COMPUTATIONAL STUDIES ON WITTIG AND ANALOGOUS REACTIONS

Abstract

The thesis entitled “Computational Studies on Wittig and Analogous Organic Reactions” is divided into five chapters, viz., (i) Introduction, (ii) Computational methods, (iii) Wittig reactions of cyclic ketones, (iv) E/Z selectivity in Wittig reaction using 2,2-dimethylcyclopentanone, and (v) A comparative study of Wittig and analogous reactions using cyclic ketones. The Wittig reaction was discovered by Georg Wittig in 1954, for which he was awarded the Nobel Prize in Chemistry in 1979. The Wittig reaction is one of the most common methods used for the stereoselective preparation of olefins. Several types of mechanism of the Wittig reaction have been reported. Generally, on the basis of the mechanisms given in literature, the Wittig reaction is thought to be occurring via a process in which a betaine intermediate is formed by the nucleophilic addition of the phosphorus ylide to the carbonyl compound in the first step followed by carbon-carbon bond rotation of betaine intermediate to form an oxaphosphetane intermediate in the second step. In the third step, the decomposition of oxaphosphetane intermediate occurs to form an alkene and a phosphine oxide. In modern picture of the Wittig reaction, the reaction is a two-step process in which a direct [2+2] cycloaddition of phosphonium ylide and carbonyl compound was occurs in the first step. In the second step, cycloreversion of oxaphosphetane intermediate occurs to form an alkene and a phosphine oxide. There is no betaine structure detected spectroscopically in the Wittig reaction. The reaction is regiospecific in nature and is the best way to form a terminal alkene with known position of the C=C double bond between carbonyl carbon and ylidic carbon. This reaction can be very suitable for the syntheses of various complex molecules because ylides are often tolerant of a variety of functional groups. The stereoselectivity of the reaction depends mostly on the nature of the reactants being used. Though the Wittig reaction was published 64 years ago, the broad applicability of the Wittig reaction has attracted much attention from chemists and the Wittig reaction is still a relevant area of study today due to its stereoselective capabilities and ability to be performed in moderate conditions. The Wittig analogous reactions: aza- and arsa-Wittig reactions follow the similar mechanism as the Wittig reaction. The aza- and arsa-Wittig reactions are a powerful tool for the formation of C=N and C=As bond, respectively. v In the last several years, computational studies on the Wittig, aza-Wittig and arsa-Wittig reactions have proliferated. Treatment of the reactions with quantum chemical methods involves calculation of geometries and energetics of reactants, reactant complexes, transition states, intermediates, product complex and products. In the present work, we investigate computationally the Wittig reaction and Wittig analogous reactions; aza- and arsa-Wittig reactions using monocyclic ketones. A comparative mechanistic studies of the Wittig reaction of cyclopropanone, cyclobutanone and cyclopentanone are carried out using Me3P=CH2 phosphonium ylide. The E/Z selectivity in the Wittig reaction using non-stabilised, semi-stabilised and stabilised Me3P and Ph3P phosphonium ylide with 2,2- dimethyl cyclopentanone is also explored. Also, a comparative mechanistic study of the Wittig, aza-Wittig and arsa-Wittig reactions of Me3P=XH ylide (X = CH, N and As) is investigated using cyclobutanone and cyclopentanone. All calculations have been performed using the Gaussian 09W suite of programs Chapter 1: Introduction The first chapter presents a general introduction to the Wittig reaction and a review of the relevant literature. Emphasis is placed on the various types of mechanism of the Wittig reaction given in its history of many publications. Betaine mechanism, Bergelson’s “C–P–O–C” betaine mechanism, Schweizer’s mechanism, Olah’s single electron transfer mechanism, Bestmann’s “P–O–C–C” betaine mechanism, McEven’s spin paired diradical mechanisms, Schlosser’s cycloaddition mechanism and Vedej’s cycloaddition mechanism are discussed in this chapter. A brief introduction on the Wittig analogous reactions; aza-Wittig and arsa-Wittig reactions is also described. A critical review of the available literature on computational studies of the Wittig reaction, aza-Wittig and arsa-Wittig is presented and comparisons with relevant experiments are also made wherever possible. vi Chapter 2: Computational methods The second chapter outlines the computational methods used. A brief introduction to ab initio SCF and Density Functional methods and a concise concept about the location and characterization of stationary points on the potential energy surface is presented. Chapter 3 Wittig reactions of cyclic ketones The third chapter deals with the computational studies of the Wittig reaction of cyclopropanone, cyclobutanone and cyclopentanone with Me3P=CH2 ylide in the gas phase as well as in solvent. The geometry optimization of all species has been done at DFT/B3LYP level using 6–31G** basis set in the gas phase and also in tetrahydrofuran (THF) solvent using integral equation formalism polarizable continuum model (IEFPCM). Frequency calculations were also performed to confirm that the structures obtained were true minima on the PES or saddle points as the case may be. IRC calculations are done from each transition state in gas phase to verify the structure moving towards the reactant and product sides. The reactions proceed via a two-step process. The structures were found: two complexes - reactant complex (RC) and product complex (PC), two transition states - one for addition (TS1) and the other for elimination (TS2) and four-membered cyclic intermediates. In this study, the generally accepted salt free oxaphosphetane mechanism involves rather than a betaine mechanism. Relative energies of the stationary species are presented. The effect of ring strain of cyclic ketones on the Wittig reaction mechanism has been investigated. The critical geometrical parameters are also reported. Molecular electrostatic potential (MEP) maps on the isodensity surface calculated for all gas phase addition transition structures and intermediates (OP1s) are optimized at B3LYP/6–31G** level of theory. vii Chapter 4: E/Z selectivity in Wittig reaction using 2,2-dimethylcyclopentanone The fourth chapter of the thesis deals with the theoretical studies on the Wittig reactions of non-stabilized (X3P=CHMe), semi-stabilized (X3P=CHPh) and stabilized (X3P=CHCO2Me) ylides (X = Me and Ph) with 2,2-dimethyl cyclopentanone to understand the E/Z selectivity. The geometry of the all stationary points are obtained at DFT/B3LYP level using 6–31G** basis set in each reaction and the nature of each stationary point was probed by frequency calculations. IRC calculations have also been performed for the gas phase reactions of Me3P ylides. In our calculations on the gas phase reactions, reversibility of the formation of OP1 has been seen in the reactions with Me3P non- and semi-stabilized ylides only. The reversibility of oxaphosphetane formation is explained by the influence of the ylide stabilization and nature of the substituents on the phosphorus of the ylide. We have shown that both the addition and elimination steps can play an important role in determining the E/Z selectivity. We have investigated that the puckering ability of addition TS does not depend on ylide stabilization but an interplay of 1,2-; 1,3- and C– H⋯O interactions decides the geometry of TS1s and that the selectivity is determined by the combined effect of 1,2- and 1,3-steric interactions, usually, in favor of the E addition TS and the E alkene, the 1,2-steric interactions playing a leading role in determining selectivity. In the reactions with all ylides, a high E selectivity was observed. For the gas phase reaction of Me3P=CHMe ylide with 2,2-dimetyl cyclopentanone (reaction 1a), geometries of all species viii were also optimized using M06–2X functional with TZVP basis set. Single point energy calculations have also been carried out for the reaction 1a at B3LYP/6–31G**(THF) and at B3LYP–D3/6–31G**(THF) level of theory using IEFPCM solvent model. Gas phase B3LYP/6– 31G** optimized geometries were used for all single point calculations. Chapter 5: A comparative study of Wittig and analogous reactions using cyclic ketones The fifth chapter presents a computational study of comparative study of the Wittig, aza-Wittig and arsa-Wittig reactions of Me3P=XH ylide (X = CH, N and As) with cyclopentanone and cyclobutanone. All calculations have been performed using B3LYP functional with 6–31G** basis set in gas phase. Calculations have also been performed using integral equation formalism polarizable continuum model (IEFPCM), with THF solvent at B3LYP/6–31G** level of theory. IRC calculations have also been performed in gas phase as well as solvent reactions. Stationary points located on potential energy surface were characterized by frequency calculations as minima or transition state. These reactions were predicted to be two-step processes with two complexes – RC and PC, two transition states – TS1 and TS2 and two four-membered cyclic intermediates (INT1 and INT2), except that INT2 was not found in the aza-Wittig reaction. The feasibility of reactions has been verified using energy barriers calculated for the reaction paths. In our calculations, the Wittig reaction is found to be most favorable both thermodynamically and kinetically. The activation barriers in the reactions of cyclopentanone are higher as compared to ix the reaction of cyclobutanone in gas phase and solution phase. The addition activation barriers of free energy slightly higher in the solvent model than in gas phase reactions