlson. V. Chem. and G. Bull. 3082 (1964). Engelhard Ind. Gates. Starrick. I. S. 47. 6 (1963). Chem. Chem. N. 53. Chem. K. and Y. Jpn. E. Bull. Jpn. Uchino. Am. Am. P. Taguchi.S. 30. 48. Esch and H. Freifelder. J. J. Okada. J. Soc. Bull. Izv. P. 10 (3). T. Kuhn. Bull. J. J. Kilroy. Am. Ireland and P. E. Org. 56. Justus Liebigs Ann.. 6th (1974). 78. Y. Adv. 2194 (1968). V. 57 (1958). Chem. Org. 52. N. Mokotoff and R. Pond. 6322 (1956). Org. Rylander. Bull. Engelhard Ind. and T. Acad. Org. Ram and J. 25 (1961). W. E. J. Shu. Bull. Chem. V. B. Greenfield. 1. 41. 57. L. 54119 (1969). Ikeno. Yoshino. N. L. H. Ohbuchi. Watanabe. Org. Oparina. M. 44. 2436 (1947). Johnson. W. L. Adv. Chem. Ann. J. Ellis. 88. 47. . Rodig and L. 2557 (1984). E. 229 (1954). Stone. Farrissey. Chem. S. Chem. N.. M. 73. 3568 (1962).606.118 (1964). Nishimura. J. Y. Fukaya. Bull. Am. A. and F. 73. P. 214. Pasek. 574 (1969). and G. J. CA 71. Jpn. Chem. Hasbrouck. W. 57. Johnson. 733 (1957). Baburao. Oilman and G.566 (1970). Chem. Pearlman. Nishimura. Beverung. Steele. B. 20. Bruice. 17. J. M. Soc. 3. Smith. 409 (1974). Bull. J. Tech. Rylander. Yoshino. Soc. I. Am. E. Soc. R. H. 2386 (1970). R. Starkovsky. Paton. 27. 33. ScL 214. P. A. Korshak. Schaeffer. T. 31. A. and P. Iverson. Ikedate and S. 35. Catai 3. Chem. Cavestri. Jpn.. J. S. 4372 (1982). G. H. Nishimura. Bull. 76. G. Pendergrass. 19. and Z. Soc. 51. Frulla. Soc. Karpenko. Chem. Sd. M. Litvin. and J. Maxted. 325 (1963). Gieseman. Soc. U. Driesen. Justus Liebigs Ann. N. 39. H. Bull. M. S. P. Nauk SSSR1 Ser. 39a. T. Chem. 26. J. I. A. J. C. 69. 31603(1973). Bull. 50. 2197 (1961). Levin and J. and S. 786 (1960).REFERENCES 131 15. V. and H. 518 (1959). Kuhn and H. and Y. Nishimura and H. 55. Tech. Chem. 45.

A. H. W.) 64. Sundin. Hamamoto. Theimer. J.817. 37. 2010 (1980). Hruby. Catal. Westrich.S.127 (1960). 83. T. J. 2119 (1965). V. Newhall. 3. Chem. Ind. Soc. H. H. P.). A. Trav. Takagi. Jr. 45. Eng. Kieboom. C. K. Goodmonson in "Catalysis of Organic Reactions" (J.S. Kosak. Weaver. HYDROGENATION OF ANILINES. Phys. Y. 727 (1957). 69.644 (1957). W. C. R. 65. 2739 (1961). E. Nishimura. E. 38. 66. 187 (1973). 76. J. 2849 (1972). ed. J. J. Ind. G. Am. 61. U. Traverse. N. J. H. Morrison. S. 1984. and F. 74. Smith. Pays-Bas 93. Org. and D. U. Chem.586 (1965). Chem. A. W. Ohtani.S. Chem. Wolfe. H. F. E. C. Whitehead. M.. T. PHENOLS AND DERIVATIVES 60. Wilson. 279. Thompson. 39 (1970). Res. Scaros. C. I. D. Smith and B. G. W. 26. and L. (London). 2. Winans. Chem. A.. Am. Tetrahedron Lett. G. F. J. 63. J. Newey. Robinson. E. and J. S. J. Van Muijlwijk. 32. Haginiva. J.. ScL Pap. T. A. Kluender. Haven. and S.2823(1983). Naito. A. 64. Eisenbraun. Johnston. 75. Patent No. C. Chem.. Chem.132 10. J. 72. Y.927. J. P. Hoffman. Adv. Kabo. and J. A. Patent No. Boekelheide. Campbell. 2809 (1961). 78. Am. and J. Chem. 67. M. Stump. M. Hasan. Jpn. M. J. A. E. T. 68. J. Chem. A. P. 70. J. F. Kwart. G. 71. Commun. 37. W. U. H. S. R. J. E. Chim. 77. Habdas. and O. Takagi. Marshall. Jr. J. Soc. 78. Wharton. Rec. Y. Sommerville. 1489 (1969). 1215 (1940). 204(1974). Shine. and H. 9. Chem. 4760 (1956). Soc. and H. L. Inst. J.34 (1972). 73. Sakai. D. L. New York. p. Dekker. C. C. E. Johnson. Patent No. S. Org. 2. Chem. Harris. Chem. Shokal and H.167. Horgan. Smith and R. Walton. S. 1420 (1970). and E. Jr. Org. Holly. Witte and V. (Jpn.. Bull. K. Wakabayashi. 62. Dryden. Org. Filppo. . 105. Van Bekkum.Soc. L. Brechbiel. Takahashi. A. Viswanatha and V. F. W.

123) tend to favor hydrogenation. oxygen-containing rings are reduced more easily than are nitrogen rings owing in part to self poisoning of the latter by loss of aromaticity with consequent increased base strength and increased tendency to adsorb preferentially on catalyst sites. Further hydrogenation over prereduced platinum oxide saturated the olefin as well to methyl hexahydrohardwickiate (64).1. 11. pyridines.18. Both types of reduction have wide synthetic application. Rhodium-on-carbon or 70% Rh-30% Pt oxide selectively reduced the furan ring of methyl hardwickiate. Furans Furans undergo both saturation and hydrogenolysis with the tendency toward hydrogenolysis increasing with increasing temperature. pyrimidines.73.99).39. leaving the trisubstituted conjugated olefin intact.96). Ring Saturation A variety of compounds fall into this category. In general. and rhodium (11. quinolines.1. ruthenium (77. as is general for this catalyst (69. The Nishimura catalyst (70% Rh-30% Pt oxide) tends also to favor hydrogenation rather than hydrogenolysis. among which are pyrroles.1.70). 133 .86.115). becoming at 250-30O0C very extensive (17.76. Palladium (13. The catalyst may have a marked influence on the course of reduction.45. and furans.11 Hydrogenation and Hydrogenolysis of Heterocycles Two types of heterocyclic compounds are discussed in this chapter: those that undergo saturation and those that undergo fission of the heterocyclic ring.18). 11. Hydrogenolysis is favored also by the presence of acid (54. Oxygen-containing rings are also more likely to undergo hydrogenolysis.

75.52. and.23. In some cases Pt-on-C proved superior to either Rh-on-C or PtO 2 .81.72'.5disubstituted pyrrolidines.2. Indoles Indoles are reduced with relative difficulty (12. Pyrroles Pyrroles are hydrogenated with more difficulty than are carbocyclic aromatics. hydrogenation will proceed nonselectively or with preference for the carbocyclic ring (19). 30% PtO AcOH COOH 26-c.88.24. (2.82). In compounds containing both rings.80).63. COOH A variety of solvents have been used successfully. N-Acetylindoles are reduced at the . HYDROGENATION AND HYDROGENOLYSIS OF HETEROCYLES Rh-on-C or 70% Rh.1. depending on structure.1 16).15. Under these conditions O-benzyl groups are retained and 2. Kaiser and Muchowski (41) reduced Af-(r-butoxycarbonyl) pyrroles to the corresponding pyrrolidines over 5% Pt-on-C at room temperature and atmospheric pressure.1. Acidic solvents are frequently used but are not necessary.i. attack presumably occurring on the intermediate vinyl ether (58). either ring may be reduced. but nowadays supported rhodium is apt to be the catalyst of choice.5-disubstituted pyrroles are reduced mainly or exclusively to the ds-2.3. 11. Extensive hydrolysis or alcoholysis may accompany reduction in aqueous or alcoholic solvent. Excellent results have been reported by Freifelder (32) using RuO 2 without solvent at 100-20O0C and 1500 psig. unless reduction of the carbocyclic ring is impeded by substituents.134 11. Platinum oxide has been used with success (6.35.u.H. 11.

catalytic hydrogenation of pyridines containing a carbocyclic aromatic ring. This difficulty can be circumvented completely by use of ruthenium (29. The relative effectiveness of catalysts depends on the reaction conditions and solvent (84). a choice stemming from a long history of success. For example.113). PtO2 NH 2 + Cl 25 C. An interesting system requiring specifically hydrobromic acid has been reported (10). but as severity of the conditions is increased. differences among catalysts diminish. which in turn are more easily reduced than the free bases. RING SATURATION 135 nitrogen ring more selectively than are unsubstituted indoles. EtOH.1. This usual selectivity can be reversed if reduction is carried out in concentrated. Industrial producers of reduced pyridines tend toward palladium or ruthenium.1. Nalkylation may become a troublesome side reaction. Acidic media favor selective reduction of the nitrogen ring (14. 1 atm 0 Selectivity may be a function of pressure as well as solvent. whether fused or detached. (16) on the hydrogenation of 4. HOAc. This sequence of activities offers a possibility for controlling selectivity in complex compounds. combining a satisfactory rate with economical use. Rhodium is the most active under mild conditions. and especially the more basic piperidine (30).3.124). 50 psig.33).40. and reduction of quinoline or isoquinoline (120) gave high yields of the 1. Pyridines and Derivatives Many pyridines have been hydrogenated with diverse catalysts. but N-alkyl compounds are reduced with more difficulty (110). 6O0C) gave quantitative yields of 4-benzylpiperidine (34). as illustrated by hydrogenation of isoquinoline hydrochloride (36).7-phenanthroline in . Nickel requires high temperatures and pressures. 1 atm). Acidic solvents are commonly used to prevent catalyst inhibition by the basic nitrogen atom of the substrate (62).2.97. Formation of pyridinium ions. Platinum is often used. besides diminishing inhibition. 250C. reduction of 4-benzylpyridine (5% Rh-on-C. occurs preferentially in the nitrogen ring.11.42. strong acid (112. 11. Palladium makes the most selective metal for hydrogenation of only one ring in bipyridyls (85). and if lower alcohols are used as solvents. Normally. is thought to change the nature of adsorption from edgewise to flat (95).4. as suggested by the data of Cardellini et al.4-tetrahydro derivative (PtO 2 . Quaternary pyridinium salts are reduced more readily than are hydrohalide salts.

Wenkert et al. PtO2 CF3COOH NCOCH3 NCOCH3 (2) (CH3CO)2O N NCOCH3 4% 2% 5% 22% 50 psig 15psig 11. Eisner (27).4. •C—CH 3 ° 3atmH 2 2 50 ml abs ElOH 5g5%Pd-on-C > (1) 45 g (2) 70% Other examples are cited by Wenkert and Wickberg (117).1.1. (118). Partial Hydrogenation Most pyridines are reduced to the corresponding piperidines. OHRa Ni or Pd(OH)2-On-BaSO4 RNHCH 2 CH 2 CH 2 CH 2 CHO . HYDROGENATION AND HYDROGENOLYSIS OF HETEROCYLES trifluoroacetic acid. a compound that resisted further attempts at reduction (31). H 2 . absorption may cease at this stage. (118) noted that in hydrogenation of any aromatic system capable of unmasking a stable.57). notably 2-amino and 2-hydroxy. vinylogous amide unit. tend to arrest the hydrogenation at the tetrahydro stage (55. and VanBergen and Kellogg (111). NCOCH3 (1) H 2 . here lower pressure favors reduction of the carbocyclic ring. Partial hydrogenation of AT-alkylpyridinium salts in hydrolytic media provides a convenient route to co-alkylaminovaleraldehydes (87). An example is reduction of 3-acetylpyridine (1) to 2. but certain substituents.56.136 11. Wenkert et al.

RING HYDROGENOLYSIS 137 11. Ring Hydrogenolysis Heterocyclic rings do not undergo hydrogenolysis readily unless they are strained.2.79).g.114). or in acidic solution so as to give the most stable carbocation (60).61. or contain a weak bond.2.37. or fewest substituents (100). Decarboxylation Hydrogenation of 3-pyridinecarboxylic acids is apt to be accompanied by extensive decarboxylation (28).2.2. (38. 11.98) and/or by use of elevated pressures (66).11. Ruthenium (33). for either carbon-oxygen bond may break with or without inversion of configuration. but this unwanted reaction can be prevented by carrying out the reaction in the presence of one equivalent of base (33. whose reductions have proved very useful in syntheses. and structure of the substrate as a whole. 11. e. or at the weakest bond (3. nor in what direction. but these exceptions constitute a wide variety of compounds.1 Oxiranes Hydrogenation of epoxides lends itself well to both synthetic applications and mechanistic studies. which carbon-oxygen bond will be broken. Its occurrence may be eliminated or greatly curtailed by the addition of small amounts of alkali (67. are activated by unsaturation. without a close analogy.1.59).4.1. . Various investigators have concluded that ring opening will occur at the carbon atom with the least steric hindrance (83). environment.119. The reaction is especially sensitive to both catalyst and environment (74).121).. N—O. It is difficult to form any rule that does not include catalyst.1. and the product may contain deoxygenated products (92.93) as well as ketones derived by isomerization (26). It is not easy to deduce. rhodium (29).2. and palladium (30) have all proved effective catalysts for reduction of pyridinecarboxylic acids to the saturated acid. Deoxygenation Deoxygenation may occur to an unacceptable extent. 11. platinum oxide (28. The reaction is complex.68.

2. Raney nickel opens ds-2. (1). the direction of ring opening is such as to give the axial alcohol. A marked influence of alkali on regiospecificity is found in the hydrogenation of 1.and stereospecificity may be influenced by the catalyst and by alkali. as illustrated in selected data of Accrombessi et al. Additionally.and ds-4-r-butylcyclohexene epoxides. Alcohols tend to favor loss of oxygen. 10 %Pd-on-C 1 atm.3-diphenylbut-2-ene epoxide with retention of configuration to give £ryf/iro-2.2-epoxydecane (68).and ethoxycyclohexanols. regardless of solvent (1). whereas palladiumon-carbon gives the inverted threo isomer.2.138 11.1. 10%Pd-on-C _ » 10% Pd-on-C O OH Both regio. Direction of Ring Opening In conformationally fixed trans.3-diphenylbutan-2-ol. I g NaOH QJ_J 96% . 20 C % Hydrocarbon Solvent 2-Propanol Ether Cyclohexane From cis isomer 20% 8% trace From trans isomer 72% 54% 8% 11. methanol and ethanol may give substantial amounts of solvolysis products. CH 3 (CH 2 J 7 CH 2 CH 2 OH < ^^ IgRa-Ni 15OmIEtOH 90% 1Og CH 3 (CH 2 J 7 CH-CH 2 O ^^ ' CH 3 (CH 2 J 7 CHCH 3 IgRa-Ni 15OmIEtOH O. nickel too gives the threo isomer (65). If a small amount of alkali is added to nickel-catalyzed reductions. HYDROGENATION AND HYDROGENOLYSIS OF HETEROCYLES Deoxygenation is sensitive to solvent and structure. in this case methoxy.

and (9)] arising from saturation of the 4. RINGHYDROGENOLYSIS 139 Hydrogenation of styrene oxide over palladium in methanol (66) gives exclusively 2-phenylethanol. the problem can be eliminated by portion-wise addition of the epoxide to the reaction.2.2. reaction parameters.6-tetrahydropyridines 3 and 4 (25). like oxiranes.108). Aziridines Aziridines. but in buffered alkaline methanol the product is 1-phenylethanol. Benzene solvent or alkali favor retention over palladium as well. Raney nickel. hydrogenolysis of 2-methyl-2phenylaziridine in ethanol occurs mainly with inversion over palladium but with retention over platinum.5-olefinic bond in the 1.11. (7).2. so as always to maintain a high catalyst-to-substrate ratio.3. Ring opening occurs mainly at the least hindered carbon-nitrogen bond. and various additives (65aJ08). undergo hydrogenolysis easily with or without inversion of configuration. (8). If alcoholysis of the epoxide by the product is troublesome. The intermediacy of an aziridine (5) was invoked to account for the unexpected array of products [(6).101. The technique is general for reactions in which the product can attack the starting material in competition with the hydrogenation.102. a OCH3 C=O o NHCO-r-Bu or Pd-on-C NHCO-f-Bu C=O I CH3 (4) ra NT ^OH I C=O NCO-f-Bu H I C=O I OCH3 (5) (3) O O NHCO-f-Bu + C=O NHCO-r-Bu I C=O C=O OCH3 (7) OCH3 (6) OCH3 OCH3 (8) (9) .2. 11. For example. unless the more hindered is activated by unsaturation or aromatic substituents (53. depending on the catalyst. or Raney cobalt.

COOC2H5 O 0. Neutral or alkaline media are frequently used. have been used to prepare a number of diketones (44) and tetraones (43). HYDROGENATION AND HYDROGENOLYSIS OF HETEROCYLES 11. Isoxazolines Kozikowski and Adamczyk (46) developed an excellent procedure for conversion of isoxazolines to /Miydroxy ketones without any epimerization at . followed by hydrogenolysis and hydrolysis. Alkylation of 3.2glO%Pd-n-C EtOH NH 2 O ~100% CH3OH-HOAc Ra-Ni COOC2H5 NH 2 O Hydrogenolysis of methylenediisoxazoles have been useful in preparing substituted resorcinols and aminophenols (7). The isoxazole annelation reaction (71. Isoxazoles Isoxazoles are stable toward many reagents yet undergo alkylation and hydrogenolysis readily. 2SmICH 3 OH PtO2 ^x\^. which may be considered masked diketones.90. but platinum and nickel have been used successfully. a vinylogous amide (9).4.91. Palladium is usually used in the hydrogenolysis of isoxazoles.\r/^'6**13 f T Il .2.3.2. Isoxazoles can be opened readily to the amino ketone. a useful grouping in synthesis (22). C6H13 latmH2 25*c ' HOC NH 2 O O Il Isoxazoles are reduced more easily than are isoxazolines and may be opened selectively (8).103) is well suited to the synthesis of steroids and other complex molecules. 11.89. The rate of hydrogenolysis may be affected markedly by the pH (104).5-dimethylisoxazole. These features make isoxazoles.140 11.

11.50).2. Their procedure was based on the observation that extensive epimerization occurred when W-2 Ra Ni. The isoxazolines were prepared by a [3 + 2] cycloaddition.] Q „„ / RaNi Q * x OH ) ' PPTS XT OTHP HO THPO = tetrahydropyranyl PPTS = pyridinium p-toluenesulfonate A two-step sequence of nitrile oxide-olefin cycloaddition and reduction of the resulting A2-isoxazolines offers a unique and attractive alternative to the classical aldol reaction and its many variants (21).NO2 !hNCO^ rnipoCHateN. . To prevent this. The procedure bypasses traditional problems. even though the hydroxy ketone did not undergo epimerization in acetic acid. . and the yield of hydroxy ketone was nearly quantitative. the reduction was carried out over W-2 Ra-Ni with 4 equiv of concentrated HCl in 5:1 methanol-water. O R2 OH Hydrogenolytic cleavage of isoxazolines has also proved useful in preparation of /?-dihydroxy ketones and /J-hydroxy carboxylic acids (47). RING HYDROGENOLYSIS 141 the a-asymmetric center. and acetic acid (122) or Pd-on-C and acetic acid (5) was used for the hydrogenolysis. including enolate equilibrium and cross condensation (20). No trans isomer formed. The same results were achieved with W-2 Ra Ni and 4 equiv of AlCl3 in 5:1 methanol-water. Raney nickel and boric acid appear equally as effective (21. These facts suggested that epimerization must occur at the /f-hydroxyimine stage via a tautomeric enamine._0.




By selection of conditions and catalyst, the intermediate hydroxyimine (11) can be directed to either the hydroxy ketone (10) or amino alcohol (12). Over platinum oxide in methanol-acetic acid-water the amino alcohol forms, whereas over alkali-free Ra-Ni in methanol-water or over 10% Pd-on-C in methanol-water containing boric acid, the hydroxy ketones form in excellent yield. Nitrile oxide cycloadditions have been applied to five-membered ring syntheses (50).
N—o ciEt3N



3equivHOAc CH 3 OH 1 H 2 O H2 W-2 Ra-Ni







Hydrogenation was accomplished over freshly prepared W-2 Ra-Ni in a 5:1 methanol-water mixture containing 3 equiv of acetic or boric acid. The hydrogenolysis has been applied smoothly to the synthesis of C-nucleosides

Reduction of 3,5-dimethylisoxazolo[5,4-b]pyridine over 5% Pd-on-C proceeded with loss of the aromatic system to give 3-(l-aminoethyliden)-5methyl-2-oxopiperidine (94). The product is a vinylogous amide, a type of structure resistant to further hydrogenation (118).

5% Pd-on-C ^ 6OaImH 2 25 0 C, acetone



A formal total synthesis of the prostaglandin F2a involved unmasking of an isoxazoline ring by hydrogenation over W-2 Raney Ni/BCl 3 /MeOH, H 2 O to reveal a /J-hydroxyketone. It was necessary in this case to deactivate the Raney



Ni prior to use by refluxing it for 3 h with acetone, in order to suppress hydrogenolysis of the benzylic protecting groups (51).
0.065ml 1 MBCl 3 SOmgRaNi 6 ml 5:1 CH 3 OHrH 2 O 1 aim H2 30min

OCH 2 OCH 2 Ph
30 mg



OCH 2 OCH 2 Ph

11.2.5. Oxazoles and Oxazolines
Extreme differences between 5% palladium-on-carbon and platinum oxide were found on reduction of the 5-aryl substituted oxazole 14. Over palladium, 15 was formed in quantitative yield by hydrogenolysis of the benzyl hydroxyl, whereas over Pt, scission of the oxazole occurred to give 13 quantitatively (48). Hydrogenation of 15 over platinum oxide gave the phenethylamide 16. OCH3

H2 PtO2

Pd-on-C HOAc '


CH 3 O

CH 3 O





A more expected difference between platinum oxide and palladium-oncarbon was found in the hydrogenolysis of 5-phenyl-2-(3,4-dimethoxybenzyl)2-oxazoline. Cleavage occurred at the benzyl-oxygen bond over both catalysts, but over platinum, the less substituted phenyl group was saturated as well (78).

4 ml HCl 200mglO%Pd-on-C 100 ml EtOH


100 ml EtOH 50 psig 50 mgPtO 2 4 ml coned HCl

O / V (CH 2 J 2 NHCCH 2



V(CH 2 )NHCCH 2 -/



1. G. C. Accrombessi, P. Geneste, J. L. Olive, and A. A. Pavia, J, Org. Chem. 45, 4139, (1980). 2. R. Adams, S. Miyano, and D. Fles, J. Am. Chem. Soc. 82, 1466 (1960). 3. E. A. Adegoke, P. Ojechi, and D. A. H. Taylor, J. Chem. Soc., 415 (1965).

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M. Asaoka, T. Mukuta, and H. Takei, Tetrahedron Lett. 22, 735 (1981). J. H. Atkinson, R. Grigg, and A. W. Johnson, J. Chem. Soc., 893 (1964). S. Auriccho, S. Morrocchi, and A. Ricca, Tetrahedron Lett., 2793 (1974). P. G. Baraldi, A. Barco, S. Benetti, F. Moroder, G. P. Pollini, and D. Simoni, J. Org. Chem. 48,1297(1983). 9. A. Barco, S. Benetti, G. P. Pollini, B. Veronesi, P. G. Baraldi, M. Guarneri, and C. B. Vicentini, Synth. Commun. 8, 219 (1978). 10. D. F. Barringer, Jr., G. Berkelhammer, S. D. Carter, L. Goldman, and A. E. Lanzilotti, J. Org. Chem. 38, 1933(1973). 11. E. R. Bissell and M. Finger, J. Org. Chem. 24, 1259 (1959). 12. V. Boekelheide and C.-T. Liu, J. Am. Chem. Soc. 74,4920 (1952). 13. D. P. Brust, D. S. Tarbell, S. M. Hecht, E. C. Hay ward, and D. L. Colebrook, J. Org. Chem. 31,2192(1966). 14. I. Butula and R. Kuhn, Angew. Chem. Int. Ed. Engl. 7, 208 (1968). 15. P. A. Cantor and C. A. VanderWerf, J. Am. Chem. Soc. 80, 970 (1958). 16. M. Cardellini, G. M. Cingolani, F. Claudi, G. Cristalli, U. Gulini, and S. Martelli, J. Org. Owm. 47, 688 (1982). 17. N. I. Chouikine and I. F. Belsky, Dokl. Akad. Nauk SSSR 115, 330 (1957). 18. N. I. Chouikine and I. F. Belsky, Actes Congr. Int. Catal, 2nd, I960, 2, 2625 (1961). 19. L. C. Craig and R. M. Hixon, J. Am. Chem. Soc. 52, 804 (1930). 20. D. P. Curran, J. Am. Chem. Soc. 104,4024 (1982). 21. D. P. Curran, S. A. Scanga, and C. J. Fenk, J. Org. Chem. 49, 3474 (1984). 22. S. D'Alcontres, Gazz. Chim. Ital. 80, 441 (1950). 23. O. Dann and W. Dimmling, Ber. Dtsch. Chem. Ges. 86, 1383 (1953). 24. L. J. Dolby, S. J. Nelson, and D. Senkovich, J. Org. Chem. 37, 3691 (1972). 25. S. K. Dubey and E. E. Knaus, Can. J. Chem. 61, 565 (1983). 26. J. C. Duchet and D. Cornet, Bull. Soc. Chim. Fr., 1135, 1141 (1975). 27. U. Eisner, Chem. Commun., 1348 (1969). 28. M. Freifelder, J. Org. Chem. 27, 4046 (1962). 29. M. Freifelder, J. Org. Chem. 28, 1135 (1963). 30. M. Freifelder, Adv. Catal. 14, 203 (1963). 31. M. Freifelder, J. Org. Chem. 29, 2895 (1964). 32. M. Freifelder, "Practical Catalytic Hydrogenation," p. 577. Wiley (Interscience), New York, 1971. 33. M. Freifelder, and G. R. Stone, J. Org. Chem. 26, 3805 (1961). 34. M. Freifelder, R. M. Robinson, and G. R Stone, J. Org. Chem. 27, 284 (1962). 35. D. W. Fuhlhage and C. A. VanderWerf, J. Am. Chem. Soc. 80, 6249 (1958). 36. J. Z. Ginos, J. Org. Chem. 40, 1191 (1975). 37. W. Herz, R. C. Ligon, H. Kanno, W. H. Schuller, and R. V. Lawrence, J. Org. Chem. 35, 3338 (1970). 38. L. Horner and E. Jurgens, Ber. Dtsch. Chem. Ges. B 90, 2184 (1957). 39. J. W. Huffman and L. E. Browder, J. Org. Chem. 29, 2598 (1964). 40. M. Janot, J. Keufer, and J. LeMen, Bull Soc. Chim. Fr., 230 (1952). 41. H. P. Kaiser, and J. M. Muchowski, J. Org. Chem. 49, 4203 (1984). 42. P. Karrer and P. Waser, HeIv. Chim. Acta 32, 409 (1949). 43. C. Kashima, J. Org. Chem. 40, 526 (1975). 44. C. Kashima, S. Tobe, N. Sugiyama, and M. Yamamoto, Bull. Chem. Soc. Jpn. 46, 310 (1973). 45. D. D. Kaufman, L. R. Worden, E. T. Lode, M. K. Strong, and N. C. Reitz, J. Org. Chem. 35, 157(1970). 46. A. P. Kozikowski and M. Adamczyk, Tetrahedron Lett. 23, 3123 (1982).



47. A. P. Kozikowski and M. Adamczyk, J. Org. Chem. 48, 366 (1983). 48. A. P. Kozikowski and A. Ames, J. Org. Chem. 45, 2550 (1980). 49. A. P. Kozikowski and S. Goldstein, J. Org. Chem. 48, 1141 (1983). 50. A. P. Kozikowski and P. D. Stein, J. Am. Chem. Soc. 104, 4023 (1982). 51. A. P. Kozikowski and P. D. Stein, J. Org. Chem. 49, 2301 (1984). 52. L. R. Kray and M. G. Reinecke, J. Org. Chem. 32, 225 (1967). 53. N. J. Leonard, K. Jann, J. V. Paukstelis, and C. K. Steinhardt, J. Org. Chem. 28,1499 (1963). 54. T. E. Londergan, N. L. Hause, and W. R. Schmitz, J. Am. Chem. Soc. 75, 4456 (1953). 55. R. E. LyIe and G. G. LyIe, J. Am. Chem. Soc. 76, 3536 (1954). 56. R. E. LyIe and S. E. Mallett, Ann. N.Y. Acad. Sd. 145, 83 (1967). 57. R. E. LyIe, E. F. Perlowski, H. J. Troscianiec, and G. G. LyIe, J. Org. Chem. 20,1761 (1955). 58. G. Lukas, J. C. N. Ma, J. A. McCloskey, and R. E. Wolff, Tetrahedron 20, 1789 (1964). 59. S. M. McElvain and R. Adams, J. Am. Chem. Soc. 45, 2738 (1923). 60. F. J. McQuillin and W. O. Ord, J. Chem. Soc., 3169 (1959). 61. F. B. Mallory and S. P. Varimbi, J. Org. Chem. 28, 1656 (1963). 62. E. B. Maxted and A. G. Walker, J. Chem. Soc., 1093 (1948). 63. J. Meinwald and H. C. J. Ottenheym, Tetrahedron 27, 3307 (1971). 64. R. Mistra, R. C. Pandey, and S. Dev, Tetrahedron 35, 2301 (1979). 65. S. Mitsui and Y. Nagahisa, Chem. Ind. (London), 1975 (1965). 65a. S. Mitsui and Y. Sugi, Tetrahedron Lett., 1287, 1291 (1969). 66. S. Mitsui, S. Imaizumi, M. Hisashige, and Y. Sugi, Tetrahedron 29,4093 (1973). 67. S. Mitsui, Y. Sugi, M. Fujimoto, and K. Yokoo, Tetrahedron 30, 31 (1974). 68. M. S. Newman, G. Underwood, and M. Renoll, J. Am. Chem. Soc. 71, 3362 (1949). 69. S. Nishimura, Bull. Chem. Soc. Jpn. 33, 566 (1960). 70. S. Nishimura and H. Taguchi, Bull. Chem. Soc. Jpn. 36, 873 (1963). 71. M. Ohashi, H. Kamachi, H. Kakisawa, and K. G. Stork, J. Am. Chem. Soc. 89, 5460 (1967). 72. C. G. Overberger, L. C. Palmer, B. S. Marks, and N. R. Byrd, J. Am. Chem. Soc. 77, 4100 (1955). 73. L. A. Paguette, A. A. Youssef, and M. L. Wise, J. Am. Chem. Soc. 89, 5246 (1967). 74. G. J. Park and R. Fuchs, J. Org. Chem. 22, 93 (1957). 75. J. M. Patterson, J. Brasch, and P. Drenchko, J. Org. Chem. 27, 1652 (1962). 76. C. W. Perry, M. V. Kalnins, and K. H. Deitcher, J. Org. Chem. 37, 4371 (1972). 77. A. A. Ponomarev and A. S. Chegolya, Dokl. Akad. Nauk SSSR 145, 812 (1962). 78. L. N. Pridgen, L. B. Killmer, and R. L. Webb, J. Org. Chem. 47, 1985 (1982). 79. M. S. Raasch, J. Org. Chem. 27, 1406 (1962). 80. H. Rapoport, C. B. Christian, and G. Spencer, J. Org. Chem. 18, 840 (1954). 81. B. Robinson, Chem. Rev. 69, 785 (1969). 82. M. M. Robison, F. P. Butler, and B. L. Robison, J. Am. Chem. Soc. 79, 2573 (1957). 83. J. M. Ross, D. S. Tarbell, W. E. Lovett, and A. D. Cross, J. Am. Chem. Soc. 78, 4675 (1956). 84. P. N. Rylander and D. R. Steele, Engelhard Ind. Tech. Bull. 3, 19 (1962). 85. P. N. Rylander and D. R. Steele, Engelhard Ind. Tech. Bull. 5, 113 (1965). 86. P. N. Rylander and D. R. Steele, Engelhard Ind. Tech. Bull. 7, 153 (1967). 87. C. Schopf, G. Herbert, R. Rausch, and G. Schroder, Angew. Chem. 69, 391 (1957). 88. E. E. Schweizer and K. K. Light, J. Org. Chem. 31, 870 (1966). 89. J. W. Scott and G. Saucy, J. Org. Chem. 37, 1652 (1972). 90. J. W. Scott, B. L. Banner, and G. Saucy, J. Org. Chem. 37, 1664 (1972). 91. J. W. Scott, R. Borer, and G. Saucy, J. Org. Chem. 37, 1659 (1972). 92. G. Senechal and D. Cornet, Bull. Soc. Chim. Fr., 773 (1971). 93. G. Senechal, J. C. Duchef, and D. Cornet, Bull. Soc. Chim. Fr., 783 (1971). 94. C. Skotsch, I. Kohlmeyer, and E. Breitmaier, Synthesis, 449 (1979).

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R. M. Skomoroski and A. Schriesheim, J. Phys. Chem. 65, 1340 (1961). H. A. Smith and J. F. Fuzek, J. Am. Chem. Soc. 71,415 (1949). A. Smith and J. H. P. Utley, Chem. Commun., 427 (1965). A. Sohma and S. Mitsui, Bull. Chem. Soc. Jpn. 43,448 (1970). D. Starr and R. M. Hixon, J. Am. Chem. Soc. 56, 1595 (1934). H. E. Stavely, J. Am. Chem. Soc. 64, 2723 (1942). C. L. Stevens and P. M. Pillai, J. Org. Chem. 37 173 (1972). C. L. Stevens, J. M. Cahoon, T. R. Potts, and P. M. Pillai, J. Org. Chem. 37, 3130 (1972). G. Stork and J. E. McMurry, J. Am. Chem. Soc. 89, 5463, 5464 (1967). G. Stork, S. Danishefsky, and M. Ohashi, J. Am. Chem. Soc. 89, 5459 (1967). Y. Sugi and S. Mitsui, Bull. Chem. Soc. Jpn. 42, 2984 (1969). Y. Sugi and S. Mitsui, Bull. Chem. Soc. Jpn. 43, 1489 (1970). Y. Sugi, M. Nagata, and S. Mitsui, Bull. Chem. Soc. Jpn. 48, 1663 (1975). T. Toth and A. Gerecs, Acta. Chim. Acad. Sd. Hung. 67(2), 229 (1971); CA 74,125322 (1971). T. J. VanBergen and R. M. Kellogg, J. Org. Chem. 36, 2256(1971). F. W. Vierhapper and E. L. Eliel, J. Am. Chem. Soc. 96, 2256 (1974). F. W. Vierhapper and E. L. Eliel, J. Org. Chem. 40, 2729 (1975). G. N. Walker, J. Org. Chem. 27, 1929 (1962). I. D. Webb and G. T. Borcherdt, J. Am. Chem. Soc. 73, 752 (1951). B. Weinstein and A. R. Craig, J. Org. Chem. 41, 875 (1976). E. Wenkert and B. Wickberg, J. Am. Chem. Soc. 87,1580 (1965). E. Wenkert, K. G. Dave, E. Haglid, R. G. Lewis, T. Oishi, R. V. Stevens, and M. Terashima, J. Org. Chem. 33, 747 (1968). W. F. Whitmore and A. L. Gebhart, J. Am. Chem. Soc. 64, 912 (1942). G. Witkop, J. Am. Chem. Soc. 70, 2617 (1948). B. Witkop and C. M. Foltz, J. Am. Chem. Soc. 79, 197 (1957). R. H. Wollenberg and J. E. Goldstein, Synthesis, 757 (1980). K. Yamakawa and M. Moroe, Tetrahedron 24, 3615 (1968). D. V. Young and H. R. Snyder, J. Am. Chem. Soc. 83, 3161 (1961).

Catalytic Dehydrohalogenation
Most halogen-carbon bonds are cleaved easily by catalytic dehydrohalogenation. The hydrogenolysis can often be done selectively in the presence of other easily reducible groups (14,25,64). In molecules containing several halogens, one can often be removed preferentially. A useful way of making an aldehyde is by cleavage of a halogen-acyl bond, a procedure known as the Rosenmund reduction.

12.1. Catalysts
Catalysts differ widely in their ability to effect dehydrohalogenation. Palladium is usually the catalyst of choice. Platinum and rhodium are relatively ineffective and are often used in hydrogenations when halogen is to be preserved. A sequential use of platinum and palladium is illustrated in




(2) 148




hydrogenation of the lactones 1. The initial reduction over platinum oxide gave l-j?-bromosantanolide "c" (2); further reduction over palladium-oncarbon gave 3 (33). In some molecules, the loss of halogen is unexpectedly facile and may occur extensively even over platinum, as illustrated by reduction of the dihydro-2benzazepine 4 to 5. The authors (53) raised the possibility that such facile loss of halogen may involve neighboring-group assistance from the amide moiety.



Nickel catalysts have been used for many dehydrohalogenations (30), but these catalysts are much more suspectible to poisoning by halide ion than are noble metals. As a result, the catalyst-to-substrate ratio must be much higher when using nickel, and reduction times are apt to be lengthy (56). Reductive deiodination of 6 to 7 was achieved over Raney nickel in methanol containing triethylamine. Despite massive loadings, the reduction was slow (20).
CH 2 I

CH 3
2 ml (C 2 Hs) 3 N 1OgRaNi

I— o KOH A
H(V^ /OCH3
/ y-v ¥ ¥



15OmICH 3 OH 2.7atmH2 25°C,48h

N°H /


6.45 g

12.2. Basic and Acidic Media
It is a common practice to add 1 mol or more of a base to dehydrohalogenations to minimize inhibition by the liberated hydrogen halide (3,18). The powerful inhibiting effect of halogen halide is illustrated by Mylroie and Stenberg (50), who reduced 9-chloromethyltriptycene to actadecahydro9-chloromethyltriptycene over palladium-on-carbon in 1 N ethanolic hydrochloric acid; without added hydrogen chloride the halogen was lost during ring saturation.

The pyridazine 9 was prepared via dehydrohalogenation of 8 using sodium acetate as acceptor (37).. may function as their own hydrogen-halide acceptor (4). Loven and Speckamp (40) concluded that selectivity in reduction of a . for they cannot always be used interchangeably.9 g CH2OCH3 2O0C (8) 4SmIHOAc 45 ml EtOH 250mgPd-on-C SgNaOCOCH3 H3C W Triethylamine was used as acceptor in dehydrochlorination of 10 to give the macrolide phoracantholide I (11) (44).68. Diamines.69). 5%Pd-on-C 2equiv(C2H 5 bN 1 aim H 2 Compounds containing a basic nitrogen. such as ethylene-. ^ ^ . have been used successfully. Diamines were thought to function through chelate formation (32). and ammonia.50psig Bases function in a more complex way than simply by acting as a halogen acceptor. amines. such as alkali and alkaline-earth hydroxides. acetates. propylene-. CATALYTIC DEHYDROHALOGENATION A number of halogen acceptors. such as 2-chloroaniline.CH2Cl ^1^ SOCl2 V . ethoxides.150 12. ^1"N [f Y^ 1 equiv ? CH3OH ' HOCH2 H C1CH^NH ^ ^ ^ 1. and the product may depend on the base used (58. The rate of reduction is greatly retarded by added hydrogen chloride. or hexamethylene diamines may function differently than monoamines. NH 3 Cl Pd-on-C MeOH 25°C.

43. Dehydrobromination of 12 to /?-tetronic acid (13) in high yield could be achieved only under narrowly circumscribed conditions (62).41. aryl.22. The yields were found to be concentration dependent. Hydrogenation of epilaurallene (14) over platinum oxide in ethanol gave a mixture of 15 and 16. (14) (16) The ease of removal of halogen decreases with increasing electronegativity.61). The molar ratio of barium hydroxide to 12 needed to solubilize 12 and to neutralize the liberated hydrobromic acid must be at least two to one. HO Br 20OmIH 2 O I g 10% Pd-on-C H 2 -Ba(OH) 2 HO CH 3 CCH 2 COC 2 H 5 O O (1) Br (2) A (12) (13) 12. One gram of 10% Pd-on-C per 33 g of 12 was required.6. less catalyst gave incomplete reductions.5. Poly halo Compounds Selective dehydrohalogenation in compounds containing more than one halogen usually can be achieved readily and in a predictable fashion. which differ by the occurrence of hydrogenolysis of the allylic oxygen. A synthesis of 2-amino-2'fluorobenzophenone provides an example of a facile selective removal of .3. The vinyl bromide is lost. vinyl (70.21.42. Halogens activated by carbonyl (3.12.47. or benzyl groups (52) are reduced more readily than are nonactivated halogens (18). allyl (43). while the nonactivated bromide is retained (63). POLYHALO COMPOUNDS 151 trichloromethyl function in piperidine sulfonamides was influenced strongly by the catalyst as well as by both the type and quantity of base. whereas at 33% concentration the yield was much lower.31.45). Concentrations of 12 in water of about 16% gave good yields of 13.71).17. Deionized water was the preferred solvent because of ease of workup.3. fluorine is usually quite difficult to remove unless highly activated (19.9. I > Br > Cl > F (39.66).

Reduction of the dichloro compound 17 over palladium black gave 18 in 98% yield (8).152 12.21.24. the greater the ease of hydrogenolysis.31).13. as well as illustrating the use of halogen as a blocking group (12. . CATALYTIC DEHYDROHALOGENATION chloride in the presence of fluoride (57).77).29. the least hindered chlorine is the most reactive. + 2 ClCO 30OmITHF 3OgNaOCOCH3 Pd-on-C 1 atm H2 X NH 2 The above general sequence for ease of removal of halogen can be used at times to advantage in improving selectivity in molecules containing other reducible functions by first displacing the halogen with one of lower electronegativity before the hydrogenation (1). Cl2C-C=O + PhN=CHC-CHPh CH3 H3C Ph Cl 0.0 g I Ph (18) 98% In polychloroanilines.2 g Pd black 2OmIC 6 H 6 8h Ph Cl Ph 1. since each loss increases the resistance to further loss (4. NH. The more halogens on a single carbon. a fact that makes stepwise dehydrohalogenation an easy process. producing the following sequence for the major products (15).

6. halogen is eliminated and a new carbon-carbon bond forms. on the other hand. and bicyclopentadienes (60). yields decrease with decreasing chain length. Rosenmund Reduction The selective hydrogenation of acid chlorides to aldehydes is known as the Rosenmund reduction (49). Pd-on-C Et 3 NHOCHO50-10O0C L Ij ^X"^ In contrast to aromatic halonitro compounds.. Pt-on-C Et 3 NHOCHO50-10O0C (^ A.6. Tetracontane was formed in 74% yield from 1-iodoeicosane (51).NH. The reaction has been used to make biphenyls (48). hydrazine. . ROSENMUNDREDUCTION 153 12. Long-chain hydrocarbons can be made in good yield by the reductive coupling of 1-iodoalkanes with hydrazine in the presence of palladium chloride or palladium metal as catalyst. is seldom seen. and methanol (as both reducing agent and solvent) have been used in these couplings. favors preferential hydrogenation of the nitro group.H. Coupling Reactions Dehydrohalogenation at times follows an unusual course. bibenzyls (11). 0 Pd CH3OH 12. Platinum. NH. 12. This latter reaction has been achieved in good yield by the method of Cortese and Heck (16). selective removal of halogen in aliphatic halonitro compounds presents little problem. who used triethylammonium formate at 50-10O0C as a reducing agent in the presence of either heterogeneous or homogeneous palladium catalyst. jT" NO. but the reverse selectivity.12.5. Hydrogen. Halonitro Compounds Selective hydrogenation of an aromatic halonitro compound to the corresponding haloaniline is a common industrial reaction. dehydrohalogenation to give the corresponding dehalonitro compound. The reaction can be done by hydrogenation over palladium-on-carbon in the presence of a hydrohalide acceptor (46.73).4.

RCH2OH-KH2 RCOCl + H 2 O » RCH3-HH2O » RCOOH + HCl In certain sensitive compounds. RCH 2 OH-KRCOCl » RCH 2 OCOR+ HCl If the resulting alcohol is susceptible to hydrogenolysis. Barnes (5) in Organic Syntheses has given detailed examples of the use of regulated and nonregulated catalysts. Hershberg and Cason (26) suggested that inhibitors always be used because of the possibility of inadvertent and uncontrolled poisoning. still further yield loss occurs through formation of water.HCl The main difficulties connected with this hydrogenation arise from overreduction to the alcohol. such as triphenylacetyl chloride. and various inhibitors are added commonly to control the extent of overhydrogenation. is also an excellent catalyst for decarbonylation of aldehydes (27. Some workers have suggested that the temperature be kept as low as possible (2.154 RCOCI -I.6. CATALYTIC DEHYDROHALOGENATION » RCHO -I. a common regulator. such .6. and decarbonylation may occur after aldehyde formation. low boiling solvents. Palladium. Procedure Rosenmund reductions are carried out usually by bubbling hydrogen through a heated solution of the acid chloride in a solvent in the presence of a palladium catalyst and running the reaction until hydrogen chloride evolution ceases (35). but other workers (23) have found nonpoisoned palladium-on-carbon catalysts to be sometimes more effective than conventional poisoned catalysts (49). which is a yield loss per se RCHO + H 2 » RCH 2 OH as well as loss because of reaction with the acid chloride.1. 12. has been examined in detail by Jethani et al. decarbonylation may be the major reaction (59).2.7) and still evolve hydrogen chloride. (34). Regulated Catalysts Rosenmund reductions are known to be sensitive to trace modifiers.28.65). the preferred catalyst for the Rosenmund reduction. 12.H 2 12. The use of quinoline-sulfur.

Butler and S. J. Durette. E. or 2. M. Soc. 34. 33. P. 767 (1976). 24. Hoffman and T. Synth. and L. and C. Chem. Technol. Med. 26. Cromwell and D. Soc. Org. N. Lange. Int. Huffman. P. 7. Schaefer. Barnes. Org. Chem. ethyldiisopropylamine (55). 62. Org. 215 (1972). Chem. 8. 26. 68. Alexander. Chem. Indian J. O. 15. Sd. W. Sato. 3. F. 29. Soc. T. L. Coll. Phillips. Chem. S. p. 3186 (1971). Dtsch. J. Chandalia. 3491 (1977). K. 1428 (1967). Chem. Jain. E. F. M. Pleven. 62B. 37. 627 (1955). 30. Successful Rosenmund reductions have been carried out in the presence of halogen acceptors. S. L.490 (1933). Chem. 13. C. Barnes and N. R. E. J. 65. Albano and D. E. R. 1704 (1974). Tetrahedron 20. 40. Bendich. Gerber. 11. N. Chem. Y. Chem. 81. A. Gregory. N. 4540 (1961). Hershberg and J. Chem. Org. Soc. A. Org. Wall. H. Chem. T. 4. and H. R. Bull. Kakuta. Santos. Horton. and T. J. F. F. A. Jpn. J. Weigel. Orochena. A. Org. and G. Pharm. References 1. Am. Org. 1037 (1980). 79. J. 77. Chem. H. and A. 23. G. Colleuille. Denton. Am. 3. R. 42. Am. Coker. Jeffrey. Chem. 1759 (1959). 34. ed. and R. J. 9. E. Ed. can be used to advantage (54).). B. 47. 197. G. Parkhurst. Soc. 992 (1959). 1625 (1964). B. L. Pummer. dimethylaniline (23). Coll. J. R. 17. J. S. Banks. Mehta. Nippon Kagaku Zasshi 91. Foye and W. N. V. 885 (1979). E/Florin. Arch. Cordier and Y. Schumann. Cason. 25. Silverstein. J. 6. Boehm and G. 3545 (1962). Chem. 742 (1956). R. Org. McCloskey. Equchi and A. J. Heck. Shieh.) 271. 2499 (1983). W. Baltzly and A. and S. Hofmann. P. Schmidt. W. Ges. Katsura. A. 1603 (1963). 45. Chem. An excellent technique for successful reduction to sensitive aldehydes is to achieve reflux at low temperatures by maintaining a vacuum on the system (23. 261 (1946). 24. Org. Simchen. 25. Cram. 420 (1965). Duchinsky. Kazama. A. J. 119 (Research pap. 28. D. 4559 (1957). T. Brady and C. 12. 3. 2. McQuillin. 19(9). D. L. Chem. J. Synthesis. . Puthenpurackel. M. I. 194 (1964). 48. A. 2687 (1962). Amakasu and K. Vol. J. such as anhydrous sodium acetate (67). Bredereck. J. Agnew. Natl. Thorn. 27. L. H. J. 29. Jpn. 5960 (1955). R. and R. Sax. J. Chem. Chem. S. Am. R. E. 27. Bur. 20. 1984. E. T. Busch and W. 32. N. Kosak. Ham and W. Burgstahler. 2938) (1959). Kawamura. Pharm. J. Chem. P. 349 (1981). and T. Org. Simpson. W. K. S. 16. 5535 (1964). Johnson. E. Soc. K. G. Kondo. W. 18. K. O. J. Conroy. CA 74. G. J. Hoffman. Schneider. Bull. Chem. A. 3519 (1969). Vol. 5. Ed. H. 27. E. 35. Wagner.6-dimethylpyridine (70). in "Catalysis of Organic Reactions" (J. 2612 (1929).36). P. 22. M. S. H. Tetrahedron 35. Stand. (Weinheim Ger. Arkley. J. Soc. G. 31. 14.. Kanakkunatt. M. Chem. 561 (1970). Sata. Soc. Fugua. A. 551 (1955). Cohen. Yoshihara. 10. J. 5. Cortese and R. Synthesis. Am.REFERENCES 155 as acetone. Chem. Isogai. 21. Org. N. and J. Assoc. T. 671 (1966). and C. C. 301 (1945). Soc. Jethani. Am. M. Org. Heidelberger. Dekker. New York. P. Ber. Synth. and P. J. E. 19. J. Walker. 605 (1982). Res.

E. R. Patent No. Marquardt and S. J. Koizumi. 11. M. 201 (1974). 66. Chem. Speckamp. Chem. N. C. Am. 70. Vanon and R. C. Hurwitz. Finkelstein. Troscianiec. Chem. 70. 3599 (1981). Ohno. Org. Wiberg and B.) 4. J. E. Sd. 58. London. Stenberg. Knutson. Pays-Bas 90. 60. 23. E. Am. Finder. Rosenmund and F. K. Chem. S. 37. and K. Org. 46. 2027 (1977). Chem. Biochemistry 3. I. Proc. 61. 45. Sd. R. H. Chem. Loven and W. 37. Reel. Moore. 65. Soc. U. Chem. 57. Gabriel. Suzuki. Rachlin. Klinge. Am. J. Ann. 78. . Monagle. Traas. K. Chem. J. 2250 (1966). A. 55. 1646 (1953). Chem. Martin. Soc. Johnson. 425 (1980). Org. 1861 (1972). and T. Tsuji and K. van Bekkum. K. Chem. and H. B. 3. and M. Boelens. S. ed. Org. J. A. 54. E. L. 1073. Bellus. A. 43. Hess. 37. Acad. 41. Soc. 387 (1955). Bull. 48. 52. vanderPlas.156 12. Mathieu. M. 172. Tetrahedron 34. W. N. E. 40. 72. Soc. D. 62. 1938 (1958). Ager. Reel. 2. D. 63. S. Suzuki. Soc.Y. 1973. 53. Mylroie and J. N. Synth. 69. D. V. Trav. L. Overberger and J. B. J. Smith. Ber. 44. Jr. Bazant. 58 (1957). Soc. 71. J. Chem. Pays-Bas 100. 56. J. H. LyIe. 71. Tautz. 333 (1959). Koudijs.723 (1959). L. D.. 39. J. M.. Chem. W. Chem. Chim. Manatt. Mosettig and R. 56. Anagnostopoulos. G. J. H. Tetrahedron Lett. J. L. K.. T. K. 42. Takken. 425 (1921). E. 186 (1970). Malherbe. and J. Nakajima. P. Chem. Whittaker. U. I. 715 (1983). J. F. Zimmer. G. 24.136. Chem. Zenitz. 31. G. B. Sargent. Hightower. R. Soc. Dtsch. 2645 (1964). L. Jpn. in "Catalysis" (J. G. 48. and C. 11. J. Chem. Tetrahedron Lett. Wagner. Trav. 6233 (1958). Schmidt and H. Chem. Am. J. 21 (1981).Y. A. Lantos. H.R. Org. Soc. Am. A. T. Lozeron. Wilt and E. React. G. 29. Trav. 214. Reinecke. 50. Org. Duschinsky. 299 (1964). Mosettig. D. 860 (1983). Peters and H. p. 4470 (1956). Perchonock.-P. van Bekkum. Whittaker. J. Acad. J. and D. C.1387 (1938). O. G. Gurien. Ges. Org. R. and R. 54B. 51. F. Commun. 1323 (1971). 73. H. J. Gordon. Macks. 255 (1973).908. A. Chim. C.815 (1964) CA 64. S. H. W. Holden. Am. G. J. Vogel. E. E. CATALYTIC DEHYDROHALOGENATION 36. Zetzsche. Jpn. 206. J. Soc. and T. 362 (1948). 776 (1949). Kraus and V. Reel. Ann. and A. C. P.1844 (1964). H. Chem. T. 47. 1565 (1950). Reeder and H. Morita. Sternback. Sd. J. 64.).S. Synthesis. 385 (1981). 2173 (1967). Roberts. and R. M. A. Mayo and M. D. Bull. 86.9515 (1964). Patent No. M. 49. Vol. Soc. D. Darling. Kikuchi.S. Edwards. Pay-Bos 93. Hara. 59. Peters and H. A. J. Chem. 54. Soc. Chem. May and E.429 (1946). Clement. Chem. J. 67. 2.Y. and J. P. D. N. W. 77. (N. D.T. Vasiliauskas. Hsu. W. and H. Org. 80. McBee and D. J. R. Mozingo. New York. Acad. Wineman.. J. L. 45. L. R. 955 (1948). 68. Pappo. P. J.1027 (1978). 1467 (1972). F. Rucker.. N. Org. Org. Elsevier. F. Chim. Rist. 1950 (1980). J. R.

Sometimes ring saturation occurs with unexpected ease. Many catalysts have been used. This chapter is organized around the type of bond being cleaved. Hydrogenolysis of the benzyl ester 2 was expected to proceed over palladium to give 8-methyl-lnaphthoic acid (1). but ring saturation is a likely competing reaction. Ring reduction was unusually facile here because it relieved peri strain (138). a mixture of 8-methyl-1.-13Miscellaneous Hydrogenolyses Catalytic hydrogenolysis is the cleavage of a molecule into fragments by hydrogen in the presence of a catalyst. combining high activity for hydrogenolysis with a low tendency to promote ring reduction.3.106).4tetrahydro-1-naphthoic acid (3) and 4 was formed. even over palladium. but it did not. CL /O. Benzyl Groups Attached to Oxygen Hydrogenolysis of benzyl-oxygen bonds occurs readily. (1) (2) (4) 28% 157 .1. 13. Rhodium may prove useful if dehydrohalogenation is to be avoided (50. but palladium is by far the most often used. It is a useful and frequent synthetic reaction. Instead.2.

l a t m H 2 20 mmol (7) (8) Compounds containing both benzylic and homobenzylic oxygenated substituents may lose either or both functions on hydrogenolysis. 13. 0. the rate increased in the order OH < O-alkyl < O-aryl < OH+-alkyl < OH2+ < OAc < OCOCF3.80).183).1. sulfuric.90). and in PhCH2OR.1. but in acetic acid reduction proceeded smoothly to give the 1hydroxyazetidine (8) (137).64. esters.158 13.7g5%Pd-on-C N-OCH22Ph I 25 0 C. Benzyl-oxygen bonds may be cleaved under conditions mild enough to leave an allylic hydroxy group (159) or an easily reduced N — OH bond intact (65. ethers. and substituents (38. and especially perchloric are often added in small amounts to promote hydrogenolysis of benzyl-oxygen .119. CH 3 CN-OCH 2 Ph SOmgPd-on-c 25 c l atmH ' 2 O Il CH 3 CNOH O Il PhCH 2 OCNHCHCOOCH 2 Ph O (5) (6) 0.54. MISCELLANEOUSHYDROGENOLYSES 13. in proportions that depend on the catalyst.1. Effect of Substrate Structure Benzyl alcohols. AT-Hydroxyamino acids can be prepared in good yield by hydrogenolysis of benzyl hydroxamates as shown in the synthesis of N6hydroxylysine (6) from 5(111).2. acetals. and phosphates all undergo hydrogenolysis readily. stereochemistry of the starting material. The rate of leaving parallels the ability of the leaving groups to bear a negative charge (89. Promoters Strong acids such as hydrochloric. No reaction occurred on attempted hydrogenolysis of the azetidine (7) over 5% Pd-on-C in ethanol.24 g 89% Solvents may have an important influence on the reduction.

Conversion to the tetraacetate 10 permitted ready hydrogenolysis to 11 if a trace of 70% perchloric acid were present.6-bis(morpholinomethyl)catechol (9) proved very difficult. . BENZYL GROUPS ATTACHED TO OXYGEN 159 functions (72). OH OAc 1. Ph HO Ph Ra-Ni O 0 O Pd-on-C HClO 4 100% O 89% 11% Another example of the use of an acid promoter is the conversion of 12 to 14 by way of lactone 13 (143).1]nonan-2-ol proceeds exclusively with retention over Raney nickel and with inversion over palladium. or with acetic or hydrochloric acids.1. Hydrogenolysis of 3.COCH3 CH 3 1 gm 10% Pd-on-C 200 ml HOAc 1OmIHClO 4 Il CH 3 O Zn CH3 BrCH2COOCH3 Tertiary amines are effective promoters in hydrogenolysis of hindered benzyl esters that otherwise may undergo cleavage only with difficulty (187).5h 25C.3. without acid.COCH3 . No reduction with palladium occurred at all until a drop of perchloric acid was added (36). a general phenomenon with phenolic Mannich bases. O . hydrogenolysis was extremely slow (161).13.60psig Pd-on-C EtOAc HClO4 substratercatalyst 50:1 CH 3 AcO AcO CH 3 (H) OAc (9) (10) Hydrogenolysis of exo-2-phenyl-9-oxabicyclo[3.

In general.168). The matrix is prepared by adsorbing the polymer on inorganic beads.11.4.144).160 13.540. Palladium makes the best catalyst for this hydrogenolysis and is used by most investigators.54.174). steric considerations may dictate the choice of catalyst (21.1.19. a palladium-poly(ethylenimine) "ghost" catalyst is said to be very effective in peptide synthesis by hydrogenolysis of carbobenzyloxy groups. hydrogenolysis usually proceeds with retention of configuration over nickel and with inversion over palladium or platinum (36. MISCELLANEOUS HYDROGENOLYSES Bases frequently impede hydrogenolysis.184).55. Carbobenzyloxy Compounds The carbobenzyloxy radical (98) and its derivatives. An advantage is that they can usually be removed easily in the presence of other sensitive functions. including nitro (6) and benzyl (101) if steric requirements are not severe (68).116-119.157. Hydrogen gas was bubbled through a . crosslinking the polymer.57).1.3. such as the p-bromo (30) or the p-nitro (4. Because different metals may attack the benzyl function from opposite sides on the molecule. An unusual type of catalyst. 13.OH f/ ^v \ Y HO Il OH JJPSIgM 2 Y I \ \~r / ff \ / -OCH3 (16) 13. Stereochemistry of Hydrogenolysis Many workers have examined the stereochemistry of hydrogenolysis of benzyl-oxygen compounds (18. With nickel. The effects of metals on stereospecificity of hydrogenolysis have been related to the affinity of the metal for oxygen (119). and leaching out the inorganic material to leave a macroporous spheroid with high surface area and high functional-group density (34).22) are widely used as protecting groups in organic synthesis (61. but hydrogenation of the flavanone 15 in aqueous potassium hydroxide over palladium gave 16 in high yield without reduction of an easily reduced aromatic ketone (48). . Hydrogenolysis of the carbobenzyloxy (cbz) function in 17 proceeded smoothly to give 18 in 95% yield. the stereochemistry of hydrogenolysis may be inverted by addition of alkali and influenced by catalyst age and pretreatment (116.

The authors believe that after deblocking.5 h with vigorous stirring. The most suitable solvent is dioxane with addition of a catalytic amount of pyrrolidinopyridine and 2% ethanol.5 g of 10% Pd-on-C at 2O0C for 1. Hydrogenolysis without double-bond saturation was attributed to strong resonance interaction between the electron-releasing indole ring and the double bond (121). under the same conditions both functions are removed with longer reaction times (101). BENZYL GROUPS ATTACHED TO OXYGEN 161 solution of 3.1.13. the cbz function can be removed selectively in the presence of another benzyl function.6 g 5% Pd-on-C 9O0C. O BocNH(CH2)3NCOCH Il OCH (19) X = H (21) X = NO 2 Boc = f-butoxycarbonyl A key step in the synthesis of 13-membered meta ansa and 14-membered para ansa peptide alkaloids involves catalytic hydrogenolysis of carbobenzyloxypeptide pentafluorophenyl esters. ^x COOCH3 ~\ I /CH3 . Surprisingly.0 ml of cone HCl and 0. the amino function remains on the surface until ring formation with the activated carboxylic function is accomplished (151).0 g of 17 in 40 ml of CH3OH containing 1. the same sequence with the more liable p-nitrobenzyl carbamate 21 was less selective. Temperature should not exceed 9O0C.^ NHCOCH Ph 2 COOCH3 O (17) (18) By careful hydrogenolysis of 19. 30 min 1 aim H 2 . NHZ 350 ml dioxane SmlabsEtOH 40mgPPY 0.

Hydrogenolysis in peptides containing sulfur. A solution of the protected peptide in methanol or dimethylformamide is mixed with 10% Pd-on-carbon (10-50% of the weight of peptide) and 2-4 equiv of ammonium formate at ambient conditions. is apt to proceed very slowly because of the poisoning action of the sulfur. HO3SO ^^ . Another technique utilizes palladium catalysts in dry methanol containing boron trifluoride. Hydrogenolysis of 22 to 23 was carried out at 50C to prevent opening of the cyclopropane ring (82). as those with cysteine or methionine.112). Oxidized sulfur is not a catalyst poison (20). The product is obtained rapidly in excellent yield. Acidity per se is not the reason for success here. MISCELLANEOUS HYDROGENOLYSES Selectivity is influenced by temperature. This general difficulty has been circumvented by using palladium black catalysts and dry. The technique is applicable also to deprotection of peptides on solid resins (7Jc) and provides . using ammonium formate as a source of hydrogen. the palladium catalyst is incorporated in the resin (83. A variety of benzyl protecting groups are easily removed.162 13.114). reduction in methanol containing p-toluenesulfonic acid or trifluoroacetic acid failed entirely (180). including those held on solid phase supports (34.NHCO2CH2Ph 750mglO%Pd-on-C 25 0 C.148). 2Oh 7SmIH 2 O HO3SO Anwer and Spatola (7b) developed a convenient hydrogen-transfer method for removal of hydrogenolyzable protecting groups under ambient conditions. n H\ 'I ^"3 \ -NHCOCH 2 Ph I H M O CH3 * 1 T ^%^ OCH3 " CH3 + C°2 +PhCH 3 (23) Catalytic hydrogenolysis of carbobenzyloxy compounds has been widely used in the synthesis of peptides (10). In the latter case. refluxing liquid ammonia as a solvent (96.

benzyl-nitrogen bond hydrogenolysis is a useful reaction.2.13. at times with added mineral acid. Platinum might be the catalyst of choice in hydrogenolysis of benzyl compounds where dehydrohalogenation is to be avoided (laJ24). BENZYL GROUPS ATTACHED TO NITROGEN 163 an alternative to hydrogen gas (148).1610. Alcohols or acetic acid. benzyl-nitrogen compounds have been reduced by a number of catalysts.1. Palladium-on-alumina was more effective than palladium-on-carbon in stepwise debenzylation (142). Catalysts As with benzyl-oxygen compounds. The facile cleavage of benzyl-nitrogen bonds has been used for preparation of optically active amino acids through induced asymmetry (70J 1. are common solvents for debenzylation (78). Selective reductions have been achieved with cyclohexene donor where normal hydrogenation procedures or formic acid donor were nonselective (69). and a wide variety of benzylamines have been reduced under mild conditions without major side reaction (72).490. but palladium is by far preferred. Good results have been .1710). Nonetheless. a method that has succeeded where normal hydrogenation failed (115). the danger of ring reduction is present (95).73). With platinum.2.-T--L—O I L-—-1---J A OCH3 13.2. 13. Ph SmiEtOH PhCH 2 O I 4mlC 6 H 1 0 20% Pd(OH)2-On-C reflux T^°^1 \\0 \\0 5. Benzyl Groups Attached to Nitrogen The benzyl-nitrogen bond undergoes hydrogenolysis with more difficulty than does the benzyl-oxygen bond.127) hydrazine (7d\ cyclohexadiene (49c\ and formic acid (37. Isopropanol as a hydrogen donor has been found to be more selective than formic acid in an 0-benzyl hydrogenolysis. Hydrogenolysis of Af-benzyl compounds can be accomplished also by hydrogen transfer. Other hydrogen-transfer agents that have been used for deprotection are cyclohexene (810.

2. Stereochemistry Benzylamines tend to undergo hydrogenolysis with inversion over both Raney nickel and palladium. New Jersey) (616)..3. the order may change (118). Effect of Structure In general. Hydrogenation of 25 in acetic acid containing hydrogen chloride over unsupported palladium followed an unusual course to give mostly a mixture of stereoisomers of structure 24 (47).40. Newark.164 13. Dibenzylamines are usually reduced over palladium stepwise. 13.75). unlike benzyl-oxygen compounds (121aJ67a). 20% palladium hydroxide-oncarbon (manufactured by Engelhard Ind. even where other palladium catalysts have failed (5. MISCELLANEOUS HYDROGENOLYSES obtained with the Pearlman (136) catalyst. the ease of hydrogenolysis of benzylamines under ambient conditions increases in the series primary < secondary < tertiary < quaternary ammonium salts (430). mainly isoflavan (26) accompanied by 27.2. under vigorous conditions. suggesting a change in mechanism as conditions change (1210). removal of the first being more rapid than removal of the second (49b). . Hydrogenation of 2-morpholinoisoflav-3-ene (25) over 10% palladium-on-carbon gave only hydrogenolysis products. benzyl-oxygen bonds are usually broken in preference to benzyl-nitrogen bonds (77b) but this order can be reversed by quaternization.2. 13. In competition.

and environment. Reverse Selectivity It is true generally that O-debenzylation take place with greater ease than does removal of AT-benzyl.167a). Hydrogenolysis is best achieved over platinum.3. The extent of hydrogenolysis in hydrogenation of l-ethoxy-3methylcyclohexene decreased in the order Pt » Os > Rh ~ Ir > Pd > Ru (124/). PhCH20(CH2)8NC2Hs CH2Ph tOH ' PhCH 2 0(CH 2 ) 8 NHC 2 H s *spi. the catalyst. the product will be relatively stable toward further reduction.S I I \*H2 / ^c= c. a finding with synthetic utility.4. the resulting olefin is readily reduced. VINYL FUNCTIONS 165 The anion associated with quaternary ammonium compounds can influence markedly the stereochemical outcome of hydrogenolysis (43b. A quantitative comparison of metals in the hydrogenation of vinyl ethers has been made. /X /^ \H 2 HH H ^ H2S — c— c— H + HX \ \ I ^ \ H H If saturation occurs first. 13.25-c 100% Inhibition of 0-benzyl hydrogenolysis was shown to be due to the presence of an amine. the order was Pt » Ir > Rh > Os » Ru ~ Pd (124J). whereas palladium (77a.162a).82aJ22b.2. but this order can be reversed if both functions are present (43). I I — C— C— X »2-. but if hydrogenolysis occurs first.13. Vinyl Functions The composition of the products derived from hydrogenation of vinyl functions is determined by the relative rates of two competing reactions.109a) tend to favor olefin saturation.3. in the case of ethyl 4-methyl-l-cyclohexenyl ether. In ethanol. 13. This ratio depends greatly on substrate structure. rhodium (109a\ or ruthenium (10a. ketal formation is a .

(CH3O)2PO O Il C7 Il /C H CH 3 I > (CH3O)2PCH2CHCOCH3 + HOP(OCH3J2 Il Il 1 (CH3O)2PCH2 O COCH3 O O O O (30) (31) A method for conversion of one of two keto functions to the methylene involves hydrogenolysis of an enol phosphate. obtained by hydrogenolysis followed by hydrogenation (460).5). For effective use of subambient (-3O0C) temperatures in stopping hydrogenolysis of vinyl functions.166 13.70).5% Pd-on-C. 5%Pt-on-C EtOAc 250C. Reduction of 28 proceeded smoothly to 29 (109). Hydrogenation of the (Z)-enol phosphate 30 over PtO 2 . structure. the ratio of ketal formation to hydrogenationhydrogenolysis was Pd (4.0). Os (0. CH3 CH3 CH Extensive hydrogenolysis of vinyl ethers does not occur always over platinum. Suffice it to say. see (Wd). Ru (O). 61 g . and stereochemistry is discussed in these papers. The complex relation among solvent. In the reduction of 1ethoxy-3-methylcyclohexene. 15OaImH 2 Sometimes the structure is such that the reaction is forced into a single path regardless of catalyst. Pt (1. a great deal of contol can be exercised by choice of catalyst. catalyst. MISCELLANEOUS HYDROGENOLYSES competing reaction that varies greatly with the catalyst.5). It is likely that the high pressure and low temperature used in this experiment helped to minimize hydrogenolysis.2). Ir (0. Rh (3. or 5% Rh-on-C in EtOAc at 3 atm gave a 95% yield of 31.

and do.1. an unhindered approach of the olefin to the catalyst does not assure the absence of extensive hydrogenolysis (112aJ12bJ24f).4.4. . 13. Catalysts and Environment Comparisons of more than two metals are few.44aJ01aJ47bJ63). The extent of hydrogenolysis can also be influenced by structural changes remote from the point of unsaturation (52d). have given 95% yield of the saturated product in compounds that underwent 100% hydrogenolysis over palladium-on-carbon (175a). Steric Factors Steric factors operate by impeding access of one or the other function to the catalyst surface.44.and tetrasubstituted olefins would be expected to. but it appears that hydrogenolysis of allylic functions should increase with metal in the order Ru ~ Rh « Pt < Pd. undergo extensive hydrogenolysis (lJ7a.2. The converse is not true. Allylic compounds substituted by bulky substituents at the olefin or tri. All in all.4. ^H2 I ^N.13. Homogeneous catalysts such as (Ph3P)3RhCl. the outcome of an allylic hydrogenation is the resultant of two competing reactions. "2^ -C-C-C-X I H I H I I I Jf* —C—C—C—H ! I I H H I The rate ratio of hydrogenation to hydrogenolysis varies with the catalyst. depending on whether the catalyst used typically effects hydrogenolysis with inversion or retention (117). H2 \ C=C-C-X I \. and acid accelerating hydrogenolysis (8a.61bJ64a\ inasmuch as the olefin is relatively inaccessible to the catalyst. Allylic Functions As with vinyl compounds. H2^ >=c-c-H / I . Trace quantitives of acid or base may drastically alter catalyst performance. and environment in a partially predictable way. 13. ALLYLIC FUNCTIONS 167 13. substrate structure. small structural changes can exert large influences on the composition of the products. however.4. steric effects are important but elusive. Substituents altering access of the catalyst to the oxygen function could be expected to exert a variable influence. with base impeding.

Raney nickel (14.5. it is best to avoid those catalysts and conditions that favor isomerization.4.167). causing hydrogenolysis to occur when it would not have been expected (39b. and rhodium (130) have each been . Hydrogenolysis of an allylic carbon-oxygen bond over 10% Pd-on-C during reduction of a 2'.31. The ratio of hydrogenolysis to hydrogenation is expected to increase with increasing polarity and increasing acidity (31a. MISCELLANEOUS HYDROGENOLYSES Solvents may exert a marked influence on the products of reduction. providing a good route to various amino compounds. operated best under hydrogen-poor conditions (147a). hydrazides. hydrogenolysis of the nitrogen-nitrogen bond ensues.139. 13. palladium is probably the preferred catalyst.5.73c).185).3'-unsaturated C-nucleoside was prevented by using THF instead of methanol as solvent (66). 13. Double-bond migration to an allylic position may occur even if the double bond is required to leave a tetrasubstituted position (26a). In these cases. and azo (17 J2OJ22J52. Hydrazones and Hydrazides Hydrazones can be reduced to the hydrazine. and. which undergoes hydrolysis (36d).124b.124cJ59aJ68a). If isomerization is desired.133. 13.3. Azines and azides are cleaved to amines.52.165 J 70) and azoxy compounds that form hydrazines on reduction undergo hydrogenolysis of the nitrogen-nitrogen bond.1. 178. Isomerization of the double bond in allylic alcohols may result in aldehydes or ketones (107a).15. Allylic ethers can be converted to alcohols by isomerization with (Ph3P)3RhCl at pH 2 to the vinyl ether.45a-45c).46) and materials such as azines (33) hydrazones. Hydrogenolysis of the Nitrogen-Nitrogen Bond Hydrazines (39.155. if continued.134. Usually the rate of reduction of each of these hydrazine precursors is sufficiently greater than the rate of hydrogenolysis so that the first step provides a good synthesis of the hydrazine. Double-Bond Migration Homoallylic systems may isomerize under hydrogenation conditions to allylic systems. The reaction can have synthetic value (8b. platinum (42. if hydrogenolysis is unwanted.168 13.

cyclohexane. Hydrazines vary in their ease of hydrogenolysis. a two-phase system of benzene. or dioxane and aqueous hydrochloric acid can be used. Alternatively. followed by oxidation (12.103). usually in acidic solvent.2. however.13. Hydrazones of aromatic carbonyls can be cleaved at the benzyl-nitrogen bond. using palladium.33.5. toluene. Azines Azines can be reduced catalytically to the disubstituted hydrazines (24. The hydrogenolysis chemistry is thus that of hydrazines. the reaction is useful when carbonyl reagents have been used for purification (25). Hydrogenolysis of optically active hydrazones can be used as a means of preparing optically active amines (91). HYDROGENOLYSIS OF THE NITROGEN-NITROGEN BOND 169 used successfully in the hydrogenolysis of hydrazones. The reaction is of considerable use in the preparation of amino sugars from osazones and phenylhydrazones (67). A general method for the preparation of azo compounds is reduction of azines to the hydrazine.5. Platinum . The hydrazine can be formed in situ by hydrogenation of a mixture of hydrazine and 2 mol of carbonyl compound (32.51) and then to the amine if the reduction is continued (108). derived by addition of the initially formed amine to the starting material (160). there is sufficient difference in the rates of the two steps so that hydrazines can be isolated in good yield (74). and it may be difficult to arrest the reduction of a hydrazone at the hydrazine stage if the hydrazine is reduced easily (15). The reduction is carried out conveniently in ethanol containing ammonia over palladium-on-carbon. Ammonia is used to minimize formation of secondary amines. 3 3 O-Y \ _ / N -\ V-CH=NNHPh OCH3 100mlC6H6 lg5%Pd-on-C 50psigH 2 > CH3O^f \ _ / 13. Reductive cleavage of phenylhydrazones of carbonyl compounds provides a route to amines. Usually. the major product is a substituted hydrazine.132).128. \-CH-NNHPh / 100mlc H * * 2mll%agHCl 1 g 5 % Pd-on-C > / \ _ / - OCH3 5g g 50 P sigH 2 OCH3 Without acid present.

Oxidation of hydrazines can be done catalytically.77.c PhN=NCOOC2H5 °o02 25 C 13. The major product (33) was contaminated by several other products when reagents were mixed and hydrogenated at room temperature or above.170 13.97. Palladium. and Raney nickel (7.172). Azides Hydrogenolysis of azides provides a convenient way of introducing an amino nitrogen (13. Reduction of methyl 3'. Azido compounds are formed with inversion by nucleophilic displacement with an inorganic azide and hydrogenated with retention of configuration (153).5. Azides are stable toward a variety of reagents and hydrolytic conditions yet can be easily reduced to an amine. MISCELLANEOUSHYDROGENOLYSES catalysts in acidic media are usually used for the reduction.6 g of phenylethylamine. 200 g of acetophenone azine. 175). formed by cleavage of the N—N bond.59. The azido function has served well as an incipient amine in the synthesis of a number of nucleotides (60) and amino sugars (29.81. In especially sensitive molecules. Hydrogen absorption had ceased.93. was obtained as a by-product.135. Daub and Cannizzo (45) applied the sequence to the synthesis of meso-azobis-(a-phenylethane).135. platinum.104.164). PhNHNHCOOC2H5 ) 10o/opd°l.126) all have been used successfully under mild conditions for hydrogenation of the azido function.76. subambient temperature may prove advantageous.97. Ph Ph PhCCH3 + NH 2 NH 2 H 2 O O 150OmIEtOH> 6m|HOAc m CH3C=N-N=CCH3 95% 10%Pd-on-C 30-50 psigH 2 I EtOAc I ' Ph Ph I i CH3CHN=NCHCH3 < Ph [O] Ph CH 3 CHNHNHCHCH 3 In the hydrogenation. often selectively in the presence of other easily reduced functions (5. 1000 ml of EtOAc and 5 g of 10% Pd-on-C was shaken at 30-50 psig for 1Oh.3. Ethyl 2-arylhydrazine carboxylates were oxidized easily by bubbling air at 250C through a toluene or dioxane solution in the presence of Pd or Pt (56). Palladium has also been used effectively (129). but by the . About 7.5-dihydroxy-4'-methoxy-7-(3-azido-3carboxypropoxy)flavanone (32) in aqueous alkali proved capricious.

The most active was rhodium. If a drop does occur. The isolated yield of 33 was 95% (49).166. could be obtained. platinum is also effective (100. Katritzky and Monro (84) examined carefully the selectivity of reduction over palladium of a . A sample of 1Og of 32 was dissolved.84.169). some other function is being reduced as well. Pyridine N-oxide has been reduced over palladium. to 112 ml of ice-cold 10% KOH in a Parr hydrogenation bottle. platinum. hydroxylamines.13.158).1.6. Considered here are Af-oxides. but it was nonselective. oximes. and various heterocyclics. Amine Oxides Both amine oxides related to pyridines and aliphatic amine oxides (125) are easily reduced. OH OH (33) O There is no pressure drop in the hydrogenation of azides. a potent sweetener. One gram of 5% Pd-on-C was added and the mixture was shaken at 35 psig for 6 h. 13. by additions in small portions with stirring under an argon atmosphere. and N.6. reducing the ring as well. these reactions are discussed in separate chapters.6.and C-nitroso compounds. 13. the former the more so. Palladium is usually the preferred catalyst for this type of reduction and is used by most workers (16. HYDROGENOLYSIS OF THE NITROGEN-OXYGEN BOND 171 following procedure nearly quantitative yields of 33. rhodium. Hydrogenolysis of the Nitrogen-Oxygen Bond Catalytic cleavage of the nitrogen-oxygen bond occurs very frequently as in reduction of nitro compounds. so reaction completion can not be followed by this means.23. and ruthenium.

MISCELLANEOUS HYDROGENOLYSES variety of substituted pyridine oxides. In the presence of Raney nickel. /O RCH=C-C (1) NH 3 . Selectivity depends on both the substituent and position. NH TsO SmICH 3 OH 200mgRaNiW-2 bubbled H 2 1 atm 13. A (2) NH 2 OH * RCH-CHCONH 2 NH OH (1) EtOH Pd-on-C SOpSJgH 2 (2) H 2 O ' RCH-CHCONH 2 NH 2 NH 2 I Ph NHCOPh . Nucleoside N'-oxides have proved useful in preventing intramolecular cyclizations during manipulation of the sugar moiety. The hydroxylaminohydroxamic acid 34 gave 35 in 95% yield under mild conditions (140). PhCH-CHCONHOH ! I HONH NHCOPh 5g5%Pd-on-C 5OmIEtOH 40psig. EtOH.6.172 13. Azides.2. are reduced concomitantly with the oxide (105). A key step is the reductive removal of the oxide when needed. however. the oxide can be reduced selectively even when such easily reduced substituents as iodo are present. 25 0 C PhCH-CHCONH 2 NH 2 NHCOPh (34) 2g (35) A convenient synthesis of a. Hydroxylamines Hydroxylamines are reduced readily to the amine over palladium./?-diamino acids from azlactones involves catalytic hydrogenolysis of a hydroxylamino function over palladium-oncarbon (141).

Hydrogenolysis of the Carbon-Carbon Bond Carbon-carbon bonds are not easily cleaved under mild conditions unless weakened by strain (3. These by-products.182) or activation. C-Nitroso Compounds C-Nitroso compounds with an a-hydrogen atom rearrange readily to the corresponding oxime (171) and perhaps to the unsaturated hydroxylamine (145).13. Aromatic nitroso compounds usually are considered to be intermediates in the hydrogenation of a nitroaromatic compound to the aromatic hydroxylamine or amine. if necessary. N-Nitrosoamines N-Nitrosoamines are reduced easily to the hydrazine and. Reduction of these is discussed in the chapter on oximes.4.86. It can be alleviated by dropwise addition of the substrate to the hydrogenation and use of acidic media.7.6. nitroso compounds do not accumulate in these reductions. Catalysts effective for the nitro group should also be effective for nitroso.7. Hydrogenolysis can be decreased. arising from reduction of aromatic nitro compounds.3. Palladium-on-carbon under mild conditions is used for industrial production of dialkyl hydrazines from JV-nitrosoamines. to the amine (62). by the addition of any of a variety of salts that increase the ionic strength of the medium (162). suggesting that they are reduced more easily than are nitro compounds. 13. Yields may depend markedly on the conditions of the reaction (92). . if continued. However. Iron salts have been used specifically for this purpose (102. 13. Early workers ruled out cleavage of dimethylhydrazine as the source of dimethylamine in hydrogenation of N-nitrosodimethylamine since little ammonia was found. The coupling problem is accentuated in reduction of nitroso compounds because of much higher concentrations.173). Formation of azo-type products might be troublesome.6. usually are assumed to be derived from the coupling of intermediate nitroso and hydroxylamine compounds. HYDROGENOLYSIS OF THE CARBON-CARBON BOND 173 13. The most common examples of carbon-carbon bond cleavage occur in cyclopropanes. the tetramethyltetrazene was implicated in the hydrogenolysis (131).

1080).58. Platinum or palladium are used frequently. or greatest strain (51aJ22aJ56\ Additional strain allows facile ring opening. Various generalities concerning the direction of opening have been suggested.53.150. occurred at ambient conditions to give seven parts of 4-homoprotoadamantane (37) and one part of 38 (85). Cyclopropanes carrying only phenyl substituents are cleaved exclusively at the bonds adjacent to the phenyl substituent (87). r-butyl.176). worked well where platinum oxide failed (28). but there are exceptions (113. whereas alkyl substituents favor cleavage at the bond opposite the substituent (1220). and angular-methyl substituents (179). compounds often available only with difficulty otherwise (27.174 13. More highly substituted nonfunctional Cyclopropanes open variously at the carbon with the most hydrogens (736. IaUnH 2 (36) (37) (38) In contrast. Electron-attracting substituents are often cleaved at the bond adjacent to the substituent (63. rhodium-platinum oxide (7:3). for it is difficult to decide which of several controlling factors is operative. but in vinyl and alkylidene Cyclopropanes the effect is pronounced.94. for synthesis of compounds containing quaternary carbons. An a priori determination of the direction of ring opening is not always easy. which. 0em-dialkyl.79. In one case. Nishimura's (1240) catalyst.1. MISCELLANEOUS HYDRCXJENOLYSES 13J. Hydrogenolysis of the cyclopropane ring in the strained compound 36.156). hydrogenation of 39 gives only 40. (39) (40) The catalyst exerts some influence on the bonds broken in hydrogenolysis of saturated Cyclopropanes (118). least hindrance (39aJ47c).146.154). Cyclopropanes can be formed in good yields by hydrogenation of cyclopropenes (26). . An impressive example of the marked influence of catalyst is the hydrogenation of the spirooctane 42. Cyclopropanes Cyclopropanes are now readily available and have become useful. through hydrogenolysis. EtOAc 250C.

and ethylcyclohexane is formed over palladium in similar spiro systems in amounts that depend on the solvent (17Pa).43. nonetheless.1746.1530).7. or 44 in excellent yields (186). Homogeneous catalysis usually gives hydrogenation and not hydrogenolysis.82b). 13.113).1-dimethylcyclohexane (1596).H 2 THFrH 2 Ol:! (43) 97% COOCH3 (44) 84% plus 16% 41 The above results have a precedent.7. Formation of 43 also might be expected since spiro [2.10-diazabenzo[b]biphenylene with Raney nickel in hot ethanol gave 2-phenylquinoxaline in 78% yield (9). gives 41. HYDROGENOLYSIS OF THE CARBON-CARBON BOND 175 depending on catalyst and solvent. or aromatic substituents (26c. Cyclobutanes Cyclobutanes are cleaved less readily than are cyclopropanes. .20°C. Similar fission of the fourmembered ring occurs with biphenylene itself and with substituted biphenylenes (8).98aJ74d).13. but.5] octane itself gives 1. Hydrogenation of 5. whereas platinum or rhodium tend to give hydrogenation initially (340. Alkylated vinylpropanes usually give extensive hydrogenolysis over palladium (72a. adjacent unsaturation (726.2. fission occurs without difficulty if the ring has additional strain (113.176). H2 (Ph 3 P) 3 RhCl COOCH3 2O0C COOCH3 COOCH3 (41) 100% (42) 10%Pd-on-C.

EtOAc (2) Hi.165.177. the other fragment becomes aromatic (7e). Hydrogenolysis of the oxygen-oxygen bond is most often done with palladium or platinum catalysts (35. Polar and hydrogen-bonding solvents favor hydrogenolysis (7a.3 Aromatization Hydrogenolysis of the carbon-carbon bond occurs readily when one fragment is a good leaving group and. O (46) . Extensive hydrogenolysis is apt to occur when an allyl or. In synthetic work.8. peroxy acids.110.7.26b.Pd-on-C* s *CH3 ^N5" ^ ^CH3 ^ The ozonide 45 was reduced easily to diol 46 over 10% Pd-on-C (41). MISCELLANEOUS HYDROGENOLYSES 13. more especially.115a).147.99). Heathcock and Kleinman (730) made interesting use of the hydrogenation of a hydroperoxide as a way of introducing an angular hydroxyl group in an octahydroquinoline during total synthesis of (± )-lycodoline.88. The diastereomer having the angular oxygen and the neighboring acetonyl trans predominates by 10:1.176 13. 13. noble-metal catalysts are often used without hydrogen to destroy excess hydrogen peroxide. hydroperoxides. and ozonides are very easily cleaved by catalytic hydrogenation. If the substrate also contains a double bond that is to be preserved. Hydrogenolysis of the Oxygen-Oxygen Bond The oxygen-oxygen bonds in peroxides. O HO O ( I ) O 2 . as a result of its loss.181). a benzyl group is attached to a quaternary carbon in a conjugated cyclohexadienone. Lindlar catalysts are useful (2.107.

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71. 134 3-Acetylpyridine. 142 2-Amino-2 -fluorobenzophenone. 10 a-(Acylamino)acrylic acids. 79 Agitation. 136 Allenes. 66 Asperuloside tetraacetate. 176 L-Ascorbic acid. 171-172 a-Amino acids. 6. 174 AT-Alkylpyridinium salts. 118 Acetophenone azine. 14. 71 Acetylenes. reductive.5-dimethoxyindanone hydrochloride. 73-74 185 . 136 Alkylation. 62 Acetylenic amines. 10. 106 Aromatic hydroxylamines. 37 1T-AlIyI intermediates. 30 Allylic compounds. 105 Aminoacetaldehyde dimethylacetal. 109-110 JV-Acetylindoles. 69 /3-Amino ketones. 62 Acetylenic nitro compounds. 13-14. 136 Acid. 112 Aminophenols. 59 Acetylenic epoxides.4-Androstadiene-3.Index of Compounds and Methods Acetal formation. 151 2-Amino-l-indanol. 31 Air-sensitivity. effect of. 74-75 Autodecomposition temperature. 53-62 Acetylenic aldehydes.17-dione. 42 Asymmetric hydrogenation. 110 l-Amino-2-cyanonaphthalene. 89 Amino benzyl alcohols. 126 w-Alkylaminovaleraldehydes. 21 Axial alcohols. 90. 110 2-Amino-4. 69 /3-Amino nitriles. 139 Aldehydes. 123-126 o-Anisidine. 59 Acetylenic glycols. effect of. 100 4-Amino-2-nitro-l-(Af-piperidyl)benzene. 40-41 Anhydrides. 154 Acidity. 66-75 Alkali. 78-80 Acid chlorides. 107 Ammonium formate. 170 Acetylacetone. 40 4-Androsten-3. 83 0-Aminobenzamide. 140 /?-Aminophenol. 162 l. 11 Alkylidene cyclopropanes. 59 Acetylenic ketones. 104 L-Alanyl-L-proline. 15 Adipic acid. 78-80 Anilines. 97 Amino sugars. 85 Alcoholysis.17-dione. 69 3-(l-Aminoethyliden)-5-methyl-2-oxopiperidine. 41-44 Allylic functions. 61 Acetylenic carbinols. 60 Acetylenic esters. 68 Acetophenone. 89. 160 Alkoxyanilines. 167 Amine oxides. 36. 106-107 Aromatization.

71 Bibenzyls. 79 N. 79 7-Butyrolactones. 2-3 concentration. 170 INDEX OF COMPOUNDS AND METHODS B (Z)-2-Benzamide(acetamido)-3-(2-thienyl)-2propenoic acid. 133 pretreatment. 16. 97 CAMP. 149 o-nitrophenol. effect of. 36 Catalyst(s). 135 Biacetyl. 125 aniline. 118 ammonia. 97 Benzyl groups. 175 Bipyridyls. 35 Carvomenthene. 120 Butyrolactones. 97 4-r-Butylcyclohexanol. 119 Benzoic acid. 34 boron trifluoride. 125 ammonia. 135 4-Benzylpyridine. 97 Benzylic oxygenated substituents. 35 Carene-3. 97 preparation of. 74 3. 125 ammonium dihydrogen phosphate.4-Butanediol. 125 chlorobenzene. 47 Bromo esters. 153 Bicyclopentadienes. 86 acidic carbons.2-Bis(diphenylphosphino)ferrocenyl]ethyl alcohol. 158 Benzylamines. 129 Biphenyl. 56 . 97-98 MBenzyl-M-Cr-butoxycarbonylJspennidine. 138 1-r-Butylnaphthalene.[7V-(r-Butoxycarbonyl)-3 -aminopropyl] -N(3-cyanopropyl)benzylamine. 119 Carane. 6. 32. 74 4-r-Butylcyclohexanone. 31 age. 31 cost. 34 choosing. 135 Bis-(4-aminophenyl)-methane. 24-25 loading. 12-13 poison and inhibitors alkali. 157-165 Benzyl hydroxamates. 158-160 acetic acid. 106 halide ion. 106 hydrogen chloride. 106 sulfur. 153 Biphenylene. 67. 61 2-Carene. 80 l-/3-Bromosantanolide "c. 67. 1-7 activity. 169-170 Azlactones. 6. effect of. 160 promoters and modifiers. 170-172 Azines. 56. 172 meso-Azobis-(a-phenylethane). 125 fl?>[ff>l'. 160 aging. 162 cadmium. 159 Blocking group. 119. 73. o'-Biphenol. 86 life. 96. 149 0. 111 Azides. 68 4-f-Butylcyclohexene epoxides. 162 water. 158 4-Benzylpiperidine." 149 1. 121 Benzene. 138 amines. 54 carbonates. 106 o-chloronitrobenzene. 160-163 Carbon-carbon bond formation. 22-23 prereduction. 119. 106 0.0' -dichloroazobenzene. 86. 43 Butyronitriles. 48 Benz[j]anthracene. 56 benzene. 153 o.6-Bis(morpholinomethyl)catechol.0' -hydrazoanisole. 124 Qo'-azoxyanisole. 142 induction period. 24 deactivation.186 Azaindoles. 96. 96. 106. 117 Benzonitriles. 152 BPPM. 35 Carbobenzyloxy compounds. 86 alkali.

15 D Damsin. 33 "Dead-end" complex. 86. 55 Af-methylmorpholine. 74 5a.INDEX OF COMPOUNDS AND METHODS diethylaniline. 55 sodium bromide. 80. 68 iron salts. 86 5a-Cholestan-3/3-ol. 97 2-(#-Cyanoethyl)cyclohexanone. 158 tartaric acid.6-di-f-butylphenol. 45 4-Cyclohexylcyclohexanol. 67 ferrous sulfate. 163 Cyclohexenols. 175 Cyclohexadiene. effect of. 174 (7?>Cycphos. 40 gold. 40 Cinnolines. 108 morpholine. 23-25 187 2-Chloroaniline. 14. 61 sodium nitrite. economics of. 163 1. 108 N-ethylmorpholine. 55 zirconium. 108 ethylenediamine. 40 potassium hydroxide. 55 triethylamine. 150 Chloroanilines. 14. 17. 54 purchased. 128 4-Chloro-2. 32 Coupling reactions. 173 lead. 129 Cyclopropanes. 40. 67. 9 Decarbonylation. 108 piperidine. 55 9-Chloromethyltriptycene. 59. 38 Concentration. 43 sodium hydroxide. 129 4-Cyclohexylcyclohexyl methyl ether. 54-55 water. 125 iron. 35. choosing. 8. choosing of. 68. 75 sodium cyanide.4-Cyclohexanedione. 158-159 piperazine. 149 Chloronitroaromatics. 75 tertiary amines.and 5/3-Cholestan-3-ones.and mwis-Decalin. 7.[6-Cyanohex-2(Z>enyl] -3 -(methoxycarbonyl)cyclopentanone. 96. 61 pyridine. 158 hydroxides. 23 recycle. 48 Debenzylation. 128 Cyclohexanone. 113 Citronellol. 55 hydrobromic acid. 99 cis. 86 quinoline 54-57 quinolme-sulfur. 86. 126 Cyclohexene. 58 Decahydroquinoline. 4 use. 72. 56 potassium acetate. 6 cis-2-Decalone. 127 a-Chloroethynyl compounds. 58 Cyclobutanes. 154 reuse of. 108 perchloric acid. 86. 43. 108. 56 sulfuric acid. 154 ruthenium. 124 regulated. 148-155 . 174 Cyclopropenes. 151 Conditions. 153 /3-Cyano ethers. 117 p-Cyclohexylphenol. 135 hydrochloric acid. 118 zinc. 56 dimethylsulfoxide. 99 trans-2. 106 ethanolamine. 56 pyrroline. 56. 137 Dehydrohalogenation. 42-43 stannous chloride. 38 ci$-j3-Decalone. 25. 5 Coronopilin. 159 tin. 71. 24 regeneration. 124 support. 54. 72-74 Chuangxinmycin. 154 Decarboxylation. 44 Cinnamaldehyde. 55 silver. 107-109 2-Chlorobenzoxazole. 67 sulfur compounds. 129 f/y-a-Cyclohexylglycine. 108 ferrous chloride.

6-Dioxaspiro[4. 74 1. 164 2.1-Dimethylcyclohexane.5-Dimethyl-2-acetoxy-4-hexene. 45 2. 54 Diphenylmethane. 142 3. 173 1. 127 1. 173 3. 120 Diketones. 151 Epimerization.4-Dinitroanisole. 43 1. 59 Dialkyl hydrazines.2'-Dinitrobiphenyls. 139 Edible hydrogenated fats. 138 Diphenylethylene.5-Diketones.5-Dimethyl-l. 130 ds-2. 97.4-Dimethylphenol. 112 2.2-Epoxydec-4-ene. 60 DIPAMP. 112 2-jS-Dinitrostyrenes.1-Diesters.5-Diacetoxy-2. 100 4. 175 5. 71-72 0-Diketones. 113 Diaminotoluene. resistance.4-Dichlorophenylhydroxylamine.4-Diketones. 112 2. 69 1. 175 Dibenzylamine. 127 2.3-Diphenylbut-2-ene epoxide.8-dimethoxy-l-tetralone. 112 2. 127 3.5]decanes.4-Dihydroxyphenylalanine. 128 2. 13. 113 2.2-Epoxydec-4-yne. 17 2.6-Di-r-butylcyclohexanone.3-cyclohexanedione. 40 . 59 INDEX OF COMPOUNDS AND METHODS Dimethylamine. 72 3. 29-37.5diene-2.5-Diacetoxy-2.5-Dimethylmorpholine. 62 1.4-Dimethylcyclohexanone.4-6]pyridine. 59 2. 125 Dielectric constant. 43 Dihydrothebainone. 6 6-Demethyl-6-deoxytetracycline. 107 Enalapril maleate. 40 Dihydropyrazines. 47 1. 72 2. 57 Dihydro-2-benzazepine.5-Dimethyh'soxazolo[5. 138 fZ>l.5-dimethyl-3-hexyne. 97 Disproportionation. 12 l.2. 47 Diphenyl ether. 113 DIOP.4]nonanes. 137-139 without ring reduction.4-Dinitro-l-(AT-piperidyl)benzene.5-Dimethoxy-2-oximino-l-indanone.14-Dihydroeremophilone.10-Diazabenzo[6]biphenylene. 62 Epilaurallene. 149 Dihydrocoronopilin.4-Dinitroaniline. 168 Dropwise addition.5-Dihydroxyphenylacetic acid. 111 5.4-Dichloronitrobenzene.5-Dimethylisoxazole. 127 3. 69 3. 36 Double-bond migration. 21 Dicyclohexyl ether. 32 13. 43 Dihydrothebainol. 107 Electrophilicity. 118. 34 Electronic factors. 119 Dipropylamine. 69-70. 113 Diaminobiphenyls.8-Diisopropylnaphthalene. 111 2. 140 Epinephrine hydrochloride. 54 Diphenylethyne.5-dimethyl-3-hexene.2-Diaminobiphenyl. 109. 20 3.5-Dihydropyrene.5-Dialkyl-A3-4-dehydroindolizidine alkaloids. 47 Dioxane.4-Dinitroalky !benzenes. 60 l.1]heptane-2.3-Dicarbethoxy-5. 108 2. 100 Dimethylbicyclo[2. 127 Dihydrothebaine. 69 1. 120 3.4-Di-f-buty !naphthalene. 69 4. 60 Eremophilone. 90 Deoxygenation. 173 3. 173 portion-wise addition.4-Dinitrophenol. 130 Dicyclohexylamine. 95. 166 Enynones.5-Dimethoxy-2-aminoindan.3-Dimethylcyclohexanone.2-Epoxydecane.3-dicarboxylate. 121 Dihydroresorcinol. 101 4. 36-39 Dienones.6-Dioxaspiro[4. 85 Enol phosphate. 140 3.188 Dehydronicotine. 8 Dienes. 127 Dimethylhydrazine. 60 l. 79 Diffusion.8-Dihydroxynaphthalene.

175 4-Homoprotoadamantane. 79. 32 transfer. 13-16. 158 1-Hydroxyazetidine. 128. 118-119 Exocyclic olefins. 134 Induction periods. 105 8-Hydroxy-l-tetralone. 165-166 Ethyl adipate. 120-121 Glucose. 153. 95 Ethoxycyclohexanols. reactors. 118. 31. 168-169 Hydrogen availability. 163 cyclohexadiene. 46 Indoles.Z. 105 cis. 17-21 materials of construction. 158 Homogeneous catalysis. 168-169 Hydrazine. 107 Formic acid. 133-134 Fused rings. 57 effect of. 45.Z>3. 117 Hexahydromandelic acid. 163 formic acid. 158 o-(2-Hydroxycyclohexyl)phenol. 123. 153 Isocoronopilin. 133-147 Hexahydrobenzoic acid. see also Catalysts 1-Iodoeicosane. 163. 138 l-Ethoxy-3-methylcyclohexene.6. 107. 6 Inhibitors. 36 189 36-41. 20-21 rupture disks. 112. 172 M-Hydroxylysine. Impurities. 165 Ethyl orsellinate. 107. 21 Hydrolysis. 100. 31 Halonitro aromatics. 89 L-Gulono-l. 129 4-Hydroxydodec-2-ynoic acid. 128 N-Hydroxyamino acids. 162-163 agents. 108 Halonitro compounds. 80 1. 80 Ethyl p-aminobenzoate. 16 Hexamethylene glycol. 174 Hydrazides. 158 9. 78-80 O-(Ethoxycarbonyl)-3-methoxymandelonitrile. 170 Ethyl 4-methyl-l-cyclohexenyl ether. 124 Ethyl 2-arylhydrazine carboxylates. 163 Furans. 45. 134 N-acetylindoles. 112 Hydrazones. 127 Fatty acids. 32 Isodamsin. 32-33. 163 hydrazine. 163 cyclohexene. 84 Ethylbenzene. 168 Homobenzylic oxygenated substituents. 169 hydrate. 167-168. 129 Ethyl-4-aminocyclohexane carboxylate. 17. 21 safety of. effect of. 85 Ethyl pyrrole-3-acetate. 70 Ethyl /?-tolyl ether. 121 2-Hydroxy-3-nitronpropanoic acid. 33 Isoflavan. 176 Hydroquinone. 54 Heterocycles. 164 Isomerization.9-Heneicosatrienol. 55 Hydroxylamines. 37 Fixed-bed processes. 54. 79 Homoallylic systems. 168 .INDEX OF COMPOUNDS AND METHODS Esters. 30. 2 Fluoroaniline. 153 Haptophilicity. 31 elimination. 2 trickle-bed. 129 Ethyl 2-Oxo-4-phenyl butanoate. 100 Hydroperoxides. 74. 70 Ethyl pyrrole-3-glyoxalate. 66 H I Half-hydrogenated states. 8. 67 Glyoxylic acid. 163 reduction. 2 flooded-bed. influence of. 16-17 Hydrogenation. 46 Indenones. 46-47.and fm/zs-Indanone.6-Hexanediol. 31. 72 (Z.10-Hydroxymethyltriptycene.4-lactone.

2.5-dihydroxy-4-methoxy-7-(3-azido3-carboxypropoxy)flavanone. 176 M Maleic anhydride. 157 2-Methyl-2-phenylaziridine. see also Catalysts choosing. 164 /?-(7V-Morpholino)nitrobenzene. 84 Isoquinuclidone.190 Isoprene. 157 5-Methylthebaine. 17 Methylcyclohexane. 166 0-Keto amides.3. 33 3-Methylcyclohexene. 33. 36 tf-Limonene. 57 2-(m-Methoxyphenylethylamine). 41 4-Methyl-3-cyclohexenyl ethyl ether. 128. 104-114 Nitroaldehydes. 48 (±)-Lycodoline. 140 l-Methyl-4-isopropyl-cyclohexene. 79 Mandelic acid. 75 Methyl indole-4-carboxylate. 56 Ketal. 4-5 effect of. 6 o-Nitroanisole. 113 Methyl 3-oxoalkanoate. 43 Mevinolin.4-benzenediamine. 119 2-Naphthol. 33 Methylenediisoxazoles. 149 Nicotine. 75 (S>a-Methylbenzylamine. 35 Methylcyclohexylcarbinol. 170 Naphthalene. 133 Methyl 3-hydroxyalkanoates. 126 Methoxycyclohexanols. 110 . 118 5-Methyldihydrothebaine. 110-111 o-Nitroaniline. 140-142 INDEX OF COMPOUNDS AND METHODS Methyl hardwickiate. 41 1-Methylcyclohexene. 159 Masked functions. 33 4-Methoxypyridine. 17 8-Methyl-l-naphthoic acid. 11. 85 l-Methyl-4-f-butylcyclohexene. 95 4-(4-Methoxyphenyl)-3-(2-nitro-4methoxyphenyl)-l-pentene. 17 2-Methylcyclohexene. 105-106 Nitrobenzene. 111 0-Nitrobenzonitrile.4-tetrahydro-l-naphthoic acid. 133 Methyl hexahydrohardwickiate. 38 Isoquinuclidine. 118 8-Methyl-l. 66-75 Labeling. formation of. 53 2-Morpholinoisoflav-3-ene. 6 Nitriles. 43 Methylenecyclohexane. 94-101 Nitro compounds. 158. 129 Natural oils. use during alkylation. 41 Methyl 3 '. 33 4-Methylcyclohexene. 69 Ketones. 35. 60 Ligand synthesis. 84 Isoxazoles. 14-15 Limonene. 38 Minocycline.2-benzenediamine. 17 Lock-and-key concept. 6 Nicotyrine. 139 Methylphenylcarbinol. 89 p-Methoxyaniline. 90 Molecular queuing. 69 /3-Keto esters. 31 Methoxatin. 109 N tfAcis-Jasmanate. 15-16 Mandelonitrile. 13 8 5-(Methoxymethoxy)-2-pentenal. 176 Leukotrienes. 111 4-Nitro-l . 13 Leaving group. 33 4-Methyl-l-cyclohexenyl ether. 140 Isoxazolines. 35 4-Methylcyclohexyl ethyl ether. 88 Metal concentration. 95 Mannich bases. 107 2-Nitro-l . 68. 34 Neighboring-group assistance.

129-130. 162 Perhydrorosin. 139 Pressure. 41 Nucleoside N-oxides. 135 Phenols. 94. 176 a-Phellandrene. 31. 109. 110 2-Nitrophenylacetaldehyde oximes. 176 Parr hydrogenator. 135-137 Progargylamines. 94-101 Oximino ketones. 176 Peroxy acids. 6 Phenylethanol. 17 l-Phenyl-5-chlorotetrazole. 85 Ozonides. 36-39 Polyhalo compounds. 29-30 Osazones. 95. 95. 60 Norepinephrine. effect of. 31 Olefinic epoxides. 56 2-Oxo-4-phenylbutanoate. 17 Pheromones. 100 Oxiranes. 109 3-Nonyn-l-ol. 151-152 Porphobilinogen. 29-48 mechanisms of. 14 Peptides. 113 Nitroketones. 111 Phenylhydrazones. 139 Phenylethylamine. 90. 109-110 Olefinic sulfur compounds. 109 f/y-a-Phenylglycine. 37 Prostaglandins.3. 143-144 Oxazolines. 107 Piperazines. 117 Peri strain.6-diynol. 55 Phoracantholide I. 175 1-Phenyltetrazolyl ether of tyrosine. 98 Portion-wise addition. 39-41. 18-20 1. 37 2. 60 Olefinic nitro compounds. 128 Phenylcyclohexane.10-dodecadiene-2ynamide. 61 Propionitrile.3-Pentadiene. 128 exo-2-Phenyl-9-oxabicyclo[3. 109 Nitropyridines. 118-120 5-Phenyl-2-(3. hydrogenation of. 10 1-Phenylethanol. 111 Polycyclic systems. 157 Peroxides. 127-128. 107 Phenylisocyanate. 111 3-Nitro-2-methylbenzoic acid. 129 2-Phenylquinoxaline. 170 ^-Phenylethylamines. 120. 119 . 118 Phenylalanine.4-Pentanediol. 173 N-Nitrosoamines. 80 PAMPO.INDEX OF COMPOUNDS AND METHODS o-Nitrobenzyl ketones. 126-130 Phenylacetaldehyde oxime. 137-139 4-Oxo-mmm7/zs-7. 111 C-Nitroso compounds. 17 4. 44-48 Olefins. 9 Octane. 169 Phenylhydroxylamine.7-Phenanthroline. 87 Nucleophilicity. 37 A9-10-Octalin. 169 Oxazoles. 176 Oximes. 111 Nitroenamines. 47. 37 /3-Octalone. 113 Nitronitriles. 149 A1^-OcIaIm. 97 Propylene. 150 Phosphinic acid. 111 •y-Nitroketones. 169-170.1]nonan-2-ol. 172 191 Octadeca-3. 159 /?-Phenylphenol. 109 Phenylacetic acid. 111 l-(2-Nitrobenzy l)pyrrol-2-aldehyde. 101 2-Oximino-l-indanone. 120. 69 a-Oximino ketones. 119-120 Polyenes. 55 Protecting group. 54 Octadecahydro-9-chloromethyltriptycene.4-dimethoxybenzyl)-2~ oxazoline. 144 o-Phenylenediamine. 173 0-Nitrostyrene. 143-144 Oxidation. 110-111 a-Nitroketones.

109.5]octane. 175-176 reactive. 41 A5 Steroids. 11-13 runaway reactions. 153 1. 138-142.192 Pupukeanone. 46-47. 41 3-oxo-4-ene. 119 Toluene diisocyanate. 128 Safety in catalytic hydrogenations. 175 Stereochemistry. 7. 21 Ruthenium tetraoxide. 125-127. 138-141. 41. 41-42. 170 Tertiary amines. 135-137 3-Pyridinecarboxylic acids. 8-11. 5-6. 66. 40-41 . effect of. 161-162. Temperature. 37 2. 7 Solvent(s) effect of. 139 Tetrasubstituted double bonds. 100. 43 Thermodynamic selectivity. 13. 31-32 Pyrazines. 168-169.6-Tetrahydropyridines. 45. 43 Tetrasubstituted olefins.2. 99-101. 111 Pyridine. 79 Synergism. 134-135.3. 174 Rosenmund reduction. 126 Regulated catalysts. 25 Spirooctane. 10-11 Sorbitol.1. 118. 41 influence of solvent on. 57 Steric factors. 59. 99-100 Selectivity. 117-119. 154 Tripropylamine. 85-91. 67 Space-time yield. 57 Toluene. 10-11 Reductive alkylation. 31. 111 INDEX OF COMPOUNDS AND METHODS 57-59. 125-127. 54 Tricarbonylchrornium complexes. 164 Racemization. 153 Tetrahydrofuran. 79. 94. 70. 33-34. 128 Reactive solvents. 105.6-Trichloro-s-triazines. 121 1. 67-70. 166. 79 fl?>Tetrahydrofuran-2-carboxaldehyde. 46-47. 72 Styrene oxide. 43 Substrate purity. 111 Trans hydrogenation. 72-75. 151 Thebaine. 159 Tetracontane. 118-120. 95-96. 91. 59 Succinic anhydride. 56-58. 154 Resorcinol. 128 lriethylammonium formate. 35-41. 94-96. 8-10 measurement of. 101 Quarternization. 137 Pyridoxine. 126. 82-91 Reductive hydrolysis. 158-161. 149. 78. 95 Tetrahydropyrene. 137. 73. 164. 119. 128 Ruthenium trichloride. 167 Steric hinderance. 85 Tetrahydroisoquinolines. 35 Triphenylacetyl chloride. 15. of alkynes. 120. 160. 154. effect of. 140 Ring hydrogenolysis. 47-48. 153-155 Rosin. 133-137 Ring strain. 82. 13. 31.4. 112. 97 Tritium labeling. 152 Steroids 1-4-diene.4-Trimethylcycloheptane. 3.1-0] -isoindol-6(2//)one. 117 Runaway reactions. 99 Rupture disks. 35-45. 43. 87. 60 U Unsaturated carbonyl compounds. 84 Tetrahydropyrazino [2. 96 Pyrrolidines. 127. 113. 174 Spiro[2. 11. 34 /3-Tetronic acid. 137 Ring saturation. 58. 139 N-Substituted iminolactones. 164-165 Stereoselectivity. 54.

134. 95 V Valeronitrile. 165-166 Vinylic compounds. 136. 165 Vinyl functions. 66. 42 193 . 41-44 Vinylogous amide. 140-142.INDEX OF COMPOUNDS AND METHODS Unsymmetrical amines. 161 Z Zoapatanol. 97 Venting. 55 Vinyl cyclopropanes. 174 Vinyl ethers. 125 a-Vinyl carbonyl compounds.

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