8 Ketones and Aldehydes Goals for Chapter 18 I Draw and name ketones and aldehydes, and use spectral information to determine their structures 2 Propose single-step and multistep syntheses of ketones and aldehydes from compounds containing other functional groups, '3 Predict the products and propose ‘mechanisms for the reactions of ketones and aldehydes with oxidizing and reducing agents, amines, ‘alcohols, and phosphorus ylides. 4 Propose multistep syntheses using ketones and aldehydes as starting ‘materials and intermediates. Protect the carbonyl group if necessary, ‘A.Canthaxanthin (p,B-carotene-4’- diore) is one ofthe carotenoid pigments ‘that give flamingos their rosy pine color, Flamingo feathers are actualy white or light gray. The pink carotenoid pigments come trom the brine shrimp and algae they eat, which al contain caotenes, The birds digestive systems metabolize the earotenes, which dissolve in fats that {are deposited in new feathers as they ‘grow. Canthaxanthin is acded tothe ood for captive flamingos in 2005 to give ther thei characteristic pink coloration, 876 ‘canthaxanthin 18-1 Carbonyl Compounds We will stady compounds containing the carbonyl group (C=O) in detail because they ae of central importance to organic chemistry, biochemistry, and biology. Some of the common types of carbonyl compounds are listed in Table 18-1 Carbonyl compounds are everywhere. In addition to their uses as reagents and solvents, they are constituents of fabrics, flavorings, plastics, and drugs. Naturally occurring carbonyl compounds include proteins, carbohydrates, and nucleic acids that ‘make up all plants and animals. In the next few chapters, we will discuss the properties and reactions of simple carbonyl compounds. Then in Chapters 23 and 24, we will apy this carbonyl chemistry to carbohydrates, nucleic acids, and proteins. ‘The simplest carbonyl compounds are ketones and aldehydes. A ketone has to ally (or ary) groups bonded to the carbony! carbon atom An aldehyde as one alkyl (or TABLE 1841 ‘Common Classes of Carbonyl Compounds ° cones aldebydes RCH o carboxylic acids I acid chlorides RCH RoCHa. esters l amides 1 ROC—0-8! ROC—NH,18-2 Structure of the Carbonyl Group oO oO oO i of of ZN Z™, ZN, oN condensed structures RCHO CHO Ketone: ‘Two alkyl groups bonded to a carbonyl group. Aldehyde: One alkyl group and one hydrogen bonded to a carbonyl group. Ketones and aldehydes are similar in structure, and they have similar properties. There are some differences, however, particularly in their reactions with oxidizing agents and with nucleophiles. In most cases, aldehydes are more reactive than ketones, for reasons wwe discuss shorly, 18-2 Structure of the Carbonyl Group ‘The carbonyl carbon atom is sp* hybridized and bonded to three other atoms through coplanar sigma bonds oriented about 120° apart. The unhybridized p orbital overlaps with a p orbital of oxygen to form a pi bond. The double bond between carbon and oxygen is similar to an alkene C=C double bond, except that the carbonyl double bond is shorter, stronger, and polarized. length ener cy rey ketone C=O bond 1.23 A745 ki/mol R, (178 keal/mol ) worl De RTL) alkeneC=Cbond 134A 611 ki/mol (146 keal/mol) ‘The double bond of the carbonyl group has a large dipole moment because oxygen is more electronegative than carbon, and the bonding electrons are not shared equally. In particular, the less tightly held pi clectrons are pulled more strongly toward the oxygen atom, giving ketones and aldehydes larger dipole moments than most alkyl halides and ethers. We can use resonance forms to symbolize this unequal sharing of the pi electrons. major sinor The first resonance form is more important because it involves more bonds, filled octets, and less charge separation. The contribution of the second structure is evidenced by the large dipole moments of the ketones and aldehydes shown here. it It cc ¢ Compare with: aS YN, wo oCcH, Hc” “cH, w= 27D #=29D w=i9p y= 130d acetaldehyde acetone chloromethane dimethyl ether a7B78 CHAPTER 18 Ketones and Aldehydes ‘This polarization of the carbonyl group contributes to the reactivity of ketones and aldehydes: The positively polarized carbon atom acts as an electrophile (Lewis acid), and the negatively polarized oxygen acts as a nucleophile (Lewis base). 18-3 Nomenclature of Ketones and Aldehydes IUPAC Names Systematic names of ketones are derived by replacing the final -e in the alkane name with -one, The “alkane” name becomes “alkanone.” In open-chain ketones, we number the longest chain that includes the carbonyl carbon from the end closest to the carbonyl group, and we indicate the position of the carbonyl group by a number. In cyclic ketones, the carbonyl carbon atom is assigned the number 1 i ey ie i cut-cn.—cn, cert tren, é—cn,—cn, SisnPACnoneinhos sae 2a pene shen optae veott?AChumerageen ne 2natychan ne Reta ° ° too % . cH— CHF on, : cn, Sneyclpernene Denso son my pene ocikeccte — Sihonsteietan one ‘Systematic names for aldehydes are derived by replacing the final -e of the alkane name with -al. An aldchyde carbon is at the end of a chain, so it is number 1. If the aldehyde group is a substituent of a large unit (usually a ring), the suflix carbaldehyde rock a ooh oo ono cu—bon cuycnen, ec, eC, _ co cH, —cH,—cH—=cH—cHo C)ctto Ci paren cyclohexanecarbaldehyde —_2-hydroxycyclopentane-|-carbaldehyde A ketone or aldehyde group can also be named as @ substituent on a molecule with a higher priority functional group as its root. A ketone or aldehyde carbonyl is named highest) acids by the prefix oxo- if it is included as part of the longest chain in the root name. When. esters an aldehyde — CHO group is a substituent and not part of the longest chain, itis named, aldehydes by the pretix formyl. Carboxylic acids frequently contain ketone or aldehyde groups In named as substituents, cats 5 aa i ® _ °° ese I cH I nee crc, —C—cH,—cH0 n—C—C—cH,—coon eT coon (owest) halides Seoxopentanal 2-formylbenzoie acid Sdedioxobutanoie acid183 Nomenclature of Ketones and Aldehydes 879 Common Names As with other classes of compounds, ketones and aldehydes are often called by common names instead of their systematic IUPAC names. Ketone common names are formed by naming the two alkyl groups bonded to the carbonyl ‘group. Substituent locations are given using Greek letters, beginning with the carbon rnext to the carbonyl group, ° cH, O CH, CH,CH,—CH—C—cH—cH,cH, thy ethyl ketone icreespatyl ketone oo oct ae ny By tl Br—CH,—CH—C—CH—cH, — CH,—CH,—CH—C—c(CH,), {-bromocthyl isopropyl ketone tert-butyl a-methoxypropyl Ketone Some ketones have historical common names, Dimethyl ketone is always called ‘acetone, and alkyl phenyl ketones are usually named as the acyl group followed by the suffix —phenone. ° ot acetone scetophenone pPropiophencne benzophenone Common names of aldehydes are derived from the common names of the corre sponding carboxylic acids (Table 18-2). These names often reflect the Latin ot Greek term for the original source of the acid or the aldehyde. Greek letters are used with TABLE 18-2 ‘Common Names of Acids and Aldehydes poeacs ed i H—C—0H Jormica, “ants” HCH formic acid oumaldehyde (etna act) (qethanal) i i cu —c—on eee, cu—c—4 acti acid actaldchyée (ethancie acid) “ethan cH.—cH.—C—on protos pion, “tics fa" cH —cH—C—H Propionic ai propionaldehyde (propane aid) “propana), I I CH—CH—CH-C—OH bury, “outer” CH CH-CH.—C—H butte acid uryraldenyde (butane acid) (ural) ILB80 CHAPTER 18 Ketones and Aldehydes common names of aldehydes to give the locations of substituents. The first letter (a is given to the carbon atom next to the carbonyl group, which is C2 in the IUPAC name. Be 8 oct a. al CH—CH—cH—C—H CH —CH—C—H rope Common name B-bromobutyraldehyde sc-methoxypropionaldehyde TUPAC name’ S-bromobutanal 2-methoxypropanal PROBLEM-SOLVING HINT PROBLEM 18-1 he nomenclature of ketones and Give the IUPAC name and (if possible) a common name for each compound. aldehydes is reviewed in Apoenci 5 ‘the Summary of Organic Nomenclature cn—cn—cn, @ on ° w) Ph I —cH.CH, cu—ci—ch, @ 0. cn, cy, 18-4 Physical Properties of Ketones and Aldehydes Polarization of the carbonyl group creates dipole-dipole stractions between the molecules of ketones and ally des. resulting in higher boing points than for hydro- Carbons and ethers of similar molecular weights. Ketones and aldehydes have no OH or N—H bonds, however, so theit molecules cannot form hytogen bonds with each other. Their boiling points are therefore lower than those of alcohols of Similar molecular weight. The following compounds of molecular weight 58 o: 60 are ranked in order of increasing boiling poins, The ketone and the aldehyde are more polar and higher-boling than the ether and the alkane, but lower-boling than the hydrogen-bonded alcoho Il I CH,CH,CH,CH, CH,—O—CH,CH, CH,CH,—C—H_-— CH—C—CH, —CH,CH,CH,—OH butane tboxyethane propanal acetone ropan-L-ol more bps bpavrc bp 56°C pote The melting points, boiling points, and water solubilities of some representative ketones and aldehydes are given in Table 18-3, Although pure ketones and aldehydes cannot engage in hydrogen bonding with cach other, they have lone pairs of electrons and can act as hydrogen bond acceptors with other compounds having O—H or N—H bonds. For example, the —OH hydrogen of water or an alcohol can form a hydrogen bond with the unshared electrons on a carbonyl oxygen atom. s ‘hydrogen bond. wet184 Physical Properties of Ketones and Aldehydes 881 TABLE 18-3, Properties of Ketones and Aldehydes ary D Ketones propan-2-one sestone CHSCOCH 9s ‘butan-2-one sethy] ethyl Ketone (MEK) CHyCOCHCH, 86 pentan-2-one smethy n-propyl ketone CHACOCH,CH,CH 18 pestan-3-one diethyl ketone CHACH,COCH,CIy, ma hhexan-2-one CH,CO(CHS CH 37 bhexan-3-one CH,CH,COCH,CH;CH, —-55 bheptan-2-one CH,CO(CH) CH 36 Deptan-3-one CIRCH,CO(CH) CH, = beplan-t-one Aisn-propyl ketone (CH,CH,CH,),CO ot 4-methylpent-3-en-2-one mesityl oxide (cu);c=cicocn, 59 butS-en-2-one methyl vinyl ketone (MVK) CH;—=CHCOCH, “ cyclohexanone “9 acetophenone methyl phenylketone CqlisCOCH 2 propiophenone ethyl phenyl ketone CelisCOCH,CH, 2 ‘benzophenone Aiphenyl Ketone CeHisCOCSHs 48 Aldehydes ‘metanal formaldehyde HCHO or CHO 92 cthanal acetaldehyde cHCHO 123 propanal propionaldehyde cHACH,CHO 81 ‘butanal mbutyraldehyde CH(CH),cHO 7 2mothylpropanal ‘sobutyraldehyde (CH,):CHCHO 66 pentanal revaleraldchyde (CHy(CH),CHO 1 3-methylbutanal isovaleraldehyde (CH,)CHCH,CHO st hexanal caprosldchyde (CH(CH),CHO 56 Deptanal rheptaldehyde (CH(CH)sCHO 45 propenal actolein CH=CH—CHO 88 ‘but-2-enal crotonaldehyde CHh—cH=cH—cHo | =7 benzaldehyde caigcno, 56 Because of this hydrogen bonding, Ketones and aldehydes are good solvents for polar hydroxylic substances such as alcohols. They are also relatively soluble in water. ‘Table 18-3 shows that acetaldehyde and acetone are miscible (soluble in all propor- tions) with water. Other ketones and aldehydes with up to four carbon atoms are fairly soluble in water. These solubility properties are similar to those of ethers and alcohols, which also engage in hydrogen bonding with water. Formaldehyde and acetaldehyde are the most common aldehydes. Formaldehyde is @ gas at room temperature, so itis often stored and used as a 40% aqueous solution called formalin. When dry formaldehyde is needed, it can be generated by heating one of its solid derivatives, usually trioxane or paraformaldehyde. Trioxane is a cyclic trimer, containing three formaldehyde units. Paraformaldehyde is a linear polymer, containing many formaldehyde units, These solid derivatives form spontaneously when a small amount of acid catalyst is added to pure formaldehyde. (ee ee 36079 oe 80081 256 102 081 55 101081 4a 127083 16 14 082 ist 081 14 147082 04 14082 11086. 30086 157094 15 22 102 os 218 1.009 3051.08, 1082 55 2078 oe 4 Ost 0 7s 082 m1 6079 n 103082 93080 129083 oa 155 08s 0.02 33084 30 1040.86 1s 19105 03 (One syrnotor of untreated diabetes is the characteristic fruity smell of acetone in the patent’ breath Because dabetics cannot se carbohydrates propetly the body goes into a stae called ketosis, n which it produces acetone and other ketones82 CHAPTER 18 Ketones and Aldehydes HOW \/ ro 8 H KI 6 HO. on wo sal Ho ot H—C—H neon ote me formalde formalin Guemrtiemandy a ts HoH oH oH paraformaldehyde (a polymer of formaldehyde) Acetaldehyde boils near room temperature, and it can be handled as a liquid. Acetaldehyde is also used as a trimer (paraldehyde) and a tetramer (metaldehyde), formed from acetaldehyde under acid catalysis. Heating either of these compounds provides dry acetaldehyde. Paraldehyde is used in medicines as a sedative, and metal- dehyde is used as a bait and poison for snails and slugs. H cH, 1 V/ ‘c ° ' 97 ~o heat heat aay ecm MS con een bye, bp paraldehyde, bp 125 °C (a teimer of acetaldehyde) smetaldehyde, mp 245 °C (a tetramer of acetaldehyde) 18-5 Spectroscopy of Ketones and Aldehydes Chapters 12 and 13 covered some of the spectroscopic properties of ketones and aldehydes. Here we review tht matcrial and see what additional information we an tan from spectroscopy. 18-5 Infrared Spectra of Ketones and Aldehydes The carbonyl (C=O) stretching vibrations of simple ketones occur round 1710 em and simple aldchydes around 1725 em”. Because the carbonyl group has a large dipole moment, these absorptions are very strong, In addition tothe carbonyl absorption, an aldehyde shows a se of two low-frequency C—H stretching absorptions around 2710 and 2810 cm” Gat sea 2510 cm) So ~ ey R—-C—R’ r—ctn elon aldehyde Figure 12-11 (page 572) compares the IR spectra of a simple ketone and aldehyde. ‘Conjugation lowers the carbonyl stretching frequencies of ketones and aldehydes because the partial pi bonding character of the single bond between the conjugated double bonds reduces the electron density of the carbonyl pi bond. The stretching frequency of this weakened carbonyl bond is lowered to about 1685 cm, Ring strain185 Spectroscopy of Ketones and Aldehydes 883 hhas the opposite effect, raising the carbonyl stretching frequency in ketones with three-, four, and five-membered rings. seat 1S ca 6 - ;— | Qo ey Semel om PCN Jo 9 Asis em) 9 Amen) 0 Lise) Al } A ‘CH, aoe ‘acetophenone but2-ena cyctopentanone m* Transition ‘The strongest absorptions in the ultraviolet spectra of aldehydes and ketones are the ones resulting from 7 —> 7r* electronic transitions. As with alkenes, these absorptions are observable (Anax > 200:nm) only if the carbonyl double bond is conjugated with another double bond, The simplest conjugated carbonyl system is propenal, shown next, The a —> 2* transition of propenal occurs at Anas Of 210 nm (e = 11,000). Alkyl substitution increases the value of Anas by about 10 nm per alkyl group. An additional conjugated double bond increases the value o' Anan bY about 30 nm, Notice the large values of the molar absorptivities (e > 5000), similar to those observed for the = —> =r* transitions of conjugated dienes, ° (ee alkyl groups Naw = 24 nm, € = 12,500 propenal Rau = 210 nm, £ = 11,000 Uxee alkyl groups Kaw = 237 nm, # = 12,000 The n> m* Transition A very weak band of absorptions in the ultraviolet spectra of Ketones and aldehydes resulls from promoting one of the nonbonding electrons oon oxygen to a 2* antibonding orbital. This transition involves a smaller amount of energy than the 7 #* transition, soit gives a lower frequency (longer wavelength) absorption (Figure 18-6). The n> * transitions of simple, unconjugated ketones and aldehydes give absorptions with values of Anas between 280 and 300 nm. Bach double bond added in conjugation with the carbonyl group increases the value of Ares bY about 30 nm. For example, the => 7" transition of acetone Occurs at Anas of 280 nm (e = 15). ‘The n> x transitions of carbonyl groups have small molar absorptvities, gener- ally about 10 to 200, These absonptions are around 1000 times weaker than = transitions because the n —» 2 transition corresponds toa “forbidden” electronic tan- sition with a low probability of occurrence. The nonbonding orbitals on oxygen are PROBLEM-SOLVING HINT CConjucated carbonyl compounds have characteristic m—> m* alosorptions in the UY spectrum ° ‘An adeitional incteases Ange about 30 rm; an adeitiona alkyl groun increases it about 10 nm.BBB CHAPTER 18. Ketones and Aldehydes FIGURE 18-6 CComparson ofthe +9 and the p= at transitons. The n+ 2 ‘ranston quires less energy because the ronbonding (electrons ae higher in energy than the bonding electrons. mime - eviaaen © Q) 2 C—O ronbonding’” cabial, allowed” transition “forbidden” tanstion 000-200, 000 0-200 PROBLEM-SOLVING HINT. Carbonyl #* absorptions are very weak, and they ae often cbscured by stronger absorptions ‘Therefore, they are rarely as useful as the > n* absorptions ers ‘Many construction materals are made of, or bonded by, phenol- ‘formaldchyse resins, Unreacted formaldehyse tox, causing tation ofthe skin, eyes, nose, and throat, Its concentration in finshed products iscarefuly regulated to levels below 0.1 ppm. Some construction materi, such as flooring and carpeting, have ‘outgassee more formaldehyde than what s considered safe, and have required rca perpendicular to the 2r* antibonding orbitals, and there is zero overlap between these onbitals (sce Figure 18-6). This forbidden transition occurs occasionally, but much less frequently than the “allowed” sr — m* transition. PROBLEM 18-5 Oxidation of cholesterol converts the alcohol to a Ketone. Under aciie of basic oxidation conditions. he C=C double bond migrates to the mote stable. conjugated position. Before IR and NMIR spectroscopy. chemists watched the UV spectrum ofthe reaction mixture to follow the oxidation. Describe how the UV spectrum of the conjugated product, cholest-4- ‘en-3-one, difers from that of cholesterol cholesterol, cholest-tsn--one 18-6 Industrial Importance of Ketones and Aldehydes In the chemical industry, ketones and aldehydes are used as solvents, starting materi- als, and reagents for the synthesis of other products. Although formaldehyde is well known as the formalin solution used to preserve biological specimens, most of the 4 billion kilograms of formaldehyde produced each year is used to make Bakelite®, phenol-formaldehyde resins, urea-formaldehyde glues, and other polymeric products. Acetaldehyde is used primarily as a starting material in the manufacture of acetic acid, polymers, and drugs. ‘Acetone is the most important commercial ketone, with over 3 billion kilograms used each year. Both acetone and methyl ethyl ketone (butan-2-one) are common industrial solvents. These ketones dissolve a wide range of organic materials, have ‘convenient boiling points for easy distillation, and have low toxicities, Many other ketones and aldehydes are used as flavorings and additives to foods, drugs, and other products. For example, benzaldehyde is the primary component of almond extract, and (—)-carvone gives spearmint chewing gum its minty flavor. ‘Table 18-4 lists some simple ketones and aldehydes with well-known odors and flavors. Pyrethrin, isolated from pyrethrum flowers, is commercially extracted for use as a “natural” insecticide. “Natural” or not, pyrethrin can cause severe allergic reactions, nausea, vomiting, and other toxic effects in animals.Review of Syntheses of Ketones and Aldehydes 889. TABLE 18-4 Ketones and Aldehydes Used in Household Products oe o ole cH, cH, — outyradchyde saci sciopenone trane-sinnamaldehy te Odor. astery va Pistachio cinnamon User: margarine, foods foods, perfumes fice cream ‘andy, foods, drugs °. o oO ” n\_, A Odor: “earaphoraceous Doral (=) enantiomer: spearmint musky aroma (enantiomer: caraway seed Uses: Iiniments, inhalants plant insecticide candy, toothpaste, etc perfumes 18-7 Review of Syntheses of Ketones and Aldehydes In studying reactions of other functional groups, we have already encountered some of the best methods for making ketones and aldehydes. Lot's review and summarize these reactions, and then consider some additional synthetic methods. A summary table of Syntheses of ketones and aldehydes begin on page 925 18-7 Ketones and Aldehydes from Oxidation of Alcohols (Section 11-2) Ketones and aldehydes are often made by oxidizing alcohols. When we need to make a carbonyl compound, we can often use a Grignard reagent to synthesize an alcohol with the correct structure and oxidize it to the final product, In effect, you convert an, aldehyde into a ketone by adding an alkyl group to give an alcohol intermediate, which is oxidized to the ketone, Aldehyde secondary alcohol —>ketone ° on ° 1 10 | suoct I RoMex + RoC oe BO ee SE Gaignard aeyde seoondery ketone ‘ida Sodium dichromate in sulfuric acid (“chromic acid,” HyCrO,) is the traditional laboratory reagent for oxidizing secondary alcohols to ketones. Bleach (NaOCI) is an inexpensive, chromium-free alternative that also oxidizes secondary alcohols to ketones. oH : P i own AH we OK, secondary aleohol ketone890 CHAPTER 18 Ketones and Aldehydes Primary alcohols are easily over-oxidized to carboxylic acids unless the conditions are carefully controlled, Primary alcohols — aldehydes - i i nd, tattoos, gy, emus, gE oy Oxidation of a primary alcohol to an aldehyde requires careful selection of an oxidizing agent to avoid over-oxidation to the carboxylic acid. One equivalent of bleach (NaOCl!) plus the TEMPO catalyst, provides good yields of aldehydes without ‘over-oxidation, Other reagents that can convert primary alcohols to aldehydes are: PCC (pyridinium chlorochromate), a complex of chromium trioxide with pyridine; the Swem oxidation, using DMSO as the oxidant; and the Dess-Martin periodinane (DMP) oxida- tion, using a high-valence iodine compound as the oxidant, These specialized reagents are covered in Section 11-3, cH,0H cHo CT - CT (Ol w I O heptan-3-one a (a) phenylacetic acid —> 3,3-dimethyl-L-phenylbutan-2-one 18-9 Synthesis of Ketones and Aldehydes from Nitriles Nitriles can also be used as starting materials for the synthesis of ketones. Discussed in Chapter 21, nittiles are compounds containing the cyano (—C=N) functional ‘group. Because nitrogen is more electronegative than carbon, the —C—=N triple bond is polarized like the C=O bond of the carbonyl group. Nucleophiles can add to the —C=N triple bond by allacking the electrophilic carbon atom,894 CHAPTER 18. Ketones and Aldehydes A Grignard or organolithium reagent attacks a nitrile to give the magnesium salt of aan imine, Acidic hydrolysis of the imine leads to the ketone, The mechanism of this acid hydrolysis isthe reverse of acid-catalyzed imine formation, covered in Section 18-14. Note that the ketone is formed during the hydrolysis after any excess Grignard reagent hhas been destroyed. Thus, the ketone is not attacked. PX ge BY 110% Se ® voceopic stack Me sl of mise ‘nine atone MeBr Example ° or oe 0 + aoe, Be", Vemonile ——_phenynigesiam rome seszopinen mise vensopbnone Crasncsum al ‘som Aluminum hydrides can reduce nitriles to the corresponding aldehydes. Diisobutylaluminum hydride, abbreviated (/-Bu),AIH or DIBAL-H, is commonly used for the reduction of nitriles. The initial reaction forms an aluminum complex that hydrolyzes in the aqueous workup, RAUB), . ° (2) GB) ,AtH eno Rocen: SO gc# Om Re NHL \, \, in in sill aluminum complex aldehyde Example t CN WypmALH c. S {ODIEALH, SN wa DES aN, hexednonitile oxen AECHCHD) PROBLEM 18-8 Hal Predict the products of the following reactions. ‘CH,CH(CH); (a) CH,CH,CH,CH,C=N + CHCHMgBr, then 1,0" (b) CHACHLCH.CHLC=N + DIBAL-L, thea 11,0" () benzyl bromide + sodium cyanide (@) product of (c) + eyclopentylmagnesium bromide, then acidic hydrolysis (6) product of (c) + DIBAL-H, then hydrolysis PROBLEM 18-9, Show how the following transformations may be accomplished in good yield, You may ed, use any additional reagents that are n (a) bromobenzene -> propiophenone (b) CH,CH,CN— heptan-3-0n0 (€) benzoic acid — piaenyl cyclopentyl ketone (@) L-bromohep\18-10 Synthesis of Aldehydes and Ketones from Acid Chlorides and Esters 895 18-10 Synthesis of Aldehydes and Ketones from Acid Chlorides and Esters Because aldehydes are easily oxidized to acids, one might wonder whether acids are easily reduced back to aldehydes, Aldehydes tend to be more reactive than acids, however, and reducing agents that are strong enough to reduce acids also reduce aldehydes even faster. bg we fb) oe / rn te Gb) ee aenno (aot isolable) Acids can be reduced to aldehydes by first converting them to a functional group that is easier to reduce than an aldehyde: the acid chloride, Acid chlorides (acyl chlorides) are reactive derivatives of carboxylic acids in which the acidic hydroxy group is replaced by a chlorine atom, Acid chlorides are often synthesized by treatment of carboxylic acids with thionyl chloride, SOC, i i i R-C—OH + — RC—Cl + HCIf + 80,1 acid avi chloride Strong reducing agents such as LiAH, reduce acid chlorides all the way to primary alcohols. Lithium ti-ter-butoxyaluminum hydride is a milder reducing agent that reacts, faster with acid chlorides than with aldehydes. Reduction of acid chlorides with lithium tri-tert-butoxyaluminum hydride gives good yields of aldehydes. ° Lit “AO, won lithium iri-fert-butoxyaluminum byatic eo acid chloride Hoo toy hydride aldehyde Frample cH, 0 cH, soct, I I Le AmKo.-00), I on SS. ccrcn— ta ca cic —C isovalre acid inovleroyl chloride inovaleralahyde (65%) Diisobutylaluminum hydride (DIBAL-H) reduces esters directly to aldehydes at dry ice temperature, about ~78 °C. Unlike LiAIH, (Which reduces esters to primary alcohols), cold DIBAL-H usually does not reduce the aldehyde further. The initial reaction forms an aluminum complex that is stable toward further reduction, but hydrolyzes to the aldehyde in the aqueous workup, O— AUB, 0 0 A wera | amo 2 Rec OE RE ae Re \ ore T \ OR’ oR H ester aluminum complex aldehyde Example (1) DIBAL-H caso) Oo aio ‘ethyl eyclopentanecaxboxylate eyelopentanecasbaldehyde896 CHAPTER 18. Ketones and Aldehydes Synthesis of Ketones Grignard and organolithium reagents react with acid chlorides much like hydride reagents: They add R~ where a hydride reagent would add H. As we saw in Section 10-9, Grignard and organolithium reagents add to acid chlorides to give ketones, but they add again to the ketones to give tertiary alcohols. i [i] cm r—Cc-al (Gast) R'—C—R (Gast) alkoxide To stop at the ketone stage, a weaker organometallic reagent is needed: one that reacts faster with acid chlorides than with ketones. Lithium dialkyleuprates and other organocuprates (Sections 10-9F and 17-13a) react with acid chlorides to give good yields of a wide variety of ketones. ° l ROli + RCC ‘lithium dialkyleuprate acid ebloride (Gilman reagent) The lithium dialkylcuprate is formed by the reaction of two equivalents ofthe corresponding organolithium reagent with cuprous iodide. aR4i + CH > RCH + Lt ° Example i Ser a _ ee 2 Na BBR EN oui, SA oO PROBLEM 18-10 Predict the products of the following reactions: © 2° » 6 é Se) Liat Ney LAIIO-r0), aa Lato, ° i Ae @ t @)ewess ZS cua nA, See, AA, +o ° 9 eam “© 6 vAK (2) H,0 (1) DIBAI cn, HO oem18-10 Synthesis of Aldehydes and Ketones from Acid Chlorides and Esters 897 SUMMARY _ Syntheses of Ketones and Aldehydes 1. Oxidation of alcohols (Sections 11-2 and 11-3) 8, Secondary alcohols —* ketones - i Naocuons : noone Nation, __y con acho rn 2. Pinay alohly ales 6 aocyon = Nooo, dl ‘Primary alcohol eee BD aldehyde 2. Orono of aenes Secon 158) EN -& () 04-78 °C EN vm’ oes? -° * we u stone eye tex (ives aldehydes or ketones, depending onthe starting alkene) 3. Friedel-Crafts acylation (Section 17-11) ° 6. ° O ~ © R-c—cl + — « CR (+ onto) R= alkyl or aryl; aryl ketone G= hydrogen, an activating group, or halogen. The Gatterman-Koch formslation (Section 17-110) G Hcl + co + G= hydrogen, an activating group, or halogen benzaldehyde derivative 4. Hydration of alles (Section 9-9F) 8. Catalyzed by acid and mercuric salts (Markovnikow orientation) R u ° Tg! 1,504 \ 7 I Roc=c—H SS c. > RocHay sl a cons methyl ket ne Po 4 yt ketone «enol (not isolated) , Hydroboration-oxidation(amti-Markovmikov orientation) _ (1) Sia,BIT Re HG) HO, MOH” alkyne ig ‘en (not isolated) (continued) I — R—CH,—C—H aldehyde898 CHAPTER 18 Ketones and Aldehydes 5. Synthesis of ketones using organolithium reagents with carboxylic acids (Section 18-8) © oui ° IL 2RLi I #0! IL recon 28H, po ators aid L Es k ice 6. Spihss of sane ain organcciprates with acd eleries Scion 1810 i i wlia + Row — rte eters m= 17. Synthesis of ketones from nitriles (Section 18-9) N—Mex ° i Hol ROCEN + RMX > RocoR OS RR nite (RL) Me sal tone raed Aldehyde symheis by reduction of niles (Section 18.9) Rau, ° (0 0) Hor y, rocan, OCBO AT a oe Rc \ \ in i siti there complex aldehyde 9. Aldehyde synthesis by reduction of acid chlorides (Section 18-10) © Li “AMMO. i Roca RC eae HERERO ROS 10, Aldehyde syheris by reduction of enters (Seton 18-10) O—AleBO ° ° 2 wievo,amn | ano 4 Rc cee RCH RO \ ro \ ‘or’ i iH om aerrmenrm aldehyde 18-11 Reactions of Ketones and Aldehydes: Introduction to Nucleophilic Addition Ketones and aldehydes undergo many reactions to give a wide variety of useful deriva- tives. Their most common reaction is nucleophilic addition, addition of a nucleophile and a proton across the C—O double bond. The reactivity of the carbonyl group arises from the electronegativity of the oxygen atom and the resulting polarization of the cearbon-oxygen double bond. The electrophilic carbonyl carbon atom is sp* hybridized and flat, leaving it relatively unhindered and open to attack from either face of the double bond,ns of Ketones and Aldehydes Introduction to Nucleophilic Addition 899 As a nucleophile attacks the carbonyl group, the carbon atom changes hybridiza tion from sp? to sp", The electrons of the pi bond are forced out to the oxygen atom to form an alkoxide anion, which protonates to give the product of nucleophilic addition. _ mA gr BENS = yoc-O° cf ucleophiic ack alkoxide product ‘We have seen at least two examples of nucleophilic addition to ketones and alde- hhydes, A Grignard reagent (a strong nucleophile resembling a carbanion, R:~) attacks the electrophilic carbonyl carbon atom (o give an alkoxide intermediate, Subsequent protonation gives an alcohol, cu, cn, crea —t6r vies 22S cxyen,—¢—o—a shy CH; ba ba etymanesim : , rose sets atone Dean 2a Hydride reduction of a ketone or aldehyde is another example of nucleophilic addition, th hydride ion (H) serving as the nucleophile. Attack by hydride gives an alkoxide that protonates to form an alcobol OH encn,on = = Ghar ECE, + CHL H testone cH cH alkoxide sropan-2-l Weak nucleophiles, such as water and alcohols, can add to activated carbonyl groups under acidic conditions, A carbonyl group is a weak base, and it can become protonated in an acidic solution, A carbonyl group that is protonated (or bonded to some other electrophile) is strongly electrophilic, inviting attack by a weak nucleophile. oN GH Co + = . - R R activated carbonyl R The following reaction is the acid-catalyzed nucleophilic addition of water across the car bonyl group of acetone. This hydration of a ketone or aldehyde is discussed in Section 18-12. c - + HO Z hi, hi, acetone protonated, activated acetone = = so-c-—G-H == + #,0° 2 WO\ Hoy, attack by water loss of H* acetone hydrate900 CHAPTER 18 Ketones and Aldehydes In effect, the base-catalyzed addition to a carbonyl group results from nucleophilic attack of a strong nucleophile followed by protonation. Acid-catalyzed addition begins with protonation, followed by the attack of a weaker nucleophile, Many additions are reversible, with the position of the equilibrium depending on the relative stabilities of the reactants and products, In most eases, aldehydes are more reactive than ketones toward nucleophilic addi- tions. They usually react more quickly than ketones, and the position of the equilibrium Please become familar with these | ysually lies more toward the products than with ketones. The enhanced reactivity of simale mechanisms. You will see aldehydes is due to an electronic effect and a steric effect. Notice that an aldehyde has ‘many examples in the next few only one electron-donating alkyl group, making the aldehyde carbonyl group slightly ages. Also, most ofthe im more electron-poor and electrophilic (the electronic effect). Also, an aldehyde has only multistep mechanisms in ths cone bulky alkyl group (compared with two in a ketone), leaving the carbonyl group chapter are combinations of these | more exposed toward nucleophilic attack. Especially with a bulky nucleophile, the simale steps. product of attack on the aldehyde is less hindered than the product from the ketone (the steric effect) PROBLEM-SOLVING HINT. © fi wee _— mae Y a as x * R Ne etone product tos electrophilc swore crowded ° ; Re uc Noe an Y = aos R ‘a RO “a aldeyde alkoxide uct smote letephile ves crowded tes crowded PROBLEM 18-11 Show how you would accomplish the following synthetic conversions. You may use any additional zeagents and solvents you need, @ 4 » 9 Ph—CHO) —> Ph—C—Ph Ph—C—Ph —> Ph,C—olt © 9 on @ on Ph—C—Ph —> Ph—CH—Ph PhCHO —> PhcHC=ccH,cH, PROBLEM 18-12 Sodium triacetoxyborohycride, NaBIH(OAc),, is a mild reducing agent that reduces aldehydes ‘much more quickly than ketones. It can be used to reduce aldehyéles in the presence of ketones, such as inthe following reaction: ° ° ° on NaBH(OAC}, I cHcoon > Hy cH —C—cH,— CH cH, (a) Draw a complete Lewis structure for sodium riacetoxyborohydide (b) Propose a mechanism forthe reduction of an aldehyde by sodium triacetoxyborohydride. ‘The following box summarizes the base-catalyzed and acid-catalyzed mechanisms for nucleophilic addition, together with their reverse reactions.18-11 Reactions of Ketones and Aldehydes: Introduction to Nucleaphilic Addition 901 KEY MECHANISM 18-1 _Nucleophilic Additions to Carbonyl Groups Basic Conditions (strong nucleophile) Step 1: A song nucleophile adds tothe carbonyl group to form an alkoxide Sexo: + Nac—c—8- Nuc® a Step 2: A weak asi protonates the alkoxide to giv the ation product. | pue I Noc—c— FSB Nuc C 8-H Nuc EXAMPLE: Formation of a cyanohydrin (covered in Section 18-13). Step 1: A strong nucleophile adds tothe carbonyl group to form an alkoxide, benzaldehyde Step 2: A weak acid protonates the alkoxide to give the addition product, benzaldehyde cyanchydrin Reverse reaction: Deprotonation, followed by loss of the nucleophile. | I=: \ Re ne Nun ¢ 92H nur Nuer Ye PROBLEM: The formation of benzaldehyde cyanohydrin shown in the example above is reversible, Draw a mechanism for the reverse reaction, Acidic Conditions (weak nucleophile, activated carbonyl) Step 1: Protonation activates the carbonyl group toward nucleophilic attack. H iy No” — Be-g |902 CHAPTER 18 Ketones and Aldehydes EXAMPLE: Formation of a hemiacetal (covered in Section 18-16). ‘Step 1: Protonation activates the carbonyl group toward nucleophilic attack. gt a " 2 a 1 Bicnos, c te Oo cr or benzaldehyde ‘Step 2: A weak nucleophile adds to the activated (protonated) carbonyl group. Deprotonation of the product gives the hemiacetal yh ar a 3s Ip cs H + cH,on, Ny = = = s —cn, ere do-cry I HL cHOH " Ne meen Reverse reaction: Loss ofthe weak nucleophile, followed by deprotonation, - Bus — eo”) ot doe Nuc—H PROBLEM: The hemiacetal formation used in the example is reversible, Draw a mechanism for the reverse reaction. 18-12 Hydration of Ketones and Aldehydes In an aqueous solution, a ketone or an aldehyde is in equilibrium with ils hydrate, a geminal diol, With most ketones, the equilibrium favors the unhydrated keto form of be R \ a! ou fhydr. m0 + HO = tte ) v Fetonett.51 ® on eseam an) Evanple , HO OH cu—tacn, + 0 chen, y= 0.02 wee woo Hydration occurs through the nucleophilic addition mechanism shown in Mechanism 18-2, with water (in acid) or hydroxide ion (in base) serving as the nucleophile.18-12. Hydration of Ketones and Aldehydes 903 TEN RECUR CCU SuSE Ceca Inacid ‘The acid-catalyzed hydration isa typical acid-catalyzed addition tothe carbonyl group. Protonation, followed by addition of water, gives 4 protonated product, Deprotonation gives the hydrate, Step 1: Protonation, ‘Step 2: Water adds. Step 3: Deprotonation. Inbase The base-calalyzed hydration is a perfect example of base-catalyzed addition to a carbonyl group. The strong nucleophile adds, and then protonation gives the hydra Step 1: ydsoxide ads ‘Step 2: Protonation Aldehydes are more likely than ketones to form stable hydrates. The electrophilic carbonyl group of a ketone is stabilized by its two electron-donating alkyl groups, but_ | PROBLEM-SOLVING HINT. an aldehyde carbonyl has only one stabilizing alkyl group. The partial positive charge | In basic conditions a strong of the aldehyde is not as well stabilized, Aldehydes are thus more electrophilic and | nucleophile usualy adds directly less stable than ketones. Formaldehyde, with no electron-donating groups, is even less._| to te carbonyl group. In accic stable than other aldehydes, conditions, strong nucleophiles are carly present. An acid (or Lewis acid) usually protonates the el Oo carbonyl to activate it toward attack ol oll bya weak nucapnil é é ee, Re Ny ketone aidetde feamadeyde twoally groups es sabvaton —_claely unstable ‘These stability effects are apparent in the equilibrium constants for hydration of ketones and aldehydes. Ketones have values of K,, of about 10~* to 10%, For most aldehydes, the equilibrium constant for hydration is close to 1. Formaldehyde, with no alkyl groups bonded to the carbonyl carbon, has a hydration equilibrium constant of about 40. Strongly electron-withdrawing substituents on the alkyl group of a ketone or aldehyde also destabilize the carbonyl group and favor the hydrate. Chloral (richloroacetaldehyde) has an electron-withdrawing trichloromethyl group that favors the hydrate. Chloral forms a stable, crystalline hydrate that became famous in the movies as knockout drops or a Mickey Finn,904 CHAPTER 18 Ketones and Aldehydes SSeS ‘The body rapidly recuces chloral (richloroacetaldehye to trichloro- ethanol, which s responsible forthe drug's slep-inducing effec, PROBLEM-SOLVING HINT rprised to see some O—= stretch, from the hydrate, in the IR spectra of many ad The alnondscentes millpede (Apheloria montana) secretes 3 mitre of HCN and benzalenydle prevent othe” animals from eating it The millpece stores mancelonitile (benzaldehyde cyanahyetinyina reservoiz When atacke, it charges rmandelontrle rough a reaction chamber containing enzymes that cata Iyze the conversion ofthe anhysrn to benzalenyde and HCN. ° Ho. on \/ cucon—t—n + no cen k= 07 9 HO. on LA + no ae Mec kq= 40 un wn tema fomaln Ho. on \ act + no = cye—Ou PROBLEM 18-13 Propose mechanisms for (a) the acid-catalyzed hydration of chloral to form chloral hydrate. (b) the base-catalyzed hydration of acetone to form acetone hydrate, PROBLEM 18-14 ‘Rank te following compounds inorder of increasing amount of hydrate present at equilibrium, 18-13 Formation of Cyanohydrins Hydrogen cyanide (H—C=N) is a toxic, water-soluble liquid that boils at 26 °C Because it is mildly acidic, HCN is sometimes called hydrocyanic acid, H-c=I b+ HO H== HO" + pK,=92 The conjugate base of hydrogen cyanide is the cyanide ion ("*C==N¢) . Cyanide ion is a strong base and a strong nucleophile. It attacks ketones and aldehydes to give addition products called eyanohydrins. The mechanism is a base-catalyzed nucleophilic addi- tion, as shown in Mechanism 18-3. Cyanide ion attacks the carbonyl group, forming. an alkoxide ion that protonates to give the cyanohydin ‘Cyanohydrins may be formed using liquid HCN with a catalytic amount of sodium cyanide or potassium cyanide. IICN is highly toxie and volatile, however, and therefore dangerous to handle. Many procedures use a full equivalent of sodium or potassium cyanide (rather than TICN), dissolved in some other proton-donating solvent. ‘Cyanohydrin formation is reversible, and the equilibrium constant may or may not favor the eyanohydrin, These equilibrium constants follow the general reactivity trend of ketones and aldehydes: formaldehyde > other aldehydes > ketones Formaldehyde reacts quickly and quantitatively with HCN, Most other alde- ydes have equilibrium constants that favor cyanohydrin formation. Reactions of HEN with ketones have equilibrium constants that may favor either the ketones or18-13. Formation of Cyanohydrins 905 NISee WEDS 5 Formation of Cyanohyd (Cyanobydrin formation is a perfect example of base-catalyzed addition toa carbonyl group. The strong nucleophile adds in the first step to give an alkoxide. Protonation gives the cyanohydrin, \ Lo R7 SR EXAMPLE: Formation of benzaldehyde cyanohydrin. ‘Step 1: Cyanide adds tothe carbonyl. ‘Step 2: Protonation gives the eyanohydin, benzaldehyde eyanohy din (mandelonitle) the cyanohydrins, depending on the structure. Ketones that are hindered by large alkyl groups react slowly with HCN and give poor yields of eyanohydrins. ° I HO. ew Ay, tH ASS Set CH,CHy Hh CH,CHy Hh ropana ropanal eyanohyéin ‘000% i Ken HO. Lew Uh + nen SSS Sec cH,cHy cH, cH,cHy cH, wan 2-one tuan-2-006 cyano in 05%) t een HOLLLN (a5 (CH),c~ CCH), (cH),c~ cH), “te-batyletone slow reaction, poor yields ‘The failure with bulky ketones is largely due to steric effects. Cyanobydrin formation involves rehybridizing the sp? carbonyl carbon to sp’, narrowing the angle between the alkyl groups from about 120° to about 109.5°, increasing their steric interference.906 CHAPTER 18. Ketones and Aldehydes (Other names for @carbinalamine ate hemiatrinal the WUPAC term) and a-aminelechol PROBLEM 18-15 Propose a mechanism for each cyanohydrin synthesis just shown, Organic compounds containing the cyano group (—C==N) are called nitriles. ‘A cyanohydrin is therefore an a-hydroxynitrile, Nitriles hydrolyze to carboxylic acids under acidic conditions (discussed in Section 21-7D), so cyanohydrins hydro- lyze to a-hydroxy acids. This is the most convenient method for making many achydroxy acids. ° OHO I ZCN alii R-C—H + HCN => R—C—C—011 aldehyde | H eyanebyd hydroxy acid PROBLEM 18-16 Show how you would accomplish the following syntheses. (@) acctoplienone > acetophenone eyanohydrin (b) cyclopentanccarbaldehyde —> 2-cyclopentyl-2-hydroxyacetic acid (6) hexan-I-ol > 2-hydroxyheptanoic acid 18-14 Formation of Imines ‘Under the proper conditions, either ammonia or a primary amine reacts with a ketone or an aldehyde to form an imine. Imines are nitrogen analogs of ketones and alde hhydes, with a carbon-nitrogen double bond in place of the carbonyl group. Imines are commonly involved as synthetic intermediates, both in biosynthesis and in industrial synthesis, One of the best methods for making amines (both in organisms and in the lab) involves making an imine, then reducing it to the amine (Section 19-18) Like amines, imines are basic; a substituted imine is also called a Schiff base. Imine formation is an example of a large class of reactions called condensations, reac- tions that join two or more molecules, often with the loss of a small molecule such as water or an alcohol. i ia vs HY NZ AQ + sof, |e | me NS + no ketone or aldehyde PMD “NS IR-N—H R-N catindanise ine (cif) {hemiaminal) ‘The mechanism of imine formation (Key Mechanism 18-4) begins with an acid catalyzed nucleophilic addition of the amine to the carbonyl group. Attack by the amine, followed by deprotonation of the nitrogen atom, gives an unstable intermediate called a carbinolamine. ‘A carbinolamine converts to an imine by losing water and forming a double bond: a dehydration. This dehydration follows the same mechanism as the acid-catalyzed dehydration of an alcohol (Section 11-10). Protonation of the hydroxy group converts it to a good leaving group, and it leaves as water. The resulting cation is stabilized by resonance forms, including one with all octets filled and the positive charge on nitrogen, Loss of a proton gives the imine.1814 Formation of imines 907 KEY MECHANISM 18-4 Formation of Imines “This mechanism is more easily remembered by dividing it nto two pats:! 1. acid-catalyzed addition ofthe amine to the carbonyl group, 2, acid-catalyzed dehydration. First part: Acid-catalyzed addition ofthe amine tothe carbonyl group. Step 1: Protonation of the cazbonyl. ‘Step 2: Addition of the amine. ‘Step 3: Deprotonation. ‘OH Hy a ee oF A= = — + ; Royo cee (bemiaminal) eee eer eee tenet Sigp 4: Protonation ofthe —OH oop. Step 5: Loss of 0 Step 6: Deprotontion NG NZ NZ T { i a] Xe OX [+ dy ON + Hoe AY AS R H R Ha-— 2) R a a ermediats (allotted) imine EXAMPLE: Formation of benzaldehyde methyl imine. Firs pert: Aci-catalyzed ation of tbe amino tothe chou eoup Serre eee ear tee eater eel é Pp a | UTR ian, h benzaldehyde methylamine petty (ahemiaminal) "This mechanism takes place a slighily acidic pH. The amine can acta ¢stong nucleophile, s the fst half ofthis mechanism (ation to the carbons), may be drawn as either acicaalyzed or as base- Reem yur 1S-{NHPA pbeoyydanine c= i-{R] « phenytnyaraone ° Al s 1 N, wnat, ux-twn—t—sn, > cree PROBLEM 18-21 2,4-Dinitrophenylhydrazine is frequently used for making derivatives of Ketones and. aldehydes because the products (24-dinitrophenylhydrazones, called 2,44DNP derivat es) are even more likely than the phenylhydrazones to be solids with sharp melting points, Propose @ mechanism for the reaction of acetone with 2.4-dinitrophenylhydrazine in a rildly acidic solution4816 Formation of Acetals 911 PROBLEM 18-22 Predict the products ofthe following reactions, @) o ¥ cy ° + Honn, > ie © 9 @ ° modirn + mane, 2S PcHeCHCHO + NEON PROBLEM 18-23 ‘Show what amines and carbonyl compounds combine to give the following derivatives, @ ° ) © SNH Nou @ NN © NH © y CF, JO, OO s ow NO, 18-16 Formation of Acetals Under acid catalysis, ketones and aldehydes react reversibly with alcohols to form acetals. An acetal is a derivative of a ketone or an aldehyde with two alkoxy groups ‘on the same carbon atom, in place of the carbonyl group. An acetal derived from a ketone is often called a ketal.! Acetals are some of the most common organic com- pounds in the world. Table sugar, cotton fabric, and a wooden ship are all composed of acetals, We cover these common carbohydrate acetals and their polymers in Chapter 23. In the formation of an acetal, two molecules of alcohol add to the carbonyl group, and one molecule of water is eliminated, I a RO. OR" A + awnon Ba BSc 4 no Ron Rn ley soa we ROL OR BPSK Lo ro SR scot gene feat pent Although hydration is catalyzed by either acid or base, acetal formation must be acid-catalyzed, For example, consider the reaction of cyclohexanone with methanol, catalyzed by p-toluenesulfonie acid, ‘The TUPAC once éropped the term ketal, but has now eislated i sa subelas of acetals. Therefore, an aceal of aketone ean be called ether a ketal specifi) or an acetal (more gene.912 CHAPTER 18 Ketones and Aldehydes Overall reaction ° —Oyf ce pen © om toluenesulfnie acid + 2CHoH = —PeMeneloneae + HO cyclohexanone cyclohexanone slimetiyl acetal ‘The mechanism for this reaction is shown in Key Mechanism 18-5. The first step is a typical acid-catalyzed addition to the carbonyl group. The acid catalyst proton- ates the carbonyl group, and the alcohol (a weak nucleophile) attacks the protonated, activated carbonyl. Loss of a proton from the positively charged intermediate gives a hemiacetal. The hemiacetal gets its name from the Greek prefix hemi-, meaning “half.” Having added one molecule of the alcohol, the hemiacetal is halfway to becoming a “full” acetal. Like the hydrates of ketones and aldehydes, most hemiacetals are too unstable to be isolated and purified. ‘The second half of the mechanism converts the hemiacetal to the more stable acetal. Protonation of the hydroxy group, followed by loss of water, gives a resonance- stabilized carbocation, Attack on the carbocation by methanol, followed by loss of a proton, gives the acetal. Peg AUER ac Like imine formation, acetal formation is easily remembered by dividing it into two simple processes 1. The first half is an acid-catalyzed addition of the alcohol to the carbonyl group. 2. The second half isan Sy1 substitution ofthe protonated hemsacctal, First half: Acid-catalyzed addition of the alcohol tothe carbonyl group. Step 1: Protonation, Step 2: Alcohol adds ‘Step 3: Deprotonation, 7 Om " O = O Second half: Sy substitution of the protonated hemsacetal. Step 4: Protonation Step 5: Loss of water, cH—9 aa Bt hhemiacotal protonation, loss of water resonance-stabilized cation1816 Formation of Acetals 913 Step 6: Second alcohol adds Step 7: Deprotonation H cH, H-— o—cn, jen, cH—6, 6—cH, = + CH—O—H a scot PROBLEM 18-24 Propose a mechanism for the acid-catalyzed reaction of benzaldehyde with methanol to give benzaldehyde dimethyl acetal Because hydration is catalyzed by either acid or base, you might wonder why acetal formation is catalyzed only by acid. In fact, the first step (formation of the hemiacetal) can be base-catalyzed, involving attack by alkoxide ion followed by protonation to form the hemiacetal. The second step requires replacement of the hemiacetal — OH group by the alcohol —OR" group. Hydroxide ion is a poor leaving group for the Sy2 reaction, so alkoxide cannot displace the —OH group. This replacement occurs under acidic conditions, however, because protonation of the —OH group and loss of water gives a resonance-stabilized cation. Attempted base-catalyzed acetal formation [OH] poss leaving group AF . REE oe OR’ semiacotal (00 $42 displacement) tack on ketone (or aldehyde) Equilibrium of Acetal Formation Acetal formation is reversible, so the equilib- rium constant controls the proportions of reactants and products that will result, For simple aldehydes, the equilibrium constants generally favor the acetal products, For | Aceal formation is one of the example, the acid-catalyzed reaction of acetaldehyde with ethanol gives a good yield | impertant mechanisms inthis of the acetal chapter. Remember i a a two-part ‘With hindered aldehydes and with most ketones, the equilibrium constants favor | process consisting ofthese two the carbonyl compounds rather than the acetals. To enhance these reactions, the alcohol | simple mechanisms is often used as the solvent to ensure a large excess. The water formed as a by-product | 1. acidatalyzed nucleophile PROBLEM-SOLVING HINT is removed by distillation to force the equilibrium toward the right, addition to the carbonyl ‘Conversely, most acetals are hydrolyzed simply by shaking them with dilute acidin | group, and water, The large excess of water drives the equilibrium toward the ketone or aldehyde, Su! by protonation and loss ‘The mechanism is simply the reverse of acetal formation. For example, cyclohexanone | of ater then attack by the dimethyl acetal is quantitatively hydrolyzed to cyclohexanone by brief treatment with | _ alcohol dilute aqueous ac.914 CHAPTER 18 Ketones and Aldehydes cHy—0 oar, ° Fluocinolone acetonide isa steroid 1, excess HO acetal used to treat skin conditions + 0 “=>? + 2CH,OH such as eczema and psoriasis, Tae acetal group decreases the water soli ofthe parent seo enhancing its potency and allowing PROBLEM 18-25 nger duration of action. Propose a mechanism for the acid-catalyzed hydrlysis of cyclohexanone dimethyl acetal cu.on \ Cyclic Acetals Formation of an acetal using a diol as the alcohol gives a cyclic acetal. Celie acetals often have moze favorable equilibrium constants, because there is a smaller entropy loss when two molecules (a ketone and a diol) condense than when three molecules (a ketone and two molecules of an alcohol) condense. Ethylene glycol is often sed to make eyclic acetals its acetals are called ethylene acetals (or ethylene ketal ie Ho ‘uocinolone acetonide 1 ace utd & benzaldehyde ethylene glycol tiles ean Carbohydrates Sugars and other carbohydrates most commonly exist as cyclic acetals and hemiacetals. For example, glucose is a six-carbon sugar that is most stable as a hemiacetal. Lactose is a disaccharide (composed of two sugar units) that has one acetal and one hemiacetal. We discuss the structures of carbohydrates in detail in Chapter 23, on CHOH fucose slucose lactose (pen chain) (ey hemiaceta) PROBLEM-SOLVING HINT PROBLEM 18-26 wenn awatine ctor (a) CHCH,O, OCH,CH, by cH, ©) hhetriacetal, the carbonyl carbon cH—c—n atom isthe one with tw bonds to Lg FOO "OO "OO1816 Formation of Acetals 915 Piked ieee) ADCS US oh Aaa So Maca Here we apply the general principles for proposing reaction mechanisms to the hydrolysis of an acetal, These principles were introduced in Chapters 7 and 11 and are summarized in Appendix 3. Remember that you should dravw all the bonds and substituents of each carbon atom involved in a mechanism. Show each step separately, using curved arrows to show the ‘movement of electron paits (from the nucleophile to the electrophile), ‘Our problems to propose.a mechanism fr the acid-catalyzed hydrolysis ofthe following acetal o och, ‘The type of mechanism is stated to he acid-catalyzed. Therefore, we assume it involves strong clectrophiles and cationic intermediates (possibly eazbocations), but no song nucleophiles oF strong bases and certainly no carbanions or free radicals 1, Consider the carbon skeletons of the reactants and products, and decide which carbon. atoms in the products are ikely derived from which carbon atoms in the reactants. First, you must decide what products are formed by hydrolysis of the acetal. In dealing with acetals and hemiacetals, any carbon atom with two bonds to oxygen is derived from a carbonyl group. Draw an equation showing all the affected atoms. The equation shows that water must somehow add (probably by a nucleophilic atack), and the ring must be cleaved, Occ i cmH W ‘OCH, I ° 2. Consider whether any of the reactants is a strong enough electrophile to react without being activated. If not, consider how one ofthe reactants might be converted. to.a strong electrophile by protonation of a Lewis basic site (or complexation with a Lewis acid). ‘The reactant probably will not react with water until itis activated, most likely by pro- tonation. It can become protonated at either oxygen atom. We will arbitrarily choose the ring oxygen for protonation. The protonated compound is wel suited for ring cleavage to forma stabilized (and strongly electrophilic) cation. 1 Ht cH, cH, (he NS iL? 0. oot u~ Sotcu, protonation cleavage sesonancesailized eation 3. Consider how a nucleophilic site on another reactant can attack the strong electro- phile to form a bond needed in the product. Draw the product of this bond formation. | PROBLEM-SOLVING HINT [Atck by water on the eatin gives «potonsedemiacta To lose an —08 ot OH group under ac conten, consider CHOH ‘cHOH H,0H | protonating the group and losing wo ee Lc OH a neutral molecule to give a Dey ‘i CH 2G Catbocaton. 7 So—cn, n~ oct, u~Socn, tacky wate eaacet eprotonation (continued)916 CHAPTER 18. Ketones and Aldehydes PROBLEM-SOLVING HINT ‘The mechansm of a reverse reaction is normally the reverse cof the mechanism ofthe forward reaction, as long as they take place Under similar conditions I you know the mechansm for formation cof an acetal, you can always write ‘the mechanism for its hydrolysis, Using the same intermediates in reverse order. 4, Consider how the product of nucleophilic attack might be converted to the final product (Grit has the right carbon skeleton) or reactivated to form another bond needed in the product. Just as an —OH group can be lost by protonation and loss of water, the —OCH, group can be lost by protonating it and losing methanol. A protonated version ofthe product result, a on [= eae HO ‘SS 11,0" reduels resonance-sabiized intermediate 5. Draw all the steps of the mechanism, using curved arrows to show the movement of clectrons. ‘The complete mechanism is given by combining the preceding equations. You should write ‘out the mechanism to review the steps involved. ‘As further practice in proposing reaction mechanisms, do Problems 18-27 and 18-28 by ‘completing the five steps listed inthis section, PROBLEM 18-27 In the mechanism for acetal hydrolysis shown, the ring oxygen atom was protonated first, the ring was cleaved, and then the methoxy group was lost. The mechanism could also be written to show the methoxy oxygen protonating and cleaving first, followed by ring cleavage. Draw this alternative mecbanism. PROBLEM 18-28 {a) Propose a mechanism for the acid-catalyzed reaction of cyclohexanone with ethylene glycol to give cyclohexanone ethylene acetal (b) Propose a mechanism for the acid-catalyzed hydrolysis of cyclohexanone ethylene acetal. (©) Compare the mechanisms you drew in parts (a) and (b) How similar are these mechanisms, ‘comparing them in reverse order? (@) Propose & mechanism for the acid-catalyzed hydrolysis of the acetal given in Problem 18-2660. 18-17 Use of Acetals as Protecting Groups Acotals hydrolyze under acidic conditions. but they are stable to strong bases and nucleophiles. Acctals are easily made from the corresponding ketones and aldehydes and casily converted back to the parent carbonyl compounds. This easy interconversion, makes acctals attractive as protecting groups to prevent ketones and aldchydes from reacting with strong bases and nucleophiles. We first encountered protecting groups in Section 14-10, using silyl ethers to protect alcohols. ‘As an example, consider the following proposed synthesis. The necessary Grignard reagent could not be made because the aldehyde carbonyl group would react with its own nucleophilic organometallic group.1817 Use of Acetals as Protecting Groups 917 Proposed synthesis (Gncompaitle Fanetional groups) y OMgBr 9 oH o 0 ° I 1 cHcH—t—n Ho" cucu, — + ébty—crycu Sen YX Be, cyloboranone ——_ Ginponuble reagend urge congo Iv the aldehyde is protected as an acetal, however, itis unreactive toward a Grignard reagent, The “masked” aldchyde is converted to the Grignard reagent, which is allowed to react with cyclohexanone, Dilute aqueous acid both protonates the alkoxide to give the alcohol and hydrolyzes the acetal to give the deprotected aldehyde. Actual synthesis HOCH,CH,OH OOM OO serencn— tan SOBRE cycA te cc Se =a ‘masked aldehyde protect from basic reagents oH q I CH,CH,—C—H target compound Selective Acetal Formation Because aldehydes form acetals more readily than ketones, ‘we can protect an aldehyde selectively in the presence of a ketone. This selective pro- tection leaves the ketone available for modification under neutral or basic conditions without disturbing the more reactive aldchyde group. The following example shows the reduction of a ketone in the presence of a more reactive aldehyde: ° equiv ° H 01 on_ow Naw, = _“_ © © A Ht Hon H a c. Se -_ oo =6 oo PROBLEM 18-29 Show how you would accomplish the following syntheses. You may use whatever additional reagents you need, @ oO ® 0 Ho, ct, ‘CHO ‘CHO @ q Hon Ph cH, cH, cH, CH, 3 6 (continued)918 CHAPTER 18. Ketones and Aldehydes 0 ° ° Ph B:CH,CH,CCH, —> He=ccH,cH,ccn, 18-18 The Wittig Reaction We have seen carbonyl groups undergo addition by a variety of carbanion-like reagents, including Grignard reagents, organolithium reagents, and acetylide ions. In 1954, Georg, Wittig discovered a way of adding a phosphorus-stabilized carbanion to a ketone oF aldehyde. The product is not an alcohol, however, because the intermediate undergoes elimination to an alkene. In effect, the Wittig reaction converts the casbonyl group of a ketone or an aldehyde into a new C—C double bond where no bond existed before This reaction proved so useful that Wittig received the Nobel Prize in Chemistry in 1979 for this discovery, The Wittig reaction R R R R Seno Nei So Sonc(” + mp 7 7 ON “oN * R " Ph R H stone or aldehyde hosphorus ide alkene ‘The phosphorus-stabilized carbanion is an ylide (pronounced “ill’-id”)—a molecule that bears no overall charge but has a negatively charged carbon atom bonded to a positively charged heteroatom, Phosphorus ylides are prepared from tti-phenylphosphine and alkyl halides in a two-step process, The first step is nucleo- philic attack by triphenylphosphine on an unhindered (usually primary) alkyl halide. ‘The product is an alkyltriphenylphosphonium salt. The phosphonium salt is treated with a strong base (usually butyllithium) to abstract a proton from the carbon atom bonded to phosphorus. Ph- ‘> C Ph, 1 Ph, ph* YR] + Ct N | I aheucn, ce opi + HSCrx — moe “ mt BOE mt vai 1 4 Poe + ux ipenyghospine si aie x Prop. hasponium sl Ph phosphors ye Examples vi be 5 ti, Se Pap: — —— mp—cn, So pp, —— ‘methyliriphenylphosphonium salt vylide C PhP! + PhCH, Br — — benzyltephenylphosphonium salt‘The phosphorus ylide has two resonance forms: one with a double bond between carbon and phosphorus, and another with charges on carbon and phosphorus. The dou- bble-bonded resonance form requires ten electrons in the valence shell of phosphorus, using ad orbital. The pi bond between carbon and phosphorus is weak, and the charged structure is the major contributor. ‘The carbon atom actually bears a partial negative charge, balanced by a corresponding positive charge on phosphorus, PROBLEM 18-30 ‘Trimethylphosphine is a stronger nucleophile than triphenylphosphine, but its rarely used to make ylides, Why is trimethylphosphine unsuitable for making most phosphorus ylides? Because of its carbanion character, the ylide carbon atom is strongly nucleo philic, It attacks a carbonyl group to give a charge-separated intermediate called a betaine (pronounced “bay’-tuh-ene”). A betaine is an unusual compound because it contains a negatively charged oxygen and @ positively charged phosphorus on adjacent carbon atoms. Phosphorus and oxygen form strong bonds, and the attraction of opposite charges promotes the fast formation of @ four-membered oxaphosphetane ring, (In some cases, the oxaphosphetane may be formed directly by a cycloaddition, rather than via a betaine.) ‘The four-membered ring quickly collapses to give the alkene and triphenylphos- phine oxide. Triphenylphosphine oxide is exceptionally stable, and the conversion of triphenylphosphine to triphenylphosphine oxide provides the driving force for the Wittig reaction IVIse SOLUS vide ketone or aldehyde ‘Step 2: The betaine closes toa four-membered ring oxaphosphetane (frst P—O bond formed). teiphenylphosphine oxide + alkene 1818 The Wittig Reaction 319920 CHAPTER 18 Ketones and Aldehydes ‘The following examples show the formation of carbon-carbon double bonds using the Wittig reaction, Mixtures of cis and trans isomers often result when geometric isomerism is possible, Oyo eat = Ohm (cis + ans) PROBLEM 18-31 Like other strong nucleophiles. tiphenylphosphine attacks and opens epoxides. The initial product (a betaine) quickly cyclizes to an oxaphosphetane that collapses to an alkene and triphenylphosphine oxide (a) Show each step in the reaction of irans-2,3-epoxybutane with triphenylphosphine to give but-2-ene. What isthe stereochemistry of the double bond in the product? (b) Show how this sequence might be used to convert cis-cyclooctene to frans-cyelooctene Planning a Wittig Synthesis The Wittig reaction is a valuable synthetic tool that converts a carbonyl group to a carbon-carbon double bond. A wide variety of alkenes may be synthesized by the Wittig reaction. To determine the necessary reagents, mentally divide the target molecule at the double bond, and decide which of the two components should come from the carbonyl compound and which should come from the ylide. In general, the ylide should come from an unhindered alkyl halide Triphenylphosphine is a bulky reagent, reacting best with unhindered primary and methyl halides. It occasionally reacts with unhindered secondary halides, but these reactions are sluggish and often give poor yields. The following example and Solved Problem show the planning of some Wiltig syntheses Analysis nC . Se=o + Phos HC” BN as JR (preted) c: uc Ny could come ror or CHCH, . HLH, Ph, + Synthesis ome ,_ SHH, pan PAPC H119 Oxidation of Aldehydes 921 SOLVED PROBLEM 18-2 ‘Show how you would use « Wittig reaction to synthesize I-phenylbuta-1,3-diene, 1-phenylbuta1 3-diene SOLUTION ‘This molecule has two double bonds that might be formed by Wittig reactions. The central double bond could be formed ia either ‘of two ways. Both of these syntheses will probably work, and both will produce a mixture of cis and trans isomers. on ‘on satoats JFK, ct, You should complete this solution by drawing out the syntheses indicated by this analysis (Problem 18-32) PROBLEM 18-32 PROBLEM-SOLVING HINT (a) Outline the syntheses indicated in Solved Problem 18-2, beginning with aldehydes and | | Plan a Wittig synthesis so thatthe alkyl halides. less hinderes end of the double (b) Both ofthese syntheses of L-phenylbuta-1,3-diene form the central double bond. Show | | bond comes fram the ylde how you would synthesize this target molecule by forming the terminal double bond. Remember thatthe yi i made by x2 attack of tiphenylphosphine on an unhinderee aley halide, followed PROBLEM 18-33 by deprotonation. ‘Show how Wittig reactions might be used to synthesize the following compounds. In ‘each ease, start with an alkyl halide and a ketone or an aldehyde. (@) Ph—cL () Ph—C(CH, @ 1 cree 18-19 Oxidation of Aldehydes Unlike ketones, aldehydes are easily oxidized to carboxylic acids by common oxidants such as bleach (sodium hypochlorite), chromic acid, permanganate, and peroxy acids, Aldehydes oxidize so easily that air must be excluded from their Containers to avoid slow oxidation by atmospheric oxygen, Because aldchydes oxidize so easily, mild reagents such as Ag,0 can oxidize them selectively inthe presence of other oxidizable functional groups, cu, (0) I riding agen” = RTC OH R-C-H922 CHAPTER 18. Ketones and Aldehydes A Tollens testis usualy done on a smal scale, but it can also create asiver mirror ona large object. ° Examples Nacyo, 1 Tine CH GI—C— on cx, ssa act 00%) ° I Ag,0 on Ta" om eyelet ara cycles Fen euboxyie acid Silver ion, Ag, oxidizes aldehydes selectively in a convenient functional-group test for aldehydes. The Tollens test involves adding a solution of silver-ammonia complex (the Tollens reagent) to the unknown compound, If an aldehyde is present, its oxidation reduces silver ion to metallic silver in the form of a black suspension or a silver mirror deposited on the inside of the container. Simple hydrocarbons, ethers, ketones, and even alcohols do not react with the Tollens reagent. 9 lL e 1,0 I R-C—H + 2AgQNH), + 3-0 —"> 2Ag] + R—-C—O- + 4NH, + 2H,0 aldehyde Tollens reagent silver carboxylate PROBLEM 18-34 Predict the major products of the following reactions a 0 o cn LY sxe LOY = sso. eX ato @ ao = soa.con (OT rat, ‘oe ° 18-20 Reductions of Ketones and Aldehydes We have discussed several reductions of ketones and aldchydes in earlier sections. Here, we review those reactions and then cover some additional reductions that are useful in synthesis. 18-20A Hydride Reductions (Review) Ketones and aldehydes are most commonly reduced by sodium borohydride (see Sections 10-11 and 18-11), Sodium borohydride (NaBH) reduces ketones to secondary alcohols and aldehydes to primary alcobols. Lithium aluminum hydride (LiAIHL,) also accomplishes these reductions, but itis a more powerful reducing agent, and itis much, more difficult to work with. Sodium borohydride is preferred for simple reductions of ketones and aldehydes. Sodium tiacetoxyborohydride [NaBH(OAc)3] is less reactive than NaBH,, and it selectively reduces aldehydes even in the presence of ketones. i - Cm NaBH, CH,CH,OH Oe H ‘yclohexanecatbaldehyde cylohexylmethanol (95%)18.20. Reductions of Ketones and Aldehydes 9 on I ast cri08 | ,—C—cr.cn, SEBO yy ccc, butan2-one (#) brand 100%) 18-208 Catalytic Hydrogenation Like alkene double bonds, carbonyl double bonds can be reduced by catalytic hydroge- nation, Catalytic hydrogenation is slower with carbonyl groups than with olefinic double bonds, however, Before sodium borohydride was available, catalytic hydrogenation was often used to reduce aldehydes and ketones, but any olefinic double bonds were reduced as well, In the laboratory, we prefer sodium borohydride over catalytic redu tion because it reduces ketones and aldehydes faster than olefins, and no gas-handling equipment is required. Catalytic hydrogenation is still widely used in industry, how- ever, because Hy is much cheaper than NaBH, and pressure equipment is more readily available there, ‘The most common catalyst for catalytic hydrogenation of Ketones and aldehydes is Raney nickel, Raney nickel is a finely divided hydrogen-bearing form of nickel made by treating a nickel-aluminum alloy with a strong sodium hydroxide solution. The aluminum in the alloy reacts to release hydrogen, leaving behind a finely divided nickel, powder saturated with hydrogen. Pt and Rh catalysts are also used for hydrogenation of ketones and aldehydes i i f : “sy Nel, “sy ™~ 18-20€ Deoxygenation of Ketones and Aldehydes A deoxygenation replaces the cazbonyl oxygen atom of a ketone or aldchyde with two hydrogen atoms, reducing the carbonyl group past the alcohol stage all the way to a methylene group. Formally, a deoxygenation is a four-electron reduction, as shown by the following equations. These equations use H, to symbolize the actual reducing agents, according to the general principle that one molecule of Hy corresponds to a two-clectron reduction, Formally, the deoxygenation requires two molecules of Hh, corresponding to a four-lectron reduction, 2, eenaeo) ° H OH HOH I a, \/ 4 \/ a a + oN (Q-¢ reduction) oN (Qereduction) = /' oY i0 In actual use, Hh isnot a good reagent for deoxygenation of ketones and aldehydes. Deoxygenation can be accomplished by ither the Clemmensen reduction (under acidic conditions) or the Wolff-Kishner reduction (under basic conditions). ‘Clemmensen Reduction (Review) ‘The Clemmensen reduction commonly convests avylbenzenes (from Friedel-Crafts acylation, Section 17-11B) to alkylbenzenes, but it also works with other ketones and aldehydes that are not sensitive to acid, The carbonyl compound is heated with an excess of amalgamated zine (zine treated with mercury) and hydrochloric aid. The actual reduction occurs by a complex mechanism on the surface ofthe zine 923924 CHAPTER 18 Ketones and Aldehydes ° I Za(Hg) motores m—er—ercu, ‘Propiophenone nt ‘n-propylbenzene (90%) cu-cny—cno ser —eat,—cn, ‘heptanal ” mheptane (72%) o H ZaiHg) H ceteunone yloonne 5%) Wolff-Kishner Reduction Compounds that cannot survive treatment with hot acid can be deoxygenated using the WolffKishner reduction. The ketone or aldehyde is converted to its hydrazone, which is heated with a strong base such as KOH or potas sium fert-butoxide, Ethylene glycol, diethylene glycol, or another high- boiling sol- vent is used to facilitate the high temperature (140-200 °C) needed in the second step. i 1 + i. H i : ron, HW Lee uycnm 3 Uh no "Secs ao — Examples 9 xNE, lM on 156 . — Hoch, cio, cron” +N sropiopkenone bydrazone iethylne glo) ppropytbenzene (82%) oO N—NH, Not ° H ~~ eee +N, I CHS—CH, cyclohexane (80%) cyclohexanone hydruzone (DMSO, 2 sotven) ‘The mechanism for formation of the hydrazone is the same as the mechanism for imine formation (Key Mechanism 18-4 in Section 18-14). The actual reduction step involves two tautomeric proton transfers from nitrogen to carbon (Mechanism 18-7).In this strongly basic solution, we expect a proton transfer from N to C to occur by loss of 4 proton from nitrogen, followed by reprotonation on carbon. A second deprotonation sets up the intermediate for loss of nitrogen to form a carbanion. This carbanion is quickly reprotonated to give the product Pie eaueaec stu) MECHANISM 18. Formation of the Hydrazone: See Key Mechanism 18-4. Reduction step I: Proton transfer from N to C. (Basic conditions: Remove, then replace.) hydrazone remove proton from N replace proson on ©10 Reductions of Ketones and Aldehydes 925 Another deprotonation enables loss of Ny Reduction step 2: Remove second proton from N. Step 3: Lose Nz, PROBLEM 18-35 Propose a mechanism for both parts ofthe Wolil-Kishner reduction of cyclohexanone the for- ‘mation ofthe hydrazone, and then the base-calalyzed reduction with evolution ofritrogen gas. PROBLEM 18-36 Predict the major products of the following reactions: m © AA ss, @ ROW, heat oD? Nay tats) © GROW Tea” "HCL H,O” SUMMARY Reactions of Ketones and Aldehydes 1. Addition of organometallic reagents (Sections 9-7B and 10-9) 6 ow on l | Ho | ee er (Mt = teal = MEX, 0) i i x e atkoxide achat 2. Reduction Seoons 10-12 and 18-208) i T m R—C—R’ + NaBH, (or Lidl) = —> R—C—R’ #, R-C—R Tone or (or igRaney nck) i i ehyoe i H alkoxide este Pere 1 Clemmenven reduction (Scions 17-11B and 18200) ° Hon 1 Hel Z R-C—R’ + Zalligy = RTCHR’ ketone or aldehyde (continued)926 CHAPTER 18. Ketones and Aldehydes Wolff Kishner reduction (Section 18-20C) ° N—NH, . , I xox, NA ; R-C—R’ + HN—NH, —> R—c—R ES RScoR NENT ketone or alshyde Byte yr 5. thdration Seaion 18.12) ¢ Ho. on aloe + mo = RNCoR ket eye sya 4. Formation of cence (Seco 118) Oo HO) CN I -cn rotor + ney 2M poe ketene orale ‘yeneyarin —R a I RNH, == R-C-R + 4,0 Neteerachyés primey araine 6. Formation of oximes and hydrazones (Section 18-15) 9 RoCoR + ketone or adebyde hydroxylamine ROCoR’ + HAN-NHOR™ hydrazine reagent Reagent Name hyetrazine phenylhydrazine semicarbazide 1. Formation of acetals (Section 18-16) ° I Ww R-C—R + 2R OH == aldehyde or ketone alcohol 8. The Wittig reaction (Section 18-18) Zz & R phosphors ylide PhP ketone or aldehyde RO, R—coR’ acetal (or ketal) imine (Schiff base) Non H = RocoR ae we: dhydrazone derivative Derivative Name aydeazone phenylhydrazone oR’ H,0-20 Reductions of Ketones and Aldehydes 927 9. Oxidation of aldehydes (Section 18-19) ° I chromic acid, bleach, Ag” ee I Roc—H | Smee Ae RCo aldehyde acid ‘Tollens test ° 1 0 I RCH + 2Agamty, +3-0H 22s 2ag) + RCO" + ANH, + 2110 aldehyde Tllne reagent ce rtas 10. Reactions of ketones and aldehydes a their x positions ‘This large group of reactions is covered in Chapler 22. Example Adel condensation I ase | i 2cm-c—n SS cH cc cH SAE SECC CMG Cue ee Ue ead Inthe cental struc below, if R or R’ =H, the functional group isa aldehyde. IrbothR and Rae alky or aryl sroups, the functional group 6a Ketone. In general, Ketones ae more hindered to nucleophilic allack and react ‘mote slowly than aldehydes. cyamohyarin 4 imine formation— H-0, OH formation— yRmacleopilic ation MW Section 18-13, followed by RoR Hy ety, tlininain “H0. SR (Gehydration: imine Secon 114 1815 Iydeation— , ion ee ener HHO Je R ‘asym mee Peete ae HAR, ROR Section 1812 “le HQ P-R RAO. = Real fmaton~ cor VP" Hor, iclopil sdion os A, Ee ne Oi are yi assicee Nabil, ROW RoR ee etal Seeions 18-16, 1617 ee sow Hemiacetal formation ie Acetal formation is reverie der acide, revel de only acide basic or neutral conditions. conditions. Acctals are stable to basic conditions RR redaction HBr ort both Nay and Lit, redice aldehydes and ketones; ‘Sections 18-20A, 10-11 ized ylide Exp. cis-trans isomers possible: R™ Section 18-18928 CHAPTER 18 Ketones and Aldehydes GUIDE TO ORGANIC REACTIONS IN CHAPTER 18 Reactions covered in Chapter 18 are shown in red. Reactions covered in earlier chapters are shown in blue, > Nucleophilic » Nucleophilc » Basic conditions (€2) » Oxidation Papel 8 © aC =0 (Ne Adda) 2 dehyérobalogenation > eporidaion ‘Cho, 106,28 (Cho, 10, 18.22 are hs, 10,18 » ate Cue. Asom Subst) || » at C=C (eonugate adn) > tosylate elimination > oxidative cleavage ea. an au (5.9.11, 17,22 > C=O (ae, yl Subst) Mosmana cininaton| oxygen fonctional groups €410,11,20.21,22 » electrophilic a Gil. 16.19.20, > Electrophilic pace aaa) » Acidic conditions » Reductor Electrophil oer ‘Acidic conditions (€1) Reduction ayy C ect Avom Subst)] | » C=C (Coehene Addn) > El dehy érobalogeaation © hyde reduction es as ay {R501 1718 19,20,21 > deuydeatin of aeobols > hydrogenation » Radical » Radical eu a5, 9,17.18,19 > meas } ap Cfalkane balogenaton] [> w= COIR aber Bye » Pericyclic (Cope elimination) 9,17, 1819 ap C(Sandmeyer 3) Tene a » Pericycc eee > eyeloadiion (Dik Alder is © Giiman ui0,17 © Oxidation > Swrks ef > epoxidation oe Cast » Reduction > byerogenaton Essential Terms acetal ethylene acetal: aldehyde carbonyl group Clemmensen reduction {A derivative of an aldehyde or ketone having two alkoxy groups in place of the carbonyl group. The acetal of a ketone is sometimes called a ketal. (p. 911) i ci,Q 9cn, Pa CH—C—H + 2CHOH == cH—CH 4 HO acca acetaldehyde dimethyl acetal (ethylene ketal) A cyclic acetal using ethylene glycol as the alcohol. (p. 914) ‘A compound containing a carbonyl group bonded to an alkyl (or aryl) group and a hydrogen atom. (p.876) iaminal) An intermediate in the formation of an imine, having an amine and a hydroxy group, bonded to the same carbon atom. (p. 908) HO NHR yr = [R-cR == R-C-R + 10 cesbinlamine ‘mine The C=0 functional group. (p. 876) “The deoxygenation of a ketone or aldehyde by treatment with zinc amalgam and dilute HCl. (p. 923)condensation cyanohydri deoxygenation DIBAL-H hemiacetal hemiaminal hydrate hydrazone ketal ketone lithium dialkylcuprate Metafferty rangement nitele Essential Terms 928 ‘A reaction that joins two or more molecules, often with the loss of a small molecule such as water ‘of an alcohol. (p. 906) ‘A compound with a hydroxy group and a cyano group on the same carbon atom. Cyanohydrins ‘are generally made by the reaction of a ketone of aldehyde with HCN. (p. 904) ° HO. CN I \/ cH—c—cH, + HEN == cH,—COcH, sesone secon enon {A four-electron reduction that replaces the carbonyl oxygen atom of a ketone or aldehyde with ‘two hydrogen atoms. The Clemmensen reduction and the Wolf{-Kishner reduction are the two ‘most common methods of deoxygenation. (p. 923) Diiscbutylaluminum hydride, formula (-Bu),AIM. Used to reduce nitriles and esters selectively to aldehydes. (p. 894) A vinyl alcohol. Simple enols generally tautomerize to their keto forms. (p. 891) we BY oom Z — cw woe A derivative of an aldehyde or ketone similar to an acetal, but with just one alkoxy group and one hydroxy group on the former carbonyl carbon atom. (p. 912) The IUPAC term for a carbinolamine, having an amine and a hydroxy group bonded to the same carbon atom. This term is analogous to the term hemiacetal, except with an amine instead of an alkoxy group. (p. 906) (of an aldehyde or ketone) The geminal diol formed by addition of water across the carbony! double bond. (p. 902) OQ. oH I HY or-oH cye—c—u no ES cee ‘A compound containing the C—N—NH, group, formed by the reaction of a ketone or aldehyde with hydrazine, (p, 908) ‘A hydrazone made using 2,4-dinitrophenylhydrazine. (p. 910) No: on, 2 sas, 9 — =. NN NO: = ‘yelopentanone 24: DNP denvative of eyclopentanone ‘A compound with a carbon-nitrogen double bong, formed by the reaction of aketone or aldehyde with a primary amine. A substituted imine Is often called a Schiff base. (p. 906) 9 cH, cute, + cui, A cdc, + HO. —_ peters cea fn acetal derived fram a ketone. The IUPAC once abandoned this term, but later reinstated it as a subclass of acetals. (2-311) ‘A compound containing a cartionyl group bonded to two alky! or aryl groups. (p. 876) (Gilman reagent) An organometallic reagent of formula RaCuli that couples with alkyl halides and acyl halides (acid chlorides). (p- 896) ° ° I i R,Culi + RCC] > RCOR + ROG + LCL In mass spectrometry, the loss of an alkene fragment by a cyclic rearrangement of a carbonyl compound having y hydrogens. (p. 886) ‘A compound containing the cyano group, C=N. (p. 906)930 CHAPTER 18. Ketones and Aldehydes nucleophilic addition Addition of a reagent across a multiple bond by attack of a nucleophile at the electrophilic end of the multiple bond. As used in this chapter, nucleophilic addition is the addition of a nucleophile and a proton across the C=0 bond. (p. 898) oxime ‘A compound containing the C=N—OH group, formed by the reaction of a ketone or aldehyde with hydroxylamine. (p. $08) protecting group A group used to prevent a sensitive functional group from reacting while another part of the ‘molecule is being modified. The protecting group is later removed. For example, an acetal can protect a ketone or an aldehyde from reacting under basic or neutral conditions. Dilute acid removes the acetal (p. 916) Raney nickel {A finely divided, hydrogen-bearing form of nickel made by treating a nickel-aluminum alloy with strong sodium hydroxide. The aluminum in the alloy reacts to form hydrogen, leaving a finely divided nickel powder saturated with hydrogen. (p. 923) semicarbazone ‘A compound containing the C=N—NH—CONH; group, formed by the reaction of a ketone or aldehyde with semicarbazide. (p. 909) Tollens test {A test for aldehydes. The Tollens reagent is a silver-ammonia complex (Ag(NH,); “O#]. Tollens reagent oxidizes an aldehyde to a carboxylate salt and deposits a silver mirror on the inside of 2 glass container, (p. 922) Wittig reaction Reaction of an aldehyde of ketone with a phosphorus ylide to form an alkene. One of the most versatile syntheses of alkenes. (p. 918) R R. Ph R R N, \. 2 Ne? 0 Yep, omc + ap yeno + See Dem + PhiP—o x R Ph R 8 ketone or aldehyde phowphore ye alkene ‘An uncharged molecule containing a carbon atom with a negative charge bonded to a heteroatom with a positive charge. A phosphorus ylide is the nucleophilic species in the Wittig reaction. (p. 918) Wolft-Kishner reduction _Deoxygenation of a ketone or aldehyde by conversion to the hydrazone, followed by treatment with a strong base. (p. 824) vii Uae escuela net ace Each skill is followed by problem numbers exemplifying that particular sill. “T_ Name ketones and aldehydes, and draw the structures from their names. Identity their hydrates, acetals, imines, and other derivatives Problems 18-37, 38, 40, 41, and 61 2 Interpres the IR, NMR, UV, anc mass spectra of ketones and aldehycles, and use Problems 18-42, £3, 44, 45, 46,71, 73, 74, spectral information to determine the structures. 75, and 76 3 Propose single-step and multistep syntheses of ketones and aldehydes from alcohol, alkenes, alkynes, carboxylic acids nitriles, acid chlorides, esters, and aromatic compounds. Problems 18-55, 56, 60, and 64 4. Predict the products of reactions of ketones and aldehydes withthe following types of compounds, and give mechanisms where appropriate: (a) hydride reducing agents; (b) Cemmensen and Woll-Kishner reagents; (0) Grignard and ‘organolithium reagents; () phosphorus ylides (e) water; (f) hydrogen cyanide: (@) ammonia and primary amines; (h) hydroxylamine and hydrazine derivatives; () alcohols and () oxidizing agents Problems 18-38, 48, 49, 52, 54, 65, and 66 5 Use your knowledge of the mechanisms of ketone and aldehyde reactions to propose mechanisms and products of similar reactions youhave never seen Problems 18-50, 58, 62, 62, 68, 69, 70, 72, before. 13, and 75 Problems 18-50, 58, 62, 63, 68, 68, 70, 72, Problem-Solving Strategy: Proposing Reaction Mechanisms 73, and 75 6 Show how to convert ketones and aldehydes to other functional groups, and devise multistep syntheses using ketones and aldehydes as stating materials and intermediates, Problems 18-47, 51, 52, 58, and 60Study Problems 931 Study Problems 1837 Draw structures ofthe fllowng derivatives (@) the 2stainieophenylhydraronc of benzaldehyde —_(Q) the semicarbazone of eylobutanone (© cjelopropanone oxime (@) thecthyleneactl of bexan- one (©) atladelyde dint acetal (Othe methyl emaactl of formaldehyde (a) the) isomer of the etylimine of rpiophenone 0h) the hmiacctlform of Shyonypontanal 38.38 Name the followin Ketones and aldehydes. When posible, ive both a common nane and an TUPAC name f@ crycoeny.cn, () CHKCITy,COCHIAC, (6) CHACTCHO (a) PhCoPh (e) CHyCH,CH,CHO (f) CH;COCH, @ CILCHLCHCHCHICHyCHO —) Ph—-c=cH—cHo—) CHACH—=CH—cu—=cu—cuo ° fn 9 on ® w cy ‘0 ‘cHO A, 1839 Predict te major products ofthe following etons, ® » 1) DIBAL-H o ‘ Co oon, “CRS " ano © OPS commas © NE caneinea Ono HO" © oo 10" é ® Cy wzenenu, (2cHcH.t MA ono nw i) 0. @ ° Sno" CO HY eat (dose H0) , te W142 sb st ptr cyan 2.15 ppm. These absorptions have ateas in the ratio 2:3, The IR specteum shows a strong absorption at 1708 em, Propose structure for this compound,932 CHAPTER 18. Ketones and Aldehydes 18-44 The proton NMR spectrum of a compound of formula C,oH,20 follows, This compound reacts with an acidic solution of 2,4-dinitrophenylhydrarine to give a crystalline derivative, hut it gives a negative Tollens test, Propose a structure for this compound and give peak assignments to account for the signals in the spectrum. 200 180, 190 140 120 100 80 60 40 20 o ‘Olle ppm L a CigHh:0 4 0 > + T ° + + T 7 Spm) 18-45 ‘The following compounds undergo MeLafferty rearrangement in the mass spectrometer. Predict the masses ofthe resulting charged fragments, (a) pentanal| (b) S-methylhexan-2-one (6) 4-meinylhexan-2-one 18-46 An unknown compound gives a molecular ion of m/ 70 inthe mass spectrum. teats with semicarbaride hydrochloride to give a crystalline derivative, butt gives a negative Tollens test. The NMR and IK spectra follow. Propose a structure {or this compound, and give peak assignments to account for the absorptions inthe spectra, Expl 1790 em" inthe IR spectrum appears at an unustal frequency. why the signal at wavelength (rm) 108d 3 a3 4 as Ss eg 8 ss aS is 1734 dl mi 4000 3500——=—«8000S (500 2000-1800 1600 1400. 12001000 500) ‘wavenumber (em) 600 (continued)Study Problems 933 20, 0 180 0 120100) 80 40 20 ° Ofc AO pm re Problem 18-46 1 t S¢ppm) 18-47 Show how you would accomplish the following synthetic conversions efficiently and in good yield. You may use any necessary additional reagents and solvents @ Oa ao » oct, ? i @ CHB XQ ome — © 0 ° ) ° coon 4 A 7 Hn ou q ¢ 8 = \. \, @) 9 (bh) CH,OH CHO otos g-¢ 1 C no” cH, nc* cn, 18-48 The following road-map problem centers on the structure and properties of A, « key intermediate in these eactions. Give structures for compounds A through J. on sat oy a varey? | OR Jo) cant on 2) 1,0" cH,0H — * ite x Hsien, , Bierman, 5 oF ps _ 1, ee then excess NSOCUEIOAS (exces alits0,| Zl, cl934 18-49 18.50 1851 1852 18.53 1854 CHAPTER 18 Ketones and Aldehydes For cach compound, 1. name the functional group. 2. show what compound(s) result from complete hydrolysis. cnenen en, D “CxO 0" 0" o fe) 0. (© LO. ig) LN, (hy CL CD C3 Ore oO 0 iN Propose mechanisms forthe following reactions @ 0 CHORE cHQ pcH, ) @ PRNEINE HY YONEPD oo — i La con,—¢—n cut @ cH—cH, © mpeen, Ps we a Be Deo edit ba 0 © 1 © A oct, — xenon, We Ge "Cee age. Cp “NH, CH,CHNE, Show how you would accomplish the following syntheses efficiently and in good yield. You may use any necessary reagents. (@) acetaldehyde —> lactic acid, CHyCH(OH)COOH “6 A-d “4-8 ‘cH,OH ‘cx10 CHCH,CH, by of “pig” Show how you would synthesize the following derivatives from appropriate carbonyl compounds. N—OH, #' “OS ‘SD Ole CX eS Predict the products formed when cyclohexanone reacts with the following reagents (@) CHANEY () excess CHLOH, H! (6) hydroxylamine and weak acid {@) ethylene glyco! and p-toluenssulfonic acid (©) phenyliydrarine and weak acid (O. PhMgBe and then mild 1,0" () Tollens eagent (h) sodium acetlide, then mild Th0™ @ hydrazine, then hot, fased KOHL @) PhyP=CH, 6) sodium cyanide acidic hydrolysis of the product from (&) Predict the products formed when eyclohexanecatbaldehyde reacts with the following reagents (a) PhMgBr. then HyO™ (b) Tollens reagent (©) semicarbazide and weak acid (@) excess ethanol and acid (©) propane-1,3-diol, H (8, zinc amalgam and dilute hydrochloric acid18-55 18.56 1857 18.58 18.59 18.60 18-61 18-62 18-63 Study Problems 935 Show how you would synthesize actan-2-one from cach compound. You may use any necessary reagents (a) heptanal () oct-L-yne| (© 23-dimethyinon-2ene (@) octan-2-01 (© heplanoic acid © cIyCH,cN Show how you would synthesize octanal from each compound. You may use any necessary reagents {@) octan-L-ol (©) non-l-one {@) oct-l-yne (@) Lbromoheptane (©) Lbromohexane (0) octancic acid @) ethyl cctanoate Both NaBIL, and NaBD, are commercially available, and D,O is common and inexpensive. Show how you would synthesize the following labeled compounds, starting with butan-2-one. @ on © P © P cH FH, CFCC, CF —CHy— CH, D D 1 ‘When LiAIIL, reduces 3-methyleyclopentanone, the product mixture contains 60% cis-3-methyleyclopentanol and 40% trans-3-metbyleyclopentanol. Use your models, and make Unree-dimensional drawings to explain this preference for the ‘The Wittig reaction is useful for placing double bonds in less stable positions. For example, the following transformation is casily accomplished using « Wittig reaction, Oe Onn cyclohexanone methylenecyclohexane (@) Show how you would use a Witig reaction to do this, (b) Show how you might do this without using a With reaction, and then explain why the Wittig reaction is a much better syathess. Show how you would accomplish the Following syntheses. ° (@) benzene —* n-butylhenzene (b) benzonitrile —> propiophenone @ m—Cay—on —> (©) benzene —> p-methoxybenzaldehyde Tetalone ‘Thore are tree dioxane isomers: 1,2-dioxane, 1.3-dioxane, and 1.4-dioxane, One ofthese acts lke an ether and is an excellent solvent for Grignard reactions. Another one is potentially explosive when heated, The third one quickly hyedrolyzes in dilute acid, Show which isomer acts ike a simple ether, and then explain why one of them is potentially explosive. Propose a mechanism forthe acid hydrolysis of the thitd isomer. Gea} L2dioxane ——Ledioxane: Laon ‘Two structures forthe sugar glucose are shown on page 914. Interconversion of the open-chain and cyclic hemiacetal oem is catalyzed by either acid ot base. (a) Propose a mechanism for the cyclization, assuming a trae of acid is present, (b) The cyclic hemiacetal is more stable than the open-chain form. so very litle of the open-chain form is present at equilibrium. Will an aqueous solution of glucose reduce Tollens reagent and give a positive Tollens est? Explain, ‘Two structures of the sugar fructose are shown next, The cyclic stnucture predominates in aqueous solution, (@) Number the carbon atoms in the cyclic fi structure. What is the functional group at C2 in the eyelic form? (@) Propose a mechanism forthe cyclization, none ~° on assuming a trace of acid is present NS or-o11 of \, aL ¥9/ Scu.o on Irwore fructose (eset fom)936 CHAPTER 18. Ketones and Aldehydes 18-64 Hydration of alkynes (via oxymercuration) gives good yields of single compounds only with symmetrical or terminal alkynes. Show what the products would be from hydration of each compound, (a) hex-3-yne (b) hex-2-yne (©) hex-L-yne (@) cyclodecyne fe) 3-methyleyclodecyne 18.65 Which of the following compounds would give a positive Tollens test? (Remember that the Tollens test involves mild basic aqueous conditions.) (@) CH\CH,CH,COCH, (b) CH,CH;CH,CH,CHO (©) cHCH: HCH HOH, (@) CHCHACH,CH,CH(OHOCH, —_(@)_CH,CHACH,CH,CH(OCH). CL oon 18.66 Solving the following road-map problem depends on determining the steucture of A the key intermediate. Give structures for compounds A through K. D hept-t-yne Ne E F 6 cery,cati_ | (0) 0, 78°C @ ccHy,s wo Na0e cuycHyesr Eo c MCHIMEBE O10 HOAs wK @ HOt fen ay u @) Hot a 49 cH, 1 on hw, ° Ps 18-67 Within each set of structures, indicate which will react fastest, and which slowest, toward nucleophilic addition in basic conditions hk omororas ke nelken nek ROT CR CT CR, CC 18.68 One of these reacts with dilute aqueous acid and the other does not, Give a mechanism forthe one that reacts, and show why this mechanism does not work forthe other one. CD “CQ > ws 0” ?Study Problems 937 18-69 Show a complete mechanism for this equilibrium established in diethyl ether with HCl gas as catalyst, on ° Hci) Sy FLO i 18-70 Show a complete mechanism for this reaction ° np H He ™ + cHOH = + 1,0 18-71 The UV specttum of an unknown compound shows values of Ana at225 nm (© = 10,000) and at 318 nm (e = 40) ‘The mass spectrum shows a molecular on at m/: 96 and a prominent base peak at m/= 68. The IR and NMI spectea follow. Propose a structure, and show how your structure corresponds to the observed absorptions. Propose a favorable fragmentation to account for the MS base peak at m/268 (oss of C3H,). wavelength ut) as 4 gs a as Ss gg os stp 104 ao sof 60) aol 20) i doo 3500—~=C«S000=S=S «2500 7000-1800) 500 0 wavenumber 200 ts 190 40 120100 40 20 ° ep kL — TO Problemy Int 7 ® ? 7 5 (opm) "18-72 (a) Simple aminoacctals hydrolyze quickly and easily in dilute acid. Propose a mechanism for hydrolysis ofthe following aminoacetal: fo NCi putt oo Cre + cry, (continued)938 CHAPTER 18. Ketones and Aldehydes (b) The nucleosides that make up DNA have heterocyclic rings linked to deoxyribose by an aminoacctal functional ‘roup. Point out the aminoacetal linkages in deoxyeytidine and deoxyadenosine, NH; Sy N. wore 0. “NT 0 Hone, 08 a W n W ny on i ou Ht eoxyeytidine deoxyadenosine (©) The stability of our genetic code depends on the stability of DNA. We are fortunate thatthe aminoacetal linkages of DNA are not easily cleaved, Show why your mechanism for part (a) does not work so well with deoxycytidine and deoxyadenosine. 18-73 ‘The mass spectrum of unknown compound A shows a molecular ion at m/z 116 and prominent peaks at m/z 87 and m/z 101. ts UV spectrum shows no maximum above 200 am. The IR and NMR spectra of A follow. When A is ‘washed with dilute aqueous acid, extracted into dichloromethane, and the solvent evaporated, it gives a product B. B shows a strong carbonyl signal at 1715 em in the IR spectrum and a weak maximum at 274 nm (e = 16) in the UV spectrum. The mass spectrum of B shows a molecular ion of m/z 72. Determine the structures of A and B, and show the fragmentation to account for the peaks at m/z 87 and 101 wavelength um) 1082 4 354 as SS eg 8 id IS ag 6 ° 8 ormStudy Problems 938 "18-74 (A true story.) The chemistry department custodian was cleaning the organic lab when an unmarked bottle fll off a shelf and smashed on the floor, leaving a puddle of volatile Hiquid. The custodian began to wipe up the puddle, but he was ‘overcome with burning in his eyes and a feeling of having an electric drill thrust up his nose. He left the room and called the fire department, who used breathing equipment to go in and clean up the chemical. Three students were asked 10 ‘domify the chemical quickly so that the custodian could be treated and the chemical could be handled properly, The sudents took IR and NMR spectra, which follow. The UV spectrum showed Ay at 220 nm (e = 16,000). The mass spectrometer was down, so no molecular weight was available. Determine the structure of this nasty compound, and show how your structure fits the spectra wavelength (um) 3 35 4 45S 5S ef 8 teas ig Is ap 000 0 «3000800 2000 1X00 1600 1400 1200 1000 00 ‘500 Problem 18.74 0 = 90s iC o Spm)940 “18:75 “18-76 18.77 CHAPTER 18 Ketones and Aldehydes In the absence of water, o-phthalaldehyde has the structure shown. Is strongest IR absorption is at 1687 emt; the proton NMR data are shown by the structure. In the presence of water, a new compound is formed that has a strong IR absorption around 3400 em and no absorption in the C=O region. The proton NMR data are shown, Propose a structure of X consistent with this information, and suggest how X was formed, 00 Pe He H HINMR data broad singlet at § 5.0 (21) doubles at sharp singlet at 6 5.9 2H) F + 11,0 — up sing! aso ° Xo doublet at 6 7.2 2H) Aoubiet at Os doublet a 87.3 (2H) ais o-phalaldehyde CaO, Assume you area research physiologist tying to unravel a serious melabolie disorder. You have fed your lab animal Igor a deuterium-labeled substrate and now need to analyze the urinary metabolites. Show how you would differentiate these four deuterated aldchydes using mass spectrometry. Remember that devterium has mass 2, (Hint; Predict the important fragmentations, and show how the different compounds give unique peaks.) 5 I w x y Zz The family of macrolide antibiotics all have large rings (macrocycle) in which an ester is what makes the ring; acyclic esters termed a lactone. One example is amphotericin B, used as an anti-fungal treatment of last resort because of its liver and heart toxicity. Professor Martin Burke of the University of Illinois has been making analogs to retain the antifungal properties but without the toxicity, including this structure published in 2015. (Nature Chemical Biology (2015) 1doi:10,1038/nchembio.1821) The carboxylate of amphotericin B has been replaced with the urea group (shown in red), on analog of amphotericin B (@) Whereis the lactone group that forms the sing? (b) Two groups are circled, What type of functional group are they? Explain.