Chapter 12 M e c h a n i s m s of the W i t t i g 1
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W. E. McEwen , F. Mari , P. M. Lahti , L. L. Baughman, and W. J. Ward, Jr. 1
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Department of Chemistry, University of Massachusetts, Amherst, MA 01003 Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester, MA 01605
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The metal ion-catalyzed reactions of benzaldehyde with benzylidene triphenylphosphorane and benzylidenemethyldiphenylphosphorane, respectively, have been examined by molecular mechanics calculations (MMX89) and the computed results compared with experimental results for reactions carried out in tetrahydrofuran at temperatures of 15°C or lower. Mechanisms for these reactions are suggested and compared with results obtained previously for a variety of salt-free Wittig reactions modeled by use of the MNDO-PM3 molecular orbital method. In order to explain the origins of stereoselectivity in the Wittig reaction, various workers have considered two fundamentally different mechanisms throughout the years: (i) a stepwise ionic type of mechanism (2) and (ii) a direct cycloaddition mechanism (3). Wittig reactions of unstabilized ylides (alkylidenetriphenylphosphoranes) with aldehydes are mainly Z-stereoselective with respect to alkene formation, whereas the corresponding reactions of stabilized ylides are Estereoselective (4). These stereochemical results are usually not greatly influenced by solvent effects or even by the presence of lithium salts in the reaction media (4,5, 6). By contrast, the stereoselectivity of Wittig reactions of semistabilized ylides (e.g., benzylidenetriphenylphosphorane) with aldehydes are extremely sensitive to solvent effects (2e, 2k, 4a) and to the presence of metal ions (7). These solvent and metal ion effects may be indicative of an ionic reaction pathway, whereas the lack of them, especially in the case of the reaction of stabilized ylides, may indicate the operation of a different mechanistic path. The latest proposal by Vedejs (3d) is that the Wittig reaction proceeds via a concerted but asynchronous puckered 4-center cycloaddition pathway in which the stereoselectivity is determined by multiple steric effects and varying degrees of rehybridization at the phosphorus atom in the transition state. At present, there is not definitive evidence to prove that the reaction must proceed in this manner. Recent MNDO-PM3 computations by us (7,8) and somewhat related MNDO computations by Yamataka et ai (9) do not support the puckered 4-center cycloaddition hypothesis for the reactions of unstabilized ylides with aldehydes (3d). Instead, the MNDO-PM3 computations indicate that such Wittig reactions proceed through an essentially planar transition state (TS) with respect to the four central atoms, P-C-C-O. This process is 0097-6156/92/0486-0149$06.00/0 © 1992 American Chemical Society In Phosphorus Chemistry; Walsh, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
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best described as a very asynchronous cycloaddition, a borderline two-step mechanism in which the C-C bond is about 30 to 50% formed and with little evidence of P-O bond formation. This hypothetical "gas phase"reactionis a 2-center reaction with a planar, U-shaped TS because of the strong attractive ionic interaction of the Ρ and Ο atoms (7, 8). Furthermore, it has been computed that steric effects exerted by the substituents at the phosphorus, the ylidic carbon and aldehyde have little effect on the geometries of Wittig reaction transition states, which are found to be planar in all cases (7, 9). In solution, however, where solvation of the dipole centers at the phosphorus and oxygen atoms is expected, or in which the presence of metal ions may lead to complexation at the oxygen (or at least to a strong electrostatic interaction), a nonplanar 2-center TS is conceivable. We have chosen the Wittig reaction of two semistabilized ylides, benzylidenetriphenylphosphorane (1) and benzylidenediphenylmethylphosphorane (2) with benzaldehyde and pivalaldehyde, as representative cases where a wide range of stereoselectivities, depending on the reaction conditions, might be observed (7b). We and others have previously shown that stereochemical drift (10) does not occur in the conversion of eo i^-(2-hydroxy-l,2-diphenylethyl)methyldiphenylphosphonium iodide to Z-stilbene (>99.9%, 88-97% yield) in THF at -78 C by the action of nBuLi, NaHMDS or KHMDS (7b, 77). Since stereochemical drift is always faster for the erythro isomer than for die threo isomer (70), we can safely assume that the corresponding Wittigreactionsof 2 with benzaldehyde under the same conditions are kinetically controlled and not subject to stereochemical drift by way of retro-Wittig half-reactions, through reversal of oxaphosphetane formation to form the aldehyde and ylide. Similar observations have been made by other workers for the deprotonation of erythro- and threo-(2-hydroxy-l,2-diphenylethyl)triphenylphosphonium salts in aprotic solvents at low temperatures. Thus, the use of benzaldehyde inreactionswith 1 and 2, respectively, does not lead to atypical results. As further evidence of this, reactions of 1 and 2, respectively, with pivalaldehyde gave results that are similar to those observed inreactionswith benzaldehyde (72). ;
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Results and Discussion The results of thereactionsof the ylides with benzaldehyde in THF solution under a variety of conditions are given in Table I. It can be seen that at temperatures ranging from -78 C to -15 C in the presence of soluble lithium or sodium salts, high yields of stilbenes are obtained in a ratio of about 67% of Z-stilbene to 33% of E-stilbene. In the absence of salts (or when insoluble salts have been formed in the generation of the ylides), the Z/E ratio becomes less than one. Whereas the effects of Li salts on Wittig reaction stereoselectivity are well known, effects of sodium salts have received less attention. As in the case of the Li salts, the presence of Na salts tends to increase the Z/E ratio in alkene formation. However, this effect is observed only in those cases where the sodium salts are soluble and available for complexation with thereactants(Nal and NaB(C6H5)4). In cases where the metal ion is sequestered by an additive such as 15-crown-5 or DMSO or when the metal salt is not soluble in thereactionmedia (NaCl, NaBr), lower Z/E ratios in alkene formation are observed. These marked metal ion effects (7), in conjunction with well known solvent and substituent effects, suggest that an ionic mechanism is operative in the metal ion catalyzed Wittig reaction (7b). An ionic mechanism for the Wittig half-reaction of benzylidenetriphenylphosphorane with aldehydes can be envisioned as shown in Figure 1. e
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In Phosphorus Chemistry; Walsh, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
12. McEWEN ET AL.
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Mechanisms of the Wittig Reaction
Table I. Metal Ion Effects on the Z/E Ratios of the Wittig Reactions of Benzylidenetriphenylphosphorane (1) and Benzylidenemethyldiphenylphosphorane (2) with Benzaldehyde in THF Z/E Ratios: Ylidel Ylide 1 Salt Present 18/82C 36764b None 66/34C 57/43 Lia LiBr 63/37* 63/37 Lil 69/31 64/36 NaCl 51/49»> [54/46] NaBr 77/23 [76/24]c 69/3 I Nal ... 48/52* Nal + 15-crown-5 83/17»> NaB(C6H ) 3
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Salt-free conditions. See reference 7b. Reaction carried out at -15 C. Reaction carried out at -78 C.
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A nucleophilic attack of the ylide on the solvated metal-aldehyde complex could generate four possible stereoisomeric oxaphosphetanes, i.e., two pairs of enantiomers. This process is likely to occur via a 2-center reaction, where the transition state structure involves the formation of a partial C-C bond and with no P-O bond formation. Since no restriction is placed on the direction of approach of the reactants, all four stereoisomeric transition states can be formed. Ring closure would yield the respective oxaphosphetanes as two racemates. There is the possibility that the 2-center transition state described earlier would lead to the formation of metallated betaines, which are not unreasonable intermediates for Wittig reactions carried out in the presence of metal ions or polar solvents capable of stabilizing such highly polar intermediates. Recent results of reactions carried out under L i salt free conditions suggest that, in the reactions of Pisopropylidenephenyldibenzophosphorane with hydrocinnamaldehyde, intermediate betaines are not involved in the process (3f). However, this evidence does not pertain to metal-ion catalyzed Wittig reactions, and no stereocontrol issues can be addressed directly with the use of this particular system. Furthermore, ylides bearing the dibenzophosphole moiety exhibit different behavior from standard triaryl or trialkyl phosphoranes regarding Ρ rehybridization and pseudorotation, which are key issues to be considered in the mechanism of the Wittig reaction. Thus, caution must be exercised in extrapolating the results of Wittig reactions of ylides that contain the dibenzophosphole moiety to all Wittig reactions. In order to examine the stereochemical results of the reaction of benzylidenetriphenylphosphorane with benzaldehyde in the presence of L i , we have adopted a systematic approach to evaluate the relative stabilities of the different possible configurations and conformations that groups on the transition states might assume, depending on the direction of the approach of the reactants and the intramolecular interactions within the system. We have performed Molecular Mechanics calculations (MMX89) (13) for the two chastereomeric racemates that could be generated in the reaction of benzylidenetriphenylphosphorane with benzaldehyde by different approaches of the two reacting prochiral centers involved in the carboncarbon bond formation. Since the use of molecular mechanics computations does not permit the direct evaluation of transition states, we have assumed the Hammond +
In Phosphorus Chemistry; Walsh, E., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
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postulate (14) to estimate their relative energies from comparisons of the computed relative energies of the related metallated betaines. Molecular mechanics force fields provide excellent geometrical agreement between calculated and experimentally determined chemical structures for phosphorus containing compounds (75), including those involved in the Wittig reaction (76). The use of molecular mechanics computations as steric probes in molecular modeling has been well established (77). However, die possibility of multiple conformations in the system to be modeled has to be standardized in order to obtain results that are comparable. With the use of a Montecarlo-Metropolis approach to simulated annealing (18), we performed a multitorsional global optimization of dihedral angles involved in the system. Similar calculations were performed on the corresponding oxaphosphetanes, for which the configuration of each carbon that becomes part of the oxaphosphetane ring is preserved from the betaine stage to the formation of the respective oxaphosphetanes. The minimizations were carried out until self consistency in the total MMX89 energy was achieved among the different starting initial structures. As results of these calculations, the geometry of the structure of each global minimum among all possible conformations was found. However, several local minima gave total MMX89 energies very close to their correspondent global minima. The structures of the global minima of the Z-oxaphosphetane generating metallated betaines and their Ε-counterparts could be considered as representative of the most likely orientations of the substituents on the phosphorus atom, ylidic carbon and carbonyl group of the system. However, the direction of approach of the ylide to the aldehyde, and the effects on the interactions of these substituents, is better evaluated by a conformational analysis around the forming carbon-carbon bond Such an analysis was accomplished with the use of the dihedral angle driver option (17a) implemented in the MMX89 program and applied to the PC-C-O angle. Figure 2 shows the changes of the total MMX89 energy during the rotation about each of the forming C-C bonds of the Ζ and Ε-olefin generating betaines. The conformational profile shown in Figure 2 presents three clearly defined minima for the E-oxaphosphetane generating metallated betaine, whereas the Zcounterpart shows only two well defined minima in the whole conformational profile. Table Π depicts the compilation of the total MMX89 energies of the minima found in the conformational profiles of the Ζ and E-oxaphosphetane generating structures and the Ζ and Ε oxaphosphetanes themselves. Table II. Total MMX89 Energies of the Minima Found in the Conformational Profile Shown in Figure 3 Metallated betaines Oxaphosphetane generated syn gauche-synl ana gauche-synl Ζ 58.1(75) 56.5(165) 65.9(0) Ε 62.2(0) 57.3(55) 62.4(160) 58.2(305) a
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Energies arc given in kcal/mole. The 'syn* conformation of the metallated betaine (
