CYCLOADDITION REACTIONS, OF SOME PYRAZOLE DERIVATIVES ML, 229 SEViL OZCAN yen® YORSEKOCRETIM KURULD TS SROMANTASYON MERKEZL FEBRUARY 2001CYCLOADDITION REACTIONS OF SOME PYRAZOLE DERIVATIVES by SEViL OZCAN THESIS SUBMITTED TO THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES OF THE ABANT iZZET BAYSAL UNIVERSITY IN PARTIAL FULLFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN THE DEPARTMENT OF CHEMISTRY FEBRUARY 2001Approval of the Graduate School of Natural and Applied \ ty Sciences Prof.Dr. Adil Giiner Director | certify that this thesis satisfies all the requirements as a thesis for the degree of Master of Science. it Prof.Dr. Mahmut Acinii Head of Department This is to certify that we have read this thesis and that in our opinnion it is fully adequate, in scope and quality, as a thesis for the a degree master of Science. ZL [& € ' Kssoc.Prof.Dr. Nihat Celebi Supervisor Examining Committee Members 4- Prof.Dr. Mahmut Acimis I (apse fs 2- Assoc.Prof.Dr.Nihat Gelebi 3- Assoc.Prof.Dr.Cetin BozkurtTO MY PARENTS AND BROTHERABSTRACT CYCLOADDITION REACTIONS OF SOME PYRAZOLE DERIVATIVES OZCAN , Sevil M.Sc. , Department of Chemistry ‘Supervisor : Assoc. Prof.Dr.Nihat Gelebi February 2001, 104 pages In this study, the cycloaddition reactions of 1,3-dipoles and 1-Azadienes upon various dipolorophiles and dienophiles are investigated. 4-Benzoyl-2-phenylpyrazolo-[1,2-a]pyrazole derivatives as 1,3-dipoles have been studied with olefinic and acetylenic dipolorophiles. Although these betaines show 1,3-dipole character at 1,7- and 3,5- positions, they did not give any expected cycloadduct. This case can be explained on the basis of molecular orbital theory. Phenacyipyrazole derivatives react as 1-Azadienes at 2,5- positions with some acetylenic dienophiles. Additions of 2x-acetylenic dienophiles, D.MAD. and D.E.AD., to 1-phenacylpyrazole derivatives are symmetry allowed reactions and occur thermally.Theoretical approches based on Huckel calculations at the level of the frontier molecular orbital theory are to be a powerful tool for the explanation, rationalization, and estimation of the reactivity with the various thermal cycloadditions to pyrazole derivatives. Keywords: 1,3-dipoles, 1-Azadienes, dipolorophiles, _dienophiles, cycloadduct, symmetry allowed reactionsOzeET BAZI PIRAZOL TUREVLERININ SIKLO KATILMA REAKSIYONLARI OZCAN, Sevil Yiksek Lisans Tezi, Kimya Bélimii Tez Danigmani : Dog.Dr.Nihat Gelebi Subat 2001, 104 sayfa Bu caligmada 1,3-dipollerin ve 1-Azadienlerin gesitli dipolorofillerle ve dienofillerle siklo katiIma reaksiyonlari arastinimaktadir. 1,3-dipoller olarak, — 1-Benzoil-2-fenilpirazolo-[1,2-a]pirazol tirevleri baz! asetilenik dipolorofillerle aligilmistir. Bu betainler 1,7- ve 3,5- pozisyonlarinda 1,3-dipol ézellik géstermelerine ragmen beklenen siklo driinleri vermediler. Bu durum molekiler orbital kuram 1siginda agiklanabilir. Fenagilpirazol tdrevleri 2,5-pozisyonlarinda gesiti_dienofillerle 1-Azadien olarak reaksiyon verirler. 2n-asetilenik dienofilleri D.M.A.D. ve D.EAD. nin ‘-fenagilpirazol tiirevlerine katilmalari_simetri_izinli reaksiyonlardir ve termal olarak gerceklesirier. iiiHuckel hesaplamalarina dayanan teoritik yaklasimlar, frontier molekiiler orbital teori diizeyinde pirazol tirevlerine gesitli dipolorofillerin termal siklo katilmalann reaktivitelerinin agiklanmasinda, rasyonalize edilmesinde ve tahmin edilmesinde gilt bir aragtir Anahtar kelimeler : 1,3-dipoller, 1-Azadienler, dipolorofiller, dienofiller, siklo katilmalar, simetri izinli reaksiyonlar.ACKNOWLEDGEMENTS | would like to express my sincere thanks to Assoc.Prof. Dr. Nihat Gelebi, for his unceasing interest, valuable supervision, guidance and great help throughout the course of this work. | would like to thank to Assoc.Prof.Dr. Cetin Bozkurt for his helps. My special thanks go to Berrak Celebi for FT-IR spectra measurements. | would like to also present my appreciation to Seyma Ozacar, Dilek Kars and Efkan Gatiker for their valuable friendships and sincere helps. J also thank to my parents and brother Tanju Ozcan for their great helps and supports.TABLE OF CONTENTS ABSTRACT. OZET.... ACKNOWLEDGMENTS... TABLE OF CONTENTS... LIST OF TABLES.. LIST OF FIGURES.. LIST OF SYMBOLS AND ABBREVIATIONS... 4. INTRODUCTION AND GENERAL THEORY. 1.1. Cycloaddition Reactions. 1.1.1. Concerted Reactions... 1.1.2. Pericyclic Reactions. 1.1.3. Cycloaddition Reactions. 1.1.3.1.Definition and classification of cycloaddition reactions......... 1.1.3.2. Mechanism... 1.1.3.3.1,3 - Dipolar Cycloaddition Reactions. 1.2. Simplified Theory of Cycloaddition Reactions... 1.2.1. Theoretical Background... 1.2.1.2. FMO Treatment of Cycloaddition Reactions....1.2.2. Regioselectivity and Reactivity in Cycloaddition Reactions. 1.2.3. Secondary Orbital Interactions..... 1.3. Frontier Orbitals of Dienophiles or Dipolorophiles.... 1.4, 1-Benzoyl-2-phenylpyrazolo-[1,2-alpyrazole Derivatives. ae) 1.4.1. Electroselectivity of Betaines.. 1.4.2. Regioselectivity....... 1.5. Aim of This Work..... 2. RESULTS AND DISCUSSION. 2.1. Experimental Works...... AZ 2.2. Characterization of Cycloadducts. Fi. secu AT 2.3. Molecular Orbital Considerations... 66 3. CONCLUSIONS. 4, EXPERIMENTAL. REFERENCES. f : ee eeeeeeee OdLIST OF TABLES TABLES 1. Ally type classification of 1,3-dipoles.......... aA 2. 1H n.mvr. data of the adduct (14)........ 54 3. 1H nmr, data of the adduct (15)... 65 > Orbital correlations of betaines... 2 The FMO energies (B) of 1-Benzoyl-2-phenypyrazolo- [1,2-alpyrazole which show 1,3-dipolar character at 1,7-positions (the coplanar form is considered)........ 74 ° The FMO energies (8) of 1-Benzoyl-2-phenypyrazolo-[1,2-alpyrazole which show 1,3-dipolar character at 3,5- positions (the coplanar form is considered)... a4 ~_ . The FMO energies (8) of 1-Benzoyl-2-phenypyrazolo-[1,2-a]pyrazole which show 1,3-dipolar character at 1,7- positions (orthogonal form is considered)... TS . The FMO energies (B) of 1-Benzoyl-2-phenypyrazolo-[1,2-alpyrazole which show 1,3-dipolar character at 3,5- positions (orthogonal form is considered). 76 9. The FMO energies () of the dipolorophiles...... 7 10. The FMO energies (f) of 3a and 3b...... 11. Orbital Correlations of 1-Azadienes.....LIST OF FIGURES FIGURES 1. Simplified reaction — potential energy diagram for a concerted TEACHION........eeeesseeeesnseeeen 2. Simplified reaction — potential energy diagram for a two-step reaction. 3. The scheme of (a) cycloaddition, (b) electrocyclic, (c) cheletropic, (d) sigmatropic, (e) group transfer, and (f) elimination reactions. 8 4. The simple representation of a 1,3-dipolar cycloaddition. .....c.0...40 5. 1,3-dipoles (a) propargylallenyl type (b) allyl type.. 10 6. Huisgen’s parallel-planes transition state approach for the 1,3-dipoles... 42 7, Representation of (a) [.45+ «2s]and(b)[.2¢+ 228] reactions. 8. Molecular orbital picture for (a) nitrile ylide (b) azomethine ylide 9.The relative energies of frontier 7 - orbitals of the 24 1,3-dipoles. 10. Estimated frontier orbitals for the 1,3-dipoles............ ree 11. The interaction of the frontier orbitals of two molecules. 12. Regioselectivity in Diels-Alder reactions. ...............00013. 14, 15. 16. 47. 18. 19. 20. 21. 22, 23. 24, 25. 26. Possible interactions between A: 1,3-dipoles and B: dipolorophiles... Two possible regioisomers of 1,3-dipolar additions of an unsymmetrical 2 x - systern..... ‘Secondary orbital interaction of orbitals in the transition state for the dimerization of cyclopentadiene. The two stereoisomers of cyclopentadiene dimerization. Estimated 2- frontier orbital energies and coefficients dipolorophiles... Estimated frontier orbital energies and coefficients for 1- substituted butadienes... 35 Estimated frontier orbital energies and coefficients for 2- substituted butadienes. 36 Estimated frontier orbital energies and coefficients for styrene and phenyl acetylene... 37 Possible regioisomers of the cycloadducts. ee) 1-Benzoyl-2-phenylpyrazolo-[1,2-alpyrazole derivatives.....c...43 Canonical forms of 1-Benzoyl-2-phenylpyrazolo-[1,2-a]pyrazole derivatives... 44 The failed reaction of pyrazole with a-bromo-o-toluiyl chloride.. The two canonical forms of compound (13).... The ir. spectrum of 1-(m-nitrophenacyl)pyrazole.27. 28. 29. 30. 34, 32. 33. 34, 36. 37. 38. 39. The i.r. spectrum of the cycloadduct (14). a Rotamer forms of the cycloadducts..... 1H n.m.r. spectrum of the cycloadduct (14), which belongs to methyl protons. 1H n.m.r. spectrum of the cycloadduct (14), which belongs to methylene protons. |. Pictural idea of Karplus equation which implies from the plot of j against $.... .. 52 . 1H n.m.r. spectrum of the cycloadduet (14), which belongs to the resonances of Hz, Ha, Hs, Ha, Hp, AN Ho..esoscecee oe 83 The complete 1H spectrum of the cycloadduct (14). The "°C spectrum of the cycloadduct (14)......... 60 . The i.r. spectrum of the cycloadduct (15) 6A 1H nm-r. spectrum of the cycloadduct (15), including methyl protons....... . 1H n.m.r. spectrum of the cycloadduct (15), which belongs to the resonances of Hz, Hs, Hs, He, Ho, and Henne The complete 1H spectrum of the cycloadduct (19)..... Plot of energies versus reaction coordinate where symmetry is retained (—— ) and the (......a, b, C) effect of removing symmetry... Consideration of betaines as allyl anion... 68 xi41. Correlation diagrams for the 1,3-dipolar cycloaddition of a 1-Benzoyl-2-phenylpyrazolo-[1,2-alpyrazole derivative with a 69 2n- system. 42. Canonical forms of the betaines (Aryl groups are coplanar ).......72 43. Canonical forms of the betaines (Aryl groups are orthogona))...... 73 44. The relative HOMO-LUMO energy gaps between the betaines 2 and dipolorophiles.. 78 45. The relative HOMO-LUMO energy gaps between the betaines 1, 3, and 4 and dipolorophiles....... 46. Interactions of the HOMO; 3 dipole - LUMO dipotoroptiie and 80 HOMO dpotoroptiie — LUMO} dpa. 47. FMO coefficients for the dipolorophiles...... 81 48. FMO coefficients of the betaines that show 1,3-dipole reactivity at 1,7- positions(coplanar)....... ee sececeeesees 83 49. FMO coefficients of the betaines that show 1,3-dipole reactivity at 3,5- positions(coplanar)...... 50. FMO coefficients of the betaines that show 1,3-dipole reactivity at 1,7- positions(coplanar)..... 85 51. FMO coefficients of the betaines that show 1,3-dipole reactivity at 3,5 - positions(coplanar), 52. FMO coefficients of 1-phenacylpyrazole derivatives.............53. The relative HOMO-LUMO gaps between the azadienes and dienophiles..... 54, Correlation diagrams for a 1-phenacylpyrazole derivative with a 2-n- system. 90 55. Interactions of the HOMO, .Azadiene - LUMOcienoptile and HOMOgenophite ~ LUMOaiene.PMO FMO EH CNDO, MINDO HMO. LCAO, LUMO HOMO. AE B LIST OF SYMBOLS AND ABBREVIATIONS Perturbational Molecular Orbital Frontier Molecular Orbital Extended Huckel Complete Neglect of Differential Overlap Modified Intermediate Neglect of Differential Overlap Huckel Molecular Orbital Linear Combination of Atomic Orbitals Lowest Unoccupied Molecular Orbital Highest Occupied Molecular Orbital a molecular orbital an atomic orbital interaction energy the Huckel coulomb integral the Huckel resonance integral frequency (cm)4. INTRODUCTION AND GENERAL THEORY 1.1. Cycloaddition Reactions 1.1.1. Concerted Reactions Concerted reactions are the ones in which bond making and breaking occurs by way of a single transition state. Transition state is the maximum energy point corresponding to the species in the coordinate- potential energy diagram. TS Energy ——> eo) Reaction coordinate Figure 4. Simplified reaction — potential energy diagram for a concerted reaction,If the conversion of reactants into products occurs by way of more than one transition state, involving one or more intermediates the process is said to be non-concerted. Energy —___, Reaction coordinate Figure 2. Simplified reaction — potential energy diagram for a two step reaction. In this case two concerted sequences are present, those are reactants to intermediate (R- |) and intermediate to products (1 > P ). 1.1.2. Pericyclic Reactions ‘An important class of concerted reactions is the pericyclic reactions. A pericyclic reaction is defined as a change in bonding relationship that takes place as a continuous concerted reorganization of electrons. Tomaintain continuous electron flow , pericyclic reactions occur through cyclic transition states. The cyclic transition state must correspond to an arrangement of the participating orbitals that can maintain a bonding interaction between the reaction components throughout the course of reactions. The characteristic features of pericyclic reactions are as follows (i) In these reactions, no ionic or radicalic intermediates are formed. (ii) They involve no electrophilic or nucleophilic reagents. (ii) Catalysis or solvent changes do not affect these reactions. (iv) Two or more bonds are made or broken in a single concerted and cyclic transition state. (v) They are highly reactive, stereospecific and regioselective. Pericyclic reactions [1] can be subdivided into five groups i) Cycloaddition reactions : Cycloaddition reactions are the ones in which x bonds are converted to the new o bonds giving a cyclic product ( Figure 3. ( a )). ii) Electrocyclic reactions : An electrocyclic reaction is defined as the formation of a single bond between the ends of a linear system of x electrons and the reverse process ( Figure 3. (b))ili) Sigmatropic reactions : Sigmatropic processes involve a concerted reorganization of electrons during which a group is attached by a o bond migrates to a more distant terminus of an adjacent x electron system without any change in the number of c and x bonds ( Figure 3. (¢)) iv) Cheletropic reactions : In these processes two c - bonds terminating at a single atom are made or broken in a concerted manner ( Figure 3. (d) ) v) Group transfer reactions : In a group transfer reaction the characteristic changes in the bonding of participating molecules can be explained as follows ( see Figure 3. (@ )) vi) Elimination reactions : These reactions involve the following changes in the skeleton of participants ( Figure 3. (f) ) No - bonds: — n x~- bonds C.1-016~-bond —— = 1 x-bond C (b) 1 o-bond +n x-bonds ———= 10-bond +n n- bonds C We — (n+1) w-bonds + 1 lone pair === —_na-bonds + 2 0- bonds (d)no- bonds + m 7- bonds —= no - bonds + m x- bonds (e) 0-000 -0-0OCO no-bonds + m x-bonds =~ (n-1) o- bonds +(m-+1) 2- bonds + R:R’ (f) Figure 3.The scheme of (a) cycloaddition, (b) electrocyclic, (c) sigmatropic, (d) cheletropic, (e) group transfer, and (f) elimination reactions. 1.2.3. Cycloaddition reactions 1.1.3.1. Definition and classification Cycloaddition is the reaction in which two unsaturated molecules. combine to form a cyclic compound, with x electrons being used to form two new c bonds.The reaction of two alkenes to form a cyclobutane is a[ 2.x + 2m] cycloaddition; the reaction of a diene and an alkene to form a cyclohexene is called [ 4x +2 x ] cycloaddition. In general, cycloadditions can be designated by a bracket [ m +p ] where m and p represent the number of x electrons in each participant [2]. {4 + 2] cycloaddition reactions are known as Diels-Alder reactions. There are two types of Diels-Alder reactions. Normal Diels-Alder Reaction and Inverse Diels-Alder Reaction. According to Huisgen [3], cycloaddition reactions have some several characteristic features. (i) Sigma and pi bonds are interconverted. (ii) Cycloaddition reactions are concerted, so bonds are made broken by way of a single transition state. (iii) Radicals or ionic intermediates are not involved in the mechanisms of cycloadditions. (iv) Cycloaddition reactions occur thermally or photochemically. (v) Cycloadditions can be intramolecular, if a molecule contains the necessary number of x bonds ( « - bonds for retroadditions ) in its skeleton. (vi) The products of a cycloaddition need not to be isolable or stable, but the cycloadducts must occur at least as intermediates. (vii) Cycloadditions are ring closures in which the number of « bonds increases.(viii) Cycloadditions do not involve the cleavage of o bonds. The reverse is true for retroadditions. (ix) Cycloaddition reactions are highly stereospecific and regiospecific. 4.4.3.2. Mechanism ‘According to Woodward — Hoffman [4], cycloaddition reactions are symmetry controlled reactions which can be either concerted or nonconcerted. Concerted reactions are one - step reactions, while nonconcerted reactions are the ones involving biradical or dipolar intermediates. According to Epiotis [5], the majority of cycloaddition reactions are concerted, in other words, synchronous overlap of the p orbital of union is taking place at the transition state and the stereochemical consequences of the reaction simply depend on the properties of the cycloaddends. 1,3-dipolar cycloadditions were defined as being single step , four centered, no mechanism reactions by Huisgen’s group [6,7,8], in which the two new bonds are both partially formed in the transition state, although not necessarily to the same extent. Firestone [9,10] presented an altemative mechanism for 1,3-dipolar cycloadditions. In place of a one step path way with a single transition state, he proposed a two step reaction with a discrete intermediate, a spin- paired diradical, with the first step rate determining.The energy difference between a one-step and a two step cycloaddition is different. Specifically, it is expected that when the MO interactions between the cycloaddends are strong, the two step mechanism will be disfavored while when they are weak the two step mechanism will be favored. The two step mechanism is energetically more demanding [11], All mechanistic criteria underline the superiority of the concerted mechanism over the diradical hypothesis [12] 1.1.3.3. 1,3 — Dipolar cycloaddition reactions A cycloaddition of the type 3 + 2 = 5 leading to an uncharged five-membered ring is called 1,3-dipolar cycloaddition [13] (see Figure 4), The term 1,3-dipole is defined as a species which is represented by zwitterionic resonance structures and which undergoes 1,3-dipolar cycloadditions to a multiple bond system, the dipolorophile.Figure 4. The simple representation of a 1,3-dipolar cycloaddition. A 1,3-dipole has a sequence of three atoms, a-b-c, of which a has sextet of electrons in the outer shell and c has an octet with at least one unshared pair. Huisgen[12] classifies 1,3-dipoles as allyl (bent) and propargyl - alleny! type (linear) (Figure 5) 8 2 cm ° 8 Q s 8 a ——C <—» a==b——_¢t «> 4=—=b=—=c_ (a) o/ Ne —_ oN AN () Sextet Octet Structure Structure Figure 5. 1.3-dipoles as (a) propargyl — alleny! type (b) allyl type.The sextet structure of the 1,3-dipoles may contain either a double or a single bond between a and b. When a double is present, the 1,3-dipole is the propargyl — allenyl type. In the propargyl — allenyl type, the middle atom, b, whose free electron pair is borrowed by the sextet center, a, must be nitrogen. Table 1. Allyl type classification of 1,3-dipoles. SEXTET OCTET \e sy Zo NT ea ‘Azomethine Yides <—_ ‘Azomethine imines \e_-_ 2 N Cc—N—Q i rma 3 Ye Nitrones pee — > N= N— 9! poy Compounds a 2 <> 0 N— 9! Nito CompoundsNo other element has an extra pair of electrons available while remaining in the triply bonded neutral state. In the allyl type, where no double bond is present in the sextet structure, b, can be occupied by either a nitrogen or an oxygen atom [14].In the allyl type classification, there are six groups if b is occupied by nitrogen. In this classification, the carrier of anionic charge within each group is the carbanion, the imide nitrogen and the oxide oxygen. According to Huisgen [15], 1,3-dipolar cycloaddition is an orbital symmetry allowed [4 + 2 ] cycloaddition wherein the 1,3-dipole with its allyl anion type MO functions as 4 x reactant and the dipolorophile as 2 reactant. The MO symmetry correlation diagram of 1,3-dipolar cycloaddition bears a more than suprafacial resemblance to that of the Diels - Alder reaction. Figure 6. Huisgen’s parallel — planes transition state approach for the 1,3 -dipoles.Another description altributes the concertness to a Huckel aromatic type MO of the transition state (Figure 6). The allyl anion structure is responsible for the ability of the 1,3-dipole to undergo cycloaddition. 1.2. Simplified Theory of Cycloaddition Reactions 1.2.3. Theoretical Background Molecular orbital theory explains the reactivities of cycloaddition reactions by using the energy differences between the reactants and the transition states. Linear combination of atomic orbitals (LCAO) method is used in molecular orbital calculations. Interactions between two conjugated molecules with overlapping p orbitals is described in terms of the x electrons of the separate system. The orbitals that interact have been called the frontier orbitals by Fukui [16] Frontier orbitals are given the names, highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital (LUMO). The principle of conversation of orbital symmetry, explained by Fukui, Woodward and Hoffmann [17,18], provides a fruitful theoretical basis for concerted reactions.Whether a concerted reaction is allowed or not, can be predicted by orbital symmetry rules, which are also known as Woodward — Hoffmann rules [19}.The orbital symmetry rules are related to the Hiickel aromaticity. The selection rules for cycloaddition reactions can be derived from consideration of the aromaticity of the transition state. In applying the orbital symmetry, sign inversions are taken into account. Systems with zero or an even number of sign inversions are called Huckel systems. A thermal pericyclic reaction involving a Huckel system is allowed only if the total number of electrons is 4 n + 2. Systems with an odd number of sign inversions are called Mobius systems, in which a thermal pericyclic reaction is allowed, if the total number of electrons is 4n. For photochemical reactions these rules are reversed [20], |n concerted reactions, if the new bonds are formed from the same face of the x system, the reaction is a suprafacial ~ suprafacial process For [4 s+ x 2 ¢], Diels ~ Alder reactions suprafacial — suprafacial process is symmetry allowed according to Woodward — Hoffmann rules [21]. In symmetry allowed [ , 2+ 2 » ] cyclization reactions the new o bonds are formed from the opposite faces of the x system. This manner of bond formation is called antafacial - suprafacial. For the [s 4 st. 2s] suprafacial — suprafacial cycloaddition the transition state is aromatic, while for [. 2 +, 2s ] suprafacial — suprafacial 4mode it is antiaromatic and suprafacial — antarafacial mode it is aromatic (Figure 7). (b) Figure 7. Representation of (a) [x 45+ 2s] and (b)[ «26+ 26] reactions. Io Uy HR (a) (b) Figure 8. Molecular orbital picture for (a) nitrile ylide (b) azomethine ylide.Orbital symmetry analysis of 1,3-dipolar reactions has relieved that by virtue of the presence in 1,3-dipole of a 4x electronic system isoelectronic with the allyl anion (Figure 8). The regioselectivity and reactivity [14,22,23,24,25], the mechanism 16.7.8], the electroselectivity [26,27], the stereoselectivity [28], the regiospecifity [29] of cycloadditions were explained on the basis of molecular orbital theories. As two conjugated systems approach each other along the lowest energy path, the greatest stabilization upon the interaction is provided. The magnitude of this stabilization depends upon the nature of the interacting molecular orbitals of the conjugated systems and can be estimated by using the perturbational molecular orbital (PMO) and frontier molecular orbital (FMO) theories. The most popular of the available methods are Extended Huckel (EH), CNDO/ 2, and the MINDO/ 3 methods. By using CNDO/ 2 method, the coefficients and energy levels of frontier orbital can be calculated. The CNDO (complete neglect of differential overlap) method [30,31] makes the approximation that the product 2; ©; is always zero if 2, and 2 are located on the same center. The MINDO (modified intermediate neglect of differential overlap) method restores several of the integrals neglected in the CNDO method. 16Huckel molecular orbital theory utilizes the treatment of conjugated systems. It is based on the approximation that the x system can be treated independently of the o framework conjugated planar molecules and that is the x system has a great importance in determining the chemical and spectroscopic properties of conjugated polyenes and aromatic compounds. The rationalization for treating the o and x as independent of each other is based on their orthogonolity. Hw, = EY, ( schrédinger equation ) (1) H is the Hamiltonian operator, E is the energy and y's are the wave functions. By using LCAO molecular orbital equation, = YL Cun on (2) where ¥, is the "molecular orbital, Cn's are the coefficients of the n™ molecular orbital and $, is the atomic orbital for the n™ atom, another equation can be derived. HY Cab=E DS Cron (3) DX Cn (H-E) n= (4)If this is multiplied by each of the basis functions in turn and is integrated, the secular equation is obtained, one for each value of m. X Cn (Hm ES ) = 0 (5) Hmn is the Hamiltonian integral and Sma is the overlap integral. Independent — electron theory, devoloped by Hiickel is based upon the approximation that all overlap integrals are zero. [Hin ~ E 8m | = 0 (6) 3mnis the Kronecker delta, which is used to define orthonormality condition. The integrals in equation 5 are of two types, those that occur on the diagonal of the determinant, Hmm and_ those off the diagonal, Hmn (m #n). The diagonal terms are generally referred to as Coulomb integral and are given the symbol cimm or just «tif there is only one type of orbital. The off diagonals are called the resonance integrals and are given the symbol Brn or just B. The Coulomb integral, a, is related to the binding energy of an electron in a 2p orbital, which is constant for all carbon atoms but varies for heteroatoms as a result of the difference in reactivity. The resonanceintegral, 8, is related to the energy of an electron in the field of two or more nuclei. In the independent — electron Hiickel method, the electron is only affected by nearest — neighbor nuclei. Thus, B is assumed to be zero when nuclei are seperated by distances greater than the normal bonding distance. E=a+mp (7) Both a and are negative numbers and represent unspecified units of energy. 1.2.1.2 PMO Theory How a change in structure, perturbation, will affect the MO's can be understood by the help of PMO. In PMO a system under analysis is compared to an another related system for which the MO pattern is known. In molecular orbital theory, reactivity is related to the relative energies and shapes of the orbitals, which are involved during the transformation of reactants to products. The shapes of the orbitals, which affect the energy of the reactions, are quantified by atomic coefficients. PMO incorporates the concept of frontier orbital theory, which Proposes that the most important reactions between the highest molecularorbital of one reactant and the lowest molecular orbital of the other reactant. A basic postulate of PMO theory is that the strongest overlap occurs, when the interacting orbitals, with the same ‘Sign, on two reaction centers have the highest coefficients on the participating atoms. Another postulate of PMO theory is that only MO's of matching symmetry can interact for the bond formation, Thus, relative energies and symmetry of the frontier orbitals are taken into account in PMO theory. The relative energies of the frontier orbitals can be approximated by first order perturbation theory. AEu= 3) CurAa+ > 2 Cu CyB, (8) 7 rT The above equation, derived from the PMO approach to first order Changes, indicates the change in energy of the u® molecular orbital as a function of changes in Coulomb integral (electronegativity or ionization Potential ) and resonance integrals (bond energy ).cH + 5 ae = Fe C=N-N C=N-O NEN-€ NEN-N NERS ritrile nitrile nitrile diazo” sides ait : ylides imines oxides alkanes eee. =a oxides -5: Figure 9. The relative energies of frontier x - orbitals of the 1,3-dipoles. The figure 9 gives the relative energies of the frontier z-orbitals of 1,3-dipoles. The HOMO and LUMO s-orbitals of them are used as reference points and a change in energy by heteroatom substitution can be calculated by the equation, AE =)) Cy?Ac (9) where Cy is the Huckel coefficients for the frontier orbitals. Ac, is the difference in valance state ionization potentials between the carbon and the heteroatom substituted at position / in the dipole.(ev) carbonyl diazoalianes nitousoxiae, carbonyt vies oxides azides oxides o mor et x og BEo xk % 2298 EF Q Hee rp ae i 2 25 2232 7aRR 2 F 8B +18 ee +14 +9 al 49 ag t4 +4 aa —_ 22 “5 25 aul 122 8S 10.3 -135 Figure 10. Estimated frontier orbitals for the 1,3-dipoles. Substitution at the central atom will have no effect on the HOMO of the dipole, because of the node passing through the central atom. Terminal substitution will have a large lowering effect on the HOMO energy. LUMO energy of the dipole is larger lowered by substitution at the central atom than the terminal substitution. 2Sustman's [34] reactivity model is also based on the interactions of HOMO’s and LUMO’s of both the dipolorophile and of the 1,3-dipole. As the two addends approach each other their orbitals begin to interact and orbitals of suitable symmetry are formed. The resulting change in the energy between the interacting molecules from the second order perturbation equation, which is as follows (Figure 11). 2 (Ho + ofo,lY 2 2 (clo. + ol oH AB = tt) Ei - Eel Est. EY I—-fI-O a Figure 11. The interaction of the frontier orbitals of two molecules. $c ——> A—B AE is the total interaction energy, which measures the stabilization of the transition state during the process of bond formation and larger 2Bvalues of AE signify more ready reactions. Ea and Es are the corresponding frontier orbitals. The c's are the molecular orbital coefficients of A and B in the direction of maximal overlap. The PMO theory utilizes ground state frontier eigenvalues and eigenvectors in the second order perturbation theory and provides knowledge of the energetics of the transition state between the two participating frontier orbitals [33] 1.2.1.2. FMO Treatment of Cycloaddition Reactions Frontier molecular orbital theory provides the basic framework for analysis of the effect that symmetry of orbitals has upon reactivity. Cycloaddition reactions are allowed only when all overlaps between the HOMO of one reactant and the LUMO of the other are such that a positive lobe overlaps with another positive lobe and a negative lobe only with another negative lobe. To apply FMO theory, the coefficients and energies of the frontier orbitals are necessary. The interaction energy between the HOMO of one reactant and the LUMO of the second is calculated by using the second order perturbation theory [35]. The total interaction energy (AE) is a measure of the transition state stabilization (or destabilization) in the direction of maximum overlap.According to Fukui [36], reactions take place in the direction of maximal HOMO — LUMO overlap. In concerted cycloadditions that orientation should be favored in which the centers with the largest atomic coefficients interact. The use of these generalized frontier orbitals within the framework of qualitative perturbation molecular orbital theory provides a qualitative explanation of differential reactivity, regioselectivity and periselectivity in cycloadditions [37,38}. 1.2.2. Regioselectivity and Reactivity in Cycloaddition Reactions The HOMO's and the LUMO's of a diene and a dineophile are used in the construction of orbitals for the transition model. The influence of electron withdrawing and the orbital energies of the addends and hence on the symmetry orbitals is evaluated by first order HMO — perturbational theory. There are two types of Diels — Alder (abbreviated DA) reactions. The reaction occurs easily if the diene electron rich and the dineophile electron poor (normal DA) or vice versa (inverse DA).In the orbital rearrangement of a normal Diels ~ Alder reaction the orbital energies of the dienophile are lowered compared to ethylene, but the orbitals of the diene are raised in energy comparing to those of butadiene. The more electron releasing the diene in normal DA reactions, the higher the rate accelerating effect. In normal DA reactions the interactions between LUMOdienoptiie. and 25HOMOdene_ is the dominant stabilizing factor. For the inverse DA reactions the relative positions of orbitals is interchanged. The predominant interaction is between HOMOsenoptde and LUMOdere. The inverse DA reaction can be accelerated by electron releasing substituents in the dienophile. According to the substituent effects, Neutral Diels — Alder reactions is a third type of orbital rearrangement for a Diels — Alder reaction. The HOMO and LUMO seperations are similar. Electron withdrawing or releasing substituents will either raise or lower the frontier orbital energy levels. Each kind of substituent will strengten one HOMO — LUMO interaction but weaken the other. As a result, electron attraction or release should increase the reactivity. However the influence of substituents on the rate should be smaller than for normal or inverse DA and 1,3-dipolar cycloaddition. The regioselectivity [39], in which the ortho or para is favored over the meta has been explained by MO considerations. When an unsymmetrical diene adds to an unsymmetrical dienophile there are two possible products (Figure 12).ook mostly A P= SO, mostly Figure 12. Regioselectivity in Diels — Alder reaction There are also Diels — Alder reactions in which the heteroatom is part of the diene system. Heterodienes with nitrogen are known as azadienes [40]. Replacing the carbon C; in butadiene by nitrogen, the HOMO energy is lowered to a much greater extent than the LUMO energy. Azadienes would thus be predicted to be more electrophilic than butadienes and consequently display little tendency in normal HOMO diene controlled Diels — Alder reactions. The presence of the electron withdrawing substituents in azadiene results in a further lowering of the HOMO with respect to unsubstituted azadienes and an even larger drop in the LUMO energy level. This suggests that it may react efficiently with 27electron rich and neutral dienophiles such as vinyl ethers and styrene in the inverse electron demand Diels - Alder mode. As the energy minimization from the stationary point, initiated by a step along the C — C or C — N bond in one sense leads to the reactants and in the opposite sense to the product so that the Diels ~ Alder reactions with azadienes should be single step reactions analogous to the Diels — Alder reaction of butadienes, Sustmann classifies 1,3-dipolar cycloadditions into three types [10], depending on the relative disposition of 1,3-dipole and dipolorophile frontier orbitals. i) HOMO controlled 1,3-dipolar cycloadditions (the interaction of the dipole HOMO with the dipolorophile LUMO is the greatest). il) HOMO- LUMO controlled 1,3-dipolar cycloadditions (both of the frontier orbital interactions are large) ili) LUMO controlled 1,3-dipolar cycloadditions (the interaction of the dipole LUMO with the dipolorophile HOMO is the greatest). Electron donating substituent (X), extended conjugation (C) and an alkyl (R) group raising the dipole HOMO energy or extented conjugation and electron withdrawing substituent lowering the LUMO accelerate HOMO controlled reactions and decelerate LUMO controlled reactions. Electron withdrawing substituents and extended conjugation which lower TC. YOKSEKOGRETIM KUL 2g DOKOMANTASYON MERizz3the dipole LUMO energy or electron donating substituents, an alkyl group and conjugation, raising the dipolorophile HOMO energy will accelerate the LUMO controlled reactions and decelerate the HOMO controlled reactions. HOMO — LUMO controlled reactions will be accelerated by an increase of either frontier orbital interaction. B A B A B A ee } =, —_ —_— —\/ AL | AL a Wi i) ii) iii) 1,3-dipoles and Possible interactions between A: Figure 13. B: — dipolorophiles. 1,3-dipoles can add to unsymmetrically substituted dipolorophiles giving two different products.Figure 14. Two possible regioisomers of 1,3-dipolar additions of an unsymmetrical 2 x - system. 1.2.2. Secondary Orbital Interactions Woodward and Hoffmann [41,42] have suggested that the second order interactions are responsible for the preference in Diels - Alder reactions for endo, rather than exo, additions. The endo preference in Diels - Alder condensations is generally due to the secondary interaction between the next nearest atom to the olefinic site of the dienophile (atom a in the Woodward — Hoffmann notation) and a central atom (B) of the diene. 30secondary interactions —~(bond - forming # interactions) J KS Figure 15. Secondary orbital interaction of orbitals in the transition state for LUMO the dimerization of cyclopentadiene. Secondary orbital interactions cause cyclopentadiene to give two stereoisomers, endo and exo cycloadduct. Figure 16. The two stereoisomers of cyclopentadiene dimerization.1.3. Frontier Orbitals of Dienophiles or Dipolorophiles Substituted ethylenes as dienophiles or dipolorophiles can be subdivided into three classes [25,43,44,45] |) Electron rich substituents — ii) electron withdrawing substituents ii) conjugated ethylenes =>, As the two addends approach each other their orbitals begin to interact and orbitals of suitable symmetry are formed. A stabilization of the molecular complex results. The magnitude of this stabilization is a function of the energy difference between the interacting orbitals. The closer these energies, the higher the stabilization. Substituents will influence the energy of the orbitals and change their relative stabilization. First order Perturbation theory can be used whether a substituent will raise or lower the orbital energy. 32Electron withdrawing groups on the dipolorophile lower the x orbital energies as compared to ethylene, so that for electron deficient dipolorophiles, the major interaction is between the dipole HOMO and the dipolorophile LUMO. For electron rich dipolorophiles, the dipole LUMO - dipolorophile HOMO interaction is controlling. Conjugation compresses the frontier orbital separation and the resulting HOMO and LUMO both have their largest coefficients at the terminal carbon. Regioselectivity should be less for conjugated dipolorophiles than electron poor or electron rich dipolorophiles. Electron withdrawing groups and conjugating substituents on the dipolorophile lower the dipolorophile LUMO energy and electron releasing groups on the 1,3-dipole raise the dipole orbital energy. Both kinds of substitution accelerate reaction by narrowing the frontier orbital separation. Electron withdrawing groups decelerate reaction by lowering the dipole HOMO energy and electron releasing groups on the dipolorophile decelerate the rate by raising the dipolophile LUMO energy. Calculations of the hypothetical Diels — Alder reaction of butadiene and ethylene show that the HOMO levels of both addends are raised and the LUMO levels are lowered by the deformation of bond lengths of the . addends during the reaction. This leads to stronger interaction between the frontier orbitals in the transition state and was termed by Fukui and Fujimato [59] the (PNIFLS). 33a E(ev) Figure 17. Estimated x-frontier orbital energies and coefficients for dipolorophiles. The shapes and relative energies of frontier orbitals [46,47] can be Qualitatively estimated from first order perturbation theory (see eq, 8).The molecular orbital energies of the perturbed molecules are obtained from this equation and the obtained data are inserted into the secular determinant in order to get the eigenvectors of molecular orbitals. In‘-substituted butadienes, electron donating groups will decrease the coefficient at the point of attachment in the HOMO and increase that coefficient in the LUMO. The same coefficient magnitudes also result. N 2 = ob IB os i IN eB Figure 18. Estimated frontier orbitals energies and coefficients for 1- subtituted butadienes. 35E(ev) The union of two systems results in a decrease in the coefficient at the site of the attachment in both the LUMO and HOMO. According to the inductive model of electron deficient alkenes the larger terminal coefficient is on the substituted carbon in the HOMO and the unsubstituted carbon in the LUMO. cK XM € cM ¢ x 23 sg i} N 93, Figure 19. Estimated frontier orbital energies and coefficients for 2- substituted butadienes. 36Aithough the general characteristics of alkynes and alkenes are similar, acetylenes and ethylenes react different toward nucleophiles and electrophiles. Reactions of nucleophiles with acetylenes are faster than those with the corresponding ethylenes. Conversely, ethylenes undergo reactions with electrophiles more readily than the corresponding acetylenes. As a result of these chemical observations, both the LUMO. and the HOMO orbitals of acetylenes are lower in energy than those of corresponding ethylenes [43]. Ee Figure 20. Estimated frontier orbital energies and coefficients for styrene and phenylacetylene.1.4, 1-Benzoyl-2- phenylpyrazolo-[1,2-a]pyrazole Derivatives ore ONS GH; —X HX (5) (6) 4-Benzoyl-2-phenylpyrazolo[1,2-alpyrazole derivatives were first prepared in 1964 by Solomons and coworkers [49]. These betaines, we call them by this general name because of their bearing charge separation on heteroatoms nitrogen and oxygen (compound 5), fall into the class of azomethine ylides. Azomethine ylides should react readily with both electron deficient and electron rich dipolorophiles due to the narrow frontier orbital separation [20]. 4 i 3 Che a HX 384-Benzoyl-2-phenyipyrazolo-[1,2-alpyrazole derivatives react as a 1,3-dipole at the 1,7 — position and 3,5 — positions. 1.4. Electroselectivity of Betaines Betaines, are to be regarded as belonging to the 4n electron class of electrocyclic component for addition across the corresponding positions. The thermal reactions of betaines with ethylenes and acetylenes are readily rationalized by the general theories of pericyclic reactions. Therefore, with a 2n system, betaines will probably react through cyclic components at either 1—, and 7-, or 3-, and 5— positions. In this work, 1,3-dipolar_ cycloaddition of | 1-Benzoyl-2- phenylpyrazolo-[1,2-a]pyrazole derivatives were tested against various dipolorophiles. The sysnthesis of the betaines were mentioned in details in experimental section, 1.4.1, Regioselectivity FMO method have also been to discuss the regioselectivity of cycloadducts formed between the betaines and dipolorophiles (Figure 21). 39Figure 21. Possible regioisomers of the cycloadducts. 40 csie-x =o x Rx Jean =o x RyThe magnitudes of the HOMO and LUMO coefficients appear to determine the regioisomer. When there is a large bonding interaction between the frontier orbitals of the betaines and dipolorophiles, a stabilization at the transition state results. The preferred regicisomers are those in which the largest coefficient of the HOMO interacts with the largest coefficient of the LUMO. 4.5. Aim of this work The aim of this work are as follows : i) to provide an account for the structure and reactivity of ‘-phenacylpyrazole and —_1-Benzoyl-2-phenylpyrazolo[1,2-alpyrazole derivatives. The participating of these compounds in cycloaddition reactions have been demonstrated. ii) to provide an application of the PMO and FMO methods leading to discussion of the reactivities of the betaines and the prediction of the possible stereoisomers of the cycloadducts. iii) to make a comparison between the experimental results and theoretical predictions. iv) to introduce new cyclic compounds to the heterocyclic chemistry in this way. 412. RESULTS AND DISCUSSION 2.1. Experimental Works This work covers the study of cycloaddition reactions of | 1-Benzoyl-2- phenylpyrazolo-[1, 2-alpyrazole (5) and 1-phenacylpyrazole derivatives (3) [49] toward various dipolorophiles and dienophiles, respectively. The synthesis of the two compounds are schemed in figure 22 respectively and the details are given in the experimental section. The reaction of pyrazole with phenacyl bromide, p-bromo, p-chloro and m-nitrophenacyl bromide gives phenacylpyrazolium salts, which are converted to phenacylpyrazole derivatives (3) by the treatment with bases. Alkylation of these compounds (3) by the second moles of phenacylbromide derivatives gives 1,2-diphenacylpyrazolium salts (4), The dialkylated salts undergo cyclization to 1-Benzoyl-2-phenylpyrozolo- [1,2-alpyrazole derivatives when heated with aqueous sodium bicarbonate. 42co f |} Bre —c— cot, —x M) i Cy l Br—HC—C—GH,—x + reac Are Figure 22. 1-Benzoyl-2-phenypyrazolo-[1,2- alpyrazole derivatives. aThe infrared and nmr data are accordance with the structure (5), but a strong absorbtion at 6.58 y is assigned to the carbonyl group and suggests that such canonical forms as (6) are important . COT = On GH;—* CoH —X (5) (6) Figure 23. Canonical forms of 1-Benzoyl-2-phenylpyrazolo-[1,2-a]pyrazole derivatives. Although the betaines (5a-d) seem to show 1,3-dipolar character at both 1,7- and 3,5-, they did not behave as 1,3-dipoles to give expected cycloadducts when they were treated with a wide variety of cycloaddition reagents with various conditions of solvent and temperature. The reason has been explained in the section of the molecular orbital considerations. character at 9,11- positions. The synthesis of the betaine (13) is schemed in figure 24 44Phtalic anhydride was treated with ammonia and by the evolution of water, then it was converted to phtalimide. Phtalimide yielded phtalide when treated with zinc powder, copper solution and sodium hyroxide solution. Reaction of phtalide with acetic acid saturated by hydrobromic acid yielded ot - bromo toluic acid. Chlorination of a— bromo toluic acid with + NH OH NH (UL2ny 04; NaOH “HO cn He Oo (8) (9) ‘AcOH Br ° + Her AOR 7 Oo oO (10) (11) [m= Br cl (12) ° s jr CL - 5 | NH oO Og (12) (13) Figure 24. The failed reaction of pyrazole with a-bromo-o-toluiyl chloride. 4s(13) (16) Figure 25. The two canonical forms of compound (13). thionyl chloride gave the product a-bromo-o-toluiyl chloride. Pyrazole was supposed to react with c-bromo-o- toluiyl chloride to produce the betaine (13). This last step was tried by several ways, but failed. Another work of this study is to synthesize phenacylpyrazole (3a) and 1-(m-nitrophenacyl)pyrazole (2b), which will show 1-Azadiene character at the 2,5 — positions. Pyrazole (1) reacted with phenacylbromide and m- nitrophenacyl bromide to yield (2a) and (2b), which were converted to phenacylpyrazole (3a) and 1-(m-nitrophenacyl)pyrazole (3b) by ammoniumhydroxide (see Figure 22). 2 Oto (3a) 462.2. Characterization of Cycloadducts 1-Phenacylpyrazole (3a) and 1-(m-nitrophenacyl)pyrazole (3b) reacted with the dipolorophiles dimethyl acetylenedicarboxylate and diethyl acetylenedicarboxylate yielding the cycloadducts (14) and (15). The formations of cycloadducts were proved mee spectral analysis. LQ i Qe or 20 ‘oo 350030002500 20001500" ‘Wavenumberfem-f Figure 26. The ir. spectrum of 1-(m-nitrophenacy!)pyrazole. The IR spectrum of 1-(m-nitrophenacyl)pyrazole in nujol, showed carbonyl stretching band v ( C = O ) at 1706 cm. Aromatic stretching bands v ( C = C ) were observed at 1616 cm™'. The vibrational bands at 471537 and 1349 cm were due to the antisymmetric and symmetric stretchings for -NO2 group, respectively. Heats P ‘ C Q Lon NO N ° 4 {or (14) R= GH, (15) R= CH, Hp for oO The IR spectrum of (14) recorded as neat, showed overlapped carbonyl group vibration bands v ( C = O ) at 1734 cm" for the two unsaturated ester groups and a carbonyl band v ( C = O ) at 1700 cm" for the ketone group. cond a 003500 300025002000 Hamam” 400 Wareaumberiew-t] Figure 27. The ir. spectrum of the cycloadduct (14). 48Aromatic and vinylic v (C=C) stretchings corresponded to 1600 cm. The characteristic antisymmetric and symmetric - NO2 stretching bands were observed at 1534 and 1350 cm”. The nitro group is meta substituted to the benzene ring. This was proved with the vibration bands at 764 and 721 cm’. Finally, the band v(C=C) at 1640 cm’ was characterized for the enamine group. No, y 9 Lor — {or for o ° R=CH, R= Gly Figure 28. Rotamer forms of the cycloadducts. The expected structure of (14) and (15) is between the equilibrium of these rotamer forms. The large aryl groups can be either on the side near to the ester groups or on the other side far from these groups. The aryl group causes deformation on the bicyclic structure and steric effect on the ester groups. This steric effect on the ester groups is less for the adduct (15). Because ethyl group is larger than the methyl group. These effects of the aryl groups cause 49the existence of the side peaks for the protons Hs, H» and H, on the bicyclic structure and for the ester methyl and methylene protons. The 1H n.mr. spectrum of (14) shows two triplets centered at 1.02 ppm (J=7.12Hz) and at 1.24 ppm (J=7.22Hz) for the methyl protons. Figure 29. The 1H n.m.r. spectrum of (14), which belongs to methyl protons. The coupling of these triplets are not equal due to the rotamer forms of (14). The one proton triplet at 1.33 ppm was assigned to the side peak of methyl protons having the coupling of 507.15 Hz. Ester methylene protons were split into the quartets at 4.02 ppm and 4.20 ppm by methyl protons ( J = 7.12 Hz). Aside quartet Tesonates at 4.07 ppm with the coupling 7.15 Hz. The two methyl and methylene protons turn out to be non-equivalent, because one of the ester groups is attached to the nitrogen atom on the bridgehead. The singlet resonating at the lowest field, at 8.75 ppm belongs to the Hz proton. The protons of the methylene group, which lies between carbonyl group and the nitrogen atom, resonate as a two—proton singlet at 3.77 ppm. Figure 30. The 1H n.m.r. spectrum of (14), which belongs to the methylene protons. s1The protons H2,Hs and Hs are held in the W configuration. The long range coupling resonance of H, with either Hz or Hs was observed at 8.33 ppm, which was overlapped with the doublet of Hs. (J = 0.98 Hz ). The dihedral angles of Hy with Ha and H. are estimated to be 74° and 72° on the basis of Karplus equation (see Fig. 31). Molecular model suggests that the coupling constants Jue,» =0-1Hz and Jip, =0-2Hz are consistent with the Karplus equation (see eq. 11). The pseudo —triplet for Hs ( actually double of doublets due to nearly equally coupling with Hy and He ) was located at 7.58 ppm (4,4, =801Hz y,, 4, =7.96Hz). The resonance of Hg at 8.23 ppm shows the expected splitting with the coupling of 7.73 Hz. The other doublet at 8.32 ppm was due to the splitting of Hg proton by Hs having the coupling (Jy,.4,) of 8.14 Hz. 20 40 60 80 100 120 140 160. 180 + Figure 31. Pictural idea of Karplus equation which implies from the plot of J against ¢8.5 cos” }-0.28 0°<§<90° (11) 9.5 cos? -0.28 90°<$< 180 Ha was split into a doublet by Hy at 7.62 ppm (J= 1.25 Hz). The splitting of He into a doublet by H. resonates 7.54 ppm with a coupling of 2.53 Hz. The peak observed at 7.64 ppm is a side peak of Hg resulted from the steric effect of rotation. Hb is more shielded ‘compared to the protons Ha and H, because of the electron transfer from the nitrogen atom on the bridgehead. It resonates at quite a high field as a triplet due to the overlap of two doublets, split by Hs (J= 2.02 Hz) and He (J= 2.08 Hz). The doublet located at 6.38 ppm was suggested to be a side peak of Hy. The complete 1H n.m.r. analysis of the adduct (14) is shown in figure 33. The chemical shift values and coupling constants for the adduct (14) were tabulated in table 2.ab " ; Table 2.1H n.msr. data of adduct ( 14) a) MeSi as internal standart, b) in CDCls, ¢) singlet, d) doublet, e) double of doublets, f) triplet, g) quartet, h) overlapped. Chemical shift coupling contants protons values in ppm Ji Hz c 2 8.75 —_ —_ d 4 8.32 45 8.14 4,20r4,6 0.98 f 5 7.58 5.6 7.79 d 6 8.23 64 7.73 d a 7.62 a,b 1.25 b 6.32 ba 2.02 b,c 2.08 c 754 c.b 2.53 f -CH3 1.02 - CHs , - CHa ae f -CH3 1.24 - CHs3 , - CH2 7.22 = CHz- 4029 CH, ,-CHs 7.12 3 ~CH- 4.20 =CH2 ,-CHs 7.12 N-CH2- 377° — — 34— ee Le ie Wee a eaaiey ae Figure 32. The 1H n.m.r. spectrum of the cycloadduct (14), which belongs to the resonances of protons H2, Hs ,He, Ha, Hp and H.. ft out Rc Figure 33. The complete 1H n.m.r. spectrum of the cycloadduct (14).3 nmr. spectrum also proved the structure of (14). The °C carbon of CDCls resonates at 78 ppm. There are nineteen different carbon atoms of the adduct which are in accordance with the number of carbon signals and absorbtions in the "°C spectrum. Four of them are the sp® carbons, resonating in the 0-70 ppm range. Carbonyl carbon resonances appear at a very low field. (165 to 195 ppm ). Cx resonated at the lowest field. The ester carbonyl carbon which is attached to the nitrogen atom resonates at the lower field than the other ester carbonyl carbon. The sp* carbon resonances also differ due to the nitrogen atom. The resonances in the 110-160 ppm range are due to the sp” carbons of the olefinic bond and benzonoid aromatics. Some equations were used in order to estimate the exact resonance values of carbons. (see eq. 12,13, 14 and 15). 56t 8 =-23 40H (12) for sp* carbons bo = 123.3452" +Ez* +08 (43) for sp? carbons be = 128.5 + Dz (14) for benzene be = 166 + DATE (15) for ester carbonyl carbons bc = 193 + D2 (16) for ketone carbonyl carbons According to the above equation some calculations have been made and the approximate 5 values have been found in ppm. 8g =-2.3+Za-ciy#Zp-o- +Zy-con =-23+9.14101-3 = 13.9 ppm 8o,=-23+Za-con +Zp-n- =-23+225+18 = 38.2 ppm 82-23 +Za.ciy + Za-0. +Zp.con =-23491449+3 =58.8 ppm28.5 +2 0,4Zmw0, =128.5+19.6+0.0 = 148.1 ppm 865 123.3 +24 coo *Za-ctis +Za-cooet +Za-n- =123.347+106-24 = 145.8 ppm 8o= 123.3 +Za-c.n-+Za-n- =123.3-15.1-24 = 106.1 ppm oo =128.5+9+08 = 138.3 ppm 82 128.5 +Zo - cooiy + Zo-n02 =128.5+0.1-53 = 124.2 ppmAg 128.5 +Zy.no, + Zp-coor, =128.5-5.3442 = 127.4 ppm 8o5 128.5 + Z,,. no, + Zm-coc, =128.5+0.8+0.0 = 129.3 ppm 8cz 128.5 + Zp. cocitg +Zp-noo =128.5+0.146 = 135.5 ppm 8g 198.0 +Z-c44, +Zi-cn, = 193.0-1.2+65 = 198.3 ppm of 185+ Z,.c4,4 =165+11-5 =171 ppmFigure 34. The °C n.m.r. spectrum of the cycloadduct (14). The IR spectrum of the cycloadduct (15) showed similar vibrational bands with the cycloadduct (14). The ester carbonyl stretching band v (C=O) was observed as a broad band at 1742 om’. The other carbonyl stretching band at 1700 cm‘ belongs to the ketone group. The enamine group v(C=C ) gives a strong band at 1642 cm. As expected , aromatic and vinylic v(C=C) stretching bands were observed at 1614 cm’. The vibrational bands at 1534 and 1350 cm’ were characteristic antisymmetric and symmetric stretchings for - NO2 functional group. The vibration band at 720 cm" characterized the meta substituted benzene ring.“eo 3500-3000 ~—*2500 = 20n0=—«soo «10000 Wareaember(ew-1] Figure 35. The ir. spectrum of the cycloadduct (15). The two three proton nmr. singlets at 3.57 ppm and 3.75 ppm were assigned to the two ester methyl protons. The singlets at 3.7 ppm and 3.94 ppm were suggested as the side singlets for the methyl protons. The two proton singlet at 3.80 ppm was assigned to the methyl proton. Hs resonates at 7.59 ppm as a pseudo triplet which arises from the nearly equal coupling with Hs and Hy CJ =8.17 Hz J, = 7.76 Hz )Hsis split into two doublets by HH, Hy He Hy and Hg. These two doublets overlapped forming a pseudo- triplet in appearance. The splitting of Hs into a doublet by Hs was observed aat 8.22 ppm with the coupling of 7.76 Hz. The other doublet at 8.33 ppm belongs to the Hs, which was split into a doublet Figure 36. The 1H n.m.r. spectrum of the cycloadduct (15) including methyl protons. by a coupling (jy, 4.) of 8.14 Hz. The protons He, Hs, and Hs are Ms held in the W configuration. There is long range coupling of He with either Ha or Hs at 8.33 ppm, which was overlapped with the doublet of Hy Molecular model suggests that Juss = 0-1 and Jhoe= 0-2 are consistent with the Karplus equation. The dihedral angles were estimated to be 74° and 72° by Karplus equation. The splitting of He into a doublet by Hb with a coupling of 2.51 Hz is at 7.50 ppm. oThe side resonance of Hc was observed at 7.58 ppm. The doublet at 7.64 ppm belongs to Ha proton. (Jism = 1.06 Hz) with its side resonance at 7.65 ppm. Hb proton resonance as a pseudo - singlet at the high field corresponds to the chemical shift cof 6.31 ppm. Hb would have couplings with Ha and He, but this could not have been observed in the n.m.r. spectrum. The singlet at 6.39 ppm stands for the shoulder singlet of Hb proton. He proton of phenyl group resonates as a singlet at 8.75 ppm, since there are no protons on the adjacent atoms. The complete 1H n.m.r. spectrum of the adduct is shown in figure 38. The detailed 1H n.m.r. data of the compound is detailed in table 3. Figure 37. The 1H n.m.r. spectrum of the cycloadduct (15), which belongs to the protons Hz, Hs, He, Ha, Hb, and He.iz = Figure 38. The complete 1H n.m.r. spectrum of the cycloadduct (15).a,b Table 3.1H n.m.r. data of the adduct (15) chemical shift protons values in ppm © 2 8.77 4 3.33 f 5 7.59 d 6 8.22 d a 7.64 ¢ b 6.31 d c 7.50 c -CHs 3.57 c -CHs 3.75 Beer se 65 coupling constants Jy 4.20146 5.6 Hz 8.14 0.98 7.76 7.76 1.06 2.512.3. Molecular Orbital Considerations The use of molecular orbital theory for cycloaddition reactions could be understood in 1965 by a series of publications initiated by Woodward and Hoffmann [27]. Woodward and Hoffmann explained the striking chemical behavior of pericyclic reactions through the application of molecular orbital theory. These explanations aroused the interest of a considerable number of chemists. Thus, the number of papers have been published to describe theoretical approaches to cycloaddition reactions and to explain and predict the various mechanistic aspects of these reactions. Each emphasizes particular approaches within the area, like the construction of correlation diagrams [2,50], frontier orbital theory [51,52], perturbational molecular orbital theory [53,54] which are almost all based ultimately upon molecular orbital theory. Woodward and Hoffmann have based their arguments on the symmetry properties of molecular orbitals [21]. The molecules that are undergoing a pericyclic reaction have one or more elements of symmetry such as a plane center of symmetry. These elements of symmetry must be retained in a pericyclic reaction. Since the energies of the MO’s changes 66continuously throughout, the MO’s of the reactants can be corralated with the MO's of the products. Figure 39. Plot of energies versus reaction coordinate for a process where symmetry is retained (__) and the effect ( ------a,b,c ) of progressively removing the symmetry. Languet-Higgins and Abrahamson [55] applied the treatment to several simple pericyclic reactions of symmetrical molecules, assuming symmetry to be retained throughout and showed that reactions were allowed or forbidden in accordance with the predictions of Woodward-Hoffmann rules. Their approach was based on certain well known properties of molecular wave functions. If a molecule has some element of symmetry, the molecular wave function must conform to that symmetry, being either symmetric or antisymmetric, with respect to that symmetry operation. Any change in such a system taking place with retention of symmetry must leave the symmetry of wave function unchanged. If the reactants in a orreaction have a plane of symmetry, and that symmetry is retained throughout the reaction, then the wave function must remain throughout either symmetric or antisymmetric. The device of correlation diagrams can also be easily applied to 1,3-dipolar cycloadditions in which a suitable amount of symmetry is present. Figure 40, Consideration of betaines as allyl anion. 1-Benzoyl-2-phenylpyrazolo-[1,2-a]pyrazole derivatives are considered as an allyl anion across 1,7 — and 3,5 — positions to construct the correlation diagrams ( Figure 40) 68fa Perturbed ally! anion Cycloadduct MO's om and ethylene MO s aN Figure 41. Correlation diagrams for the 1,3-dipolar cycloaddition of a 1-Benzoyl-2-phenylpyrazolo-[1,2 -alpyrazole derivative with a 2n- system, The symmetry element throughout the reaction is the vertical mirror plane, m. It is then necessary to generate molecular orbitals which will be either symmetric (S) or antisymmetric (A) with respect to plane of symmetry. . 0According to Woodward — Hoffmann [56], the ground states must likewise corralate, the reaction is then allowed. 1,3-dipolar cycloaddition of 1-Benzoyl-2-phenylpyrozolo-[1,2-a]pyrazole derivatives are not thermally allowed, because the ground electronic states do not correlate. The orbital correlations obtained from figure 41 is shown in table 4. Table 4. Orbital correlations of betaines. X5<—> 05, Xaa Knot X3<—> 0, Xoa—> my Xi<—9, Totally six electrons contribute to the cycloaddition reactions of 4-Benzoyl-2-phenylpyrazolo-[1,2-alpyrazole derivatives, but there are not smooth correlations of ground states. ( X:? Xz Xs” x6 01702” m3”). Thus, the reactions are not thermally allowed. In this work, the HMO method at the level of FMO was used to estimate qualitative correlations between theory and reactivity in 1,3-dipolar cycloaddition reactions of | 1-Benzoyl-phenylpyrazolo- [1,2-alpyrazole derivatives toward olefinic and acetylenic dipolorophiles. Eigenvalues and eigenvectors were calculated by using Hickel computer 70program. The coulomb and resonance integrals for hetero atoms were excerpted from Streitwieser's parameters [57] The betaines are considered in figures 42 and 43 such that the aryl substituents are coplanar and orthogonal with the betaine plane. The HOMO and LUMO energy values of 1-Benzoyl-2-phenylpyrazolo- [1,2-alpyrazole derivatives were calculated by using Hlckel computer program are shown in tables 5, 6, 7, and 8. nA B 1 - Benzoyl - 2- phenylpyrazolo -[1,2-@ Jpyrazole igure 42. Canonical forms of the betaines (aryl groups are coplanar). nc D 1 - Benzoyl -2 - phenylpyrazolo -[1,2-a Ipyrazole Figure 43. Canonical forms of betaines (aryl groups are orthogonal).Table 5.The FMO energies (f) of 1-Benzoyl-2-phenylpyrazolo-[1,2-a] pyrazole derivatives which show 1,3-dipolar character at 1,7 — positions. ( the coplanar form is considered). _HOMO LuMo 1A 0.25725 - 0.31528 2A 0.25802 ~ 0.18978 3A 0.25168 - 0.32042 4A 0.25286 - 0.31897 Table 6.The FMO energies (8) of 1- Benzoyl-2-phenylpyrazolo-[1,2-a] pyrazole derivatives which show 1,3-dipolar character at 3,5- positions(the coplanar form is considered). _HOMO_ LUMO 1B 0.25103 - 0.31547 28 0.25180 ~ 0.18978 3B 0.24531 - 0.32049 4B 0.24652 - 0.31908 The tables 5 and 6 indicate that except 1-(m-nitro)-2- (m-nitropheny!)pyrazolo-[1,2- alpyrazole, there is no appreciable change between the HOMO — LUMO values of the betaines. This is due to the effect of the halogens which arises from the interplay between the "inductive effects through C - X « bonds and resonance effects through = electron feedback nonbonding halogen p electrons by x bonding. As a result, the MO calculations imply that there is no priori basis for predictions of the actual balance of these effects. On the other hand, the Huckel MO calculations that the HOMO - LUMO values of 1-Benzoyl-2-phenylpyrazolo-[1,2-a]pyrazole derivatives became identical, when the aryl group is orthogonal to the betaine plane. Also in this case the meta substituted betaine differs in energy from the other betaines.( tables 7 and 8) Table 7. The FMO energies (B) of 1-Benzoyl-2-phenylpyrazolo- [1,2-alpyrazole derivatives which show 1,3-dipolar character at 1,7 — positions ( orthogonal form is considered). HOMO. LUMO 1c 0.31626 = 0.40151 2c 0.31626 - 0.19116 3c 0.31626 - 0.40151 4c 0.31626 - 0.40151Table 8. The FMO energies (8) of the betaines which show 1,3-dipolar character at 3,5 - positions (orthogonal form is considered). HOMO LUMO 1D 0.31079 = 0.39969 2D 0.31079 - 0.19116 3D 0.31079 - 0.39969 4D 0.31079 - 0.39969 Table 8 shows the calculated energies of dipolorophiles used in cycloaddition reactions. The relative HOMO — LUMO gaps of the betaines have been illustrated in figure 44 and 45. 6Table 9. The FMO energies (f) of the dipolorophiles. Dipolorophile HOMO, LUMO Vinyl acetate (V. A) 0.86283, - 0.75742 Phenyl acetylene (P.A.) 0.80156 + 0.80156 Diphenyl acetylene (D. P.A.) 0.62872 - 0.62872 Diethyl acetylene — dicaboxylate ( D.E.A.D) 0.25677 - 0.56089 Dimethyl acetylene ~ dicarbxylate (D.M.A.D) 0.25677 - 0.56089 It is clearly indicated in figures 44 and 45 that the cycloaddition in each case is more LUMOpewine and HOMOspoisrphie controlled (the interaction of the betaine LUMO with its dipolorophile HOMO is greatest). 1HOMO = 0.31 0.25 ~0.80 PA. 20.75 VA. LUMO 3_D.P.A. 20.56 DMAD. & D.EAD. 0.25 D.MA.D. & D.EAD. 0.63 DPA HOMO Dipolorophile Figure 44. The relative HOMO -LUMO energy gaps between the betaines 2 and dipolorophiles. 18-0.80_ PA. 70.75 VA. LUMO 0.63 D.P.A. 0.56 DMAD. &D.EAD. LUM HOMO = 0. 0.25 0.25 DMAD. &D.EAD. 063 DPA. HOMO 0.80 PA. 0.86 VA. Figure 45. The relative HOMO -LUMO energy gaps between the betaines 1,3, and 4 and dipolorophiles. 1c. YUKSEKOGRETIN [URNA x IMANTASYON MEBKZNThe decreased HOMO ~ LUMO energy gap between betaines and the dipolorophiles leads via smaller interfrontier energy values to more ready reactions. Indeed, this was found to be detectable case for the reactions the betaines and the dipolorophiles D.E.A.D. and D.M.A.D. The betaines reacted with dipolorophiles in a few minutes by the evolution of a gas, which could not to be clarified. This shows the reaction is not a 1,3-dipolar addition. It was not stable. This case can be explained due to the coefficients of the frontier orbitals of the 1,3-dipoles. The figures 47, 48, 49, 50, and 51 show the coefficients of the betaines and the dipolorophiles at the interaction sites respectively. Q HOMO an Oe tue Lumo ye HOMO symmetry allowed symmetry forbidden Figure 46. Interactions of the HOMO 13,02 — LUMOdporopnie and LUMO, 3.dpoie - HOMO apoteropie- 80Coefficients Dipolorophiles HOMO, LUMO 0.60703 -0.20150 Vinyl acetate He==CH— HE ==CH— 0.70353 0.26604 0.28095 0.28005 Phenyl acetylene HC==C—Ph HC==C —Ph 0.48370 0.48370 0.17255 - 0.38858 Dietyl acetylene —c=—=c— —c=—c— dicarboxylate 0.17255 bree 0.17255 0.38858 Dimety| acetylene —c=c— —c=c— dicarboxylate 0.17255, 0.38858 = 0.36979 - 0.36979 Dipheny Ph—C=C¢—Ph Ph—C==C—Ph acetylene - 0.36079 0.96979 Figure 47. FMO coefficients for the dipolorophiles. The coefficients for the dipolorophiles are as expected (see Figure 47). According to the molecular orbital diagram of ethylene the coefficients of the atoms have the same sign at the HOMO leveland opposite sign at the LUMO level. But the coefficients for the betaines are not suitable for 1,3-dipolar reactions. 1,3-dipoles have the same molecular orbital diagram with the allyl anion. Thus the coefficients of the terminal atoms of 1,3-dipoles must have opposite sign at the HOMO lével and the same sign at the LUMO level. Although the highest energy orbital has the atomic orbitals of opposite sign on C; and Cy or C3 and Cs, the lowest energy orbital does not have the atomic orbitals of the same sign on these carbon atoms. This is the reason why the betaines do not take part in 1,3- dipolar cycloadditions. The reaction that they undergo with dipolorophiles D.E.A.D. and ‘D.M.A.D. can either be radicalic or ionic. 82HOMO 0.09998 1A ZNN o3s7é7—-0.33130 osooee ZN 2A, 0.36020 "33187 o.0s80s 3A ZS oase07 033101 0.00842 ossed? —- 0.33164 LUMO. -estoor ZaNN 0.43478 “or2s18 0.01485 ANN -0,06013 0.02827 -o47179 ZN 0.43405 -0.12492, sama ZN 0.43418 -0.12538 Figure 48. FMO coefficients of the betaines that show 1,3-dipole reactivity at 1,7 — positions (coplanar).HOMO. assays game 1B Ny 0.43822 -0.35087 49000 2B Ry 0.19589 0.25220 3B 0.42990 Nn -0.13908 -025167 ——gasaso 4B Sn -019410 LUMO oeago— -0 75080 Soy 0.13603, 0.08083 9.04088 Sy 0.00899 ange -o208s2 Qn 0.13886 esse. p2asos Sn -0.19790 Figure 49. FMO coefficients of the betaines that show 1,3-dipole reactivity at 3,5 — positions (coplanar).HOMO, 0.12900 1c ZANN ~098648 ste 0.12000 2c ZN, -oaieas —basi8 22000 3c ANN -096548 oasti8 0.12900 a ZN -0.26548 oast8 LUMO -0.28007 ZNN o.as007 -0.07188 0.00000 0.00060 3.00000 -0.23307 ZINN 0.49007 - 007188 023907 ZN 0.48007 - 007188 Figure 50. FMO coefficients of the betaines that show 1,3-dipole reactivity at 1,7 — positions (orthogonal).HOMO LUMO, -ossye —_0.4ssa -04s719 7084 1D Sy S77 0.15958. 9.20310 -0.2508 —oassee 0100020 a p0000 2D Sn no 0.15088 200000 -osme —_.aasea : Figure 54. Correlation diagrams for a 1-phenacylpyrazole derivative with a 2n- system. 90The symmetry element throughout the diagram is the vertical mirror plane, m. The generated molecular orbitals will be either symmetric (S) or antisymmetric (A) with respect to the plane of symmetry. The coefficients of the 1-phenacylpyrazole derivatives are in accord with the molecular orbital diagram. The ground electronic states likewise correlate, the reaction of 1-phenacylpyrazole derivatives with dienophiles is than thermally allowed. The orbital correlations obtained from figure 54 is shown in table 11. Table 11. Orbital correlations of 1- Azadienes. Xg~t—03 ; Xg<—> 7; X4—<—>oy X3<—+ 0, X2<—> 1, Xi <0, Totally six x electrons are involved respectively in the cycloaddition reactions of 1-phenacylpyrazole derivatives (3a and 3b) with 2n-electron systems, so there are smooth correlations of ground states respectively. (X9GX3_ <—> o703n?) Thus the reactions are thermally allowed.. a1HOMO goby LuMo Ew symmetry allowed symmetry allowed LUMO Figure 56. Interactions of the HOMO: -azadiene— LUMOsienophite ANd HOMO sienoptite - LUMO} .azadione.3. CONCLUSIONS The following conspicuous can be deduced from this work. The betaines which were expected to show 1,3-dipole reactivity were obtained according to the method of Solomons and his coworkers [49]. All the betaines change their colors on exposures to daylight within a certain period of time. The betaines were tested against various olefinic and acetylenic dipolorophiles. Because of the molecular orbital considerations, they did not show 1,3-dipole reactivity and did not give any expected cycloadduct. They reacted with dipolorophile D.M.A.D. in a few minutes. The reaction was completed by the evolution of a gas. If this gas was acetylene or not, was tested with bromine solution. The test gave negative result. By the help of Na fusion test, the existence of nitrogen atom in the product was proved. 4-Phenacylpyrazole derivatives, as t-azadienes were synthesized according to the method of Solomons and his coworkers [49] 1-Phenacylpyrazole derivatives were tested against olefinic and acetylenic dienophiles with different temperatures and solvents. The reactions of these compounds with D.MA.D. at approximately 50°C and with D.E.A.D. at 70°C were completed in seven days and in two 93days respectively. The HOMO - LUMO energy gaps between t-azadienes and dienophiles D.MA.D. and D.E.AD. are closer compared to the other dienophiles. 1-Phenacylpyrazole derivatives would also give cycloadducts with the dienophiles V.A. and D.P.A. The reaction of 1-(m-nitrophenacyl)pyrazole and V.A. was started at 70°C and was controlled after a month by tlc. The slow formation of the cycloadduct was observed on t.c. The reaction was stopped, since it needed longer time to reach the efficient yield. The cycloadduct formed from the addition of D.M.A.D. and D.EAD. to 1-(m-nitrophenacyl)pyrazole was in good yield and could be characterized easily. But the cycloadduct obtained by the reaction of 1-phenacypyrazole and the dienophiles was not in good yield. Because some of the cycloadduct went into Retro Diels —Alder reaction during the purification by chromotographie. As a result, the cycloadduct could not be characterized. ‘The cycloadducts change their colors on exposures to UV light. After some time they get yellow and can be observed on silica gel by the naked eye. The cycloadducts have no regioisomers due to the symmetrical dienophiles. They exist between two rotamer forms. 944.EXPERIMENTAL The melting points were determined on an Electrothermal IA 900 digital melting point apparatus. Spectra were recorded with a Jasco FT- IR ~ 430 spectrometer, Bruker 400 mHz (for 1H) and a Bruker 100 mHz (for °C). Solvents were removed with a Biichi rotavapor. The compounds were purified until they were observed as a single spot on t.L.c. Kieselgel 60 PF (254+366) were used for the preparative t.l.c. operations. 4-Phenacylpyrazole(3a). Pyrazole (3.0g,0.03mole) and phenacylbromide (6.0g, 0.03mole) in 1,2-dimethoxyethane (50ml) were allowed to stand at room temperature for 24h and then boiled under reflux for 1h. The solvents were evaporated off under vacuum and the residue was crystallized from ethanol-chloroform yielding the -~—salt_—‘t-phenacylpyrazole hydrobromide(50%),m.p., 190-193°C. This hydrobromide was stirred with concentrated aqeous ammonia for 30 min. at room temperature. The free base was extracted into chloroform by three times. The combined extracts were dried over sodium sulfate, and then evaporated to yield yellow-brown crystals. Trituration of these with hexan and ether gave pure t-phenacylpyrazole (81%); m.p., 91-92°C, Vmax (nujol) 1701cm" (ketone C=0), 1600cm" (arom. C = C) [49], 1,2-Diphenacylpyrolium bromide (4a). A solution of 1-phenacylpyrazole (1.579) and phenacylbromide (1.70g) in dimethylformamide (2ml) was 95