Oxaphosphetanes reaction mechanism

The detection of oxaphosphetanes as relatively stable Wittig intermediates led to revision of the reaction mechanism theory. An asynchronous cycloaddition between ylide and carbonyl component was proposed for the oxaphosphetane formation a transition state resembling the starting material in the case of reactive ylides and a transition state resembling oxaphosphetane in the case of moderate and stable ylides can explain the different (E/Z)-selectivities of the different ylide types [44]. 

Experimental evidence suggests that the intermediate betaine is only fomned in limited cases. In other cases, it appears that the Wittig reagent may react with the carbonyl compound in a [2+2] cycloaddition process, directly generating the oxaphosphetane. The mechanism for this reaction is still under investigation. 

Investigations of the Wittig reaction using a non-stabilized ylide (ethyli-dene triphenylphosphorane) (37) and various hindered aldehydes (38) under the same reaction conditions were performed in order to understand the factors which influence the stereochemistry of this process. It was experimentally shown, that the prevailing outcome toward the Z olefin is influenced only by changes in steric factors or different overcrowding in the pentacoordinated oxaphosphetane intermediates. The general reaction mechanism with nonstabilized ylides is presented in Scheme 11. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Monocyclic Phosphoranes. - Further studies on the mechanism and stereochemistry of the Wittig reaction have been conducted by a combination of 1H, 13C and 3 P n.m.r.2k 25. The results show that at -18°C both ois and trans diastereomeric oxaphosphetans (e.g. 17 and 18) may be observed and their decomposition to alkenes monitored by n.m.r. Evidence was presented to suggest that during this process oxaphosphetan equilibration involving the siphoning of (17) into (18) occurred in competition with alkene formation. 

This accounts for the considerable discrepancy between the alkene Z/E ratio found on work-up and the initial oxaphosphetan ais/trans ratio. By approaching the problem from the starting point of the diastereomeric phosphonium salts (19) and (20), deprotonation studies and crossover experiments showed that the retro-Wittig reaction was only detectable with the erythreo isomer (19) via the cis-oxaphosphetan (17). Furthermore, it was shown that under lithium-salt-free conditions, mixtures of (19) and (20) exhibited stereochemical drift because of a synergistic effect (of undefined mechanism) between the oxaphosphetans (17) and (18) during their decomposition to alkenes. 

In view of the reaction behavior of l,2 i.5-oxaphosphetanes (22), treated above, it appears fitting to reconsider the mechanism of the hydroxylion induced fragmentation of p-bromophosphinic acid 6443). It was assumed that formation of the phosphinate 65 is followed by that of the four-membered heterocycle 66, which spontaneously decomposes to benzalacetophenone and phenyldioxophosphorane the latter then adds water to give the phosphonie acid 43 ... 

High-level quantum mechanical calculations have been used to explore the Horner-Wandsworth-Emmons reaction in the gas phase and also with a solvation contribution evaluated using the PCM/DIR method. Ring closure of the P—O bond (TS2), to form oxaphosphetane, is rate determining in the absence of solvation however, the oxyanion becomes a true intermediate, at an energy minimum on the reaction path, only in response to the effects of solvation, whereupon its formation by carbonyl addition (TSl) becomes rate limiting. Formation of F-product is always... 

The third step is a Horne r-Wodsworth-Dnnu>ns reaction in which a C-C double bond is created by condensation of ketone 44 with the lithium salt of the p-thia/olephosphoric acid dialkyl ester 12. The desired compound 13 is obtained selectively with Irons geometry The precise mechanism of the Ho me r-Wuds orth Emmons reaction is not yet known, so the source of the irons selectivity remains uncertain. It is assumed that analogous to the Wit tig reaction. an oxaphosphetane forms as an intermediate (see also Chapter 91... 

Reaction intermediates can be detected by reaction monitoring (i.e. analyses at several reaction times), and their presence may be inferred or even observed more readily at low temperatures. In a Wittig reaction, the ylid 32 in Scheme 2.13 was produced from ethyl-triphenylphosphonium bromide and butyl lithium, and reacted with a small excess of cyclohexanone in THF at —70°C the initial product, the oxaphosphetane 33, was identified by 31P NMR and converted to the alkene product and triphenylphosphine oxide (34) above — 15°C (see also Chapter 9). These results provide relatively direct experimental evidence for the mechanism shown in Scheme 2.13 [23]. 

With phosphorus ylides as used for the Wittig Reaction, the phosphorus atom forms a strong double bond with oxygen. This leads the mechanism in a different direction, to effect olefination instead of epoxidation through intermediate oxaphosphetanes. 

Moreover the reaction runs the normal Wittig mechanism over the four-membered oxaphosphetane ring and collapses to the alkene mixture. (For mechanistic details see Chapter 10.)... 

Quantum mechanical calculations in the gas phase and DMSO solution at different temperatures can highlight the hazards of standard 0 K gas-phase calculations.259 For the Wittig reaction, a small barrier in the potential energy curve is transformed into a significant entropic barrier in the free energy profile, and the formally neutral oxaphosphetane intermediate is displaced in favour of the zwitterionic betaine in the presence of DMSO. 

We have a fairly detailed knowledge of the mechanism of the Wittig reaction (Figure 11.3). It starts with a one-step [2+2]-cycloaddition of the ylide to the aldehyde. This leads to a heterocycle called an oxaphosphetane. The oxaphosphetane decomposes in the second step—which is a one-step [2+2]-cycloreversion—to give triphenylphosphine oxide and an alkene. This decomposition takes place stereoselectively (cf. Figure 4.44) a cw-disubstituted oxaphosphetane reacts exclusively to give a cis-alkene, whereas a fraws-disubstituted oxaphosphetane gives only a trans-alkene. The reaction is stereospecific. 

Fig. 11.3. Mechanism of the Wittig reaction. kcjs is the rate constant for the formation of the cis-oxaphosphetane, kmns is the rate constant for the formation of the trans-oxaphosphetane, and kdrjft is the rate constant for the isomerization of cis- to turns-configured oxaphosphetane, which is called "stereochemical drift."...

Protic solvents or the addition of proton-active compounds after oxaphosphetane formation shift the stereoselectivity of the reaction in the direction of the ( )-form. If the Wittig reaction is carried out in C2HsOD or if the oxaphosphetane solution, prepared at —75 °C in an aprotic solvent, is treated with deuterated ethanol, then deuterium is incorporated in high yield into the ( )-olefm formed, and the degree of deuterium labelling of the coexisting (Z)-olefin is lower. On the basis of these findings the mechanism discussed below has been established (Scheme 5). 

The oxidation of530 with the ozone adduct 531 is carried out at —78 °C, giving the oxaphosphetane 532. Then, tritiated ethanol is added and the reaction mixture heated to room temperature. The rate of tritium incorporation thus obtained is very high 262) (for an explanation of the mechanism see Chapter 2). 

Stereogenic Wittig reactions of nonstabilized ylides of the structure Ph3P+—CH —R2 have been studied in-depth in many instances. They give the cis-configured oxaphosphetane rapidly, with the rate constant kcis, and reversibly (Figure 9.7). On the other hand, the same nonstabilized ylide produces the /ran.v-oxaphosphetane slowly, with the rate constant ktrans, and irreversibly. The primary product of the [2+2]-cycloaddition of a nonstabilized P ylide to a substituted aldehyde is therefore a cis-oxaphosphetane. Why this is so has not been ascertained despite the numerous suggestions about details of the mechanism which have been made. 

Mechanism In early papers, Wittig described that the reaction proceeds with the formation of betaine, which collapsed to four-membered cyclic oxaphosphetane. Either of these two intermediates decomposes to form an alkene. The decomposition of oxaphosphetane... 

Currently accepted mechanism of the Wittig reaction of aldehydes with non-stabilized ylides involves the formation of oxaphosphetanes through a [2-I-2]-cycloaddition-like reaction . The oxaphosphetanes are thermally unstable and collapse to alkene and phosphine oxide below room temperature. Under salt-free conditions there is no formation of betaine intermediates. The salt-free ylides can be prepared by the reaction of phosphines with carbenes generated in situ. Vedejs etal proposed a puckered 4-centre cyclic transition state I for sy -oxaphosphetane and planar structure J for anff-oxaphosphetane. In general, the flnfi-oxaphosphetane J is more stable than the syn-oxaphosphetane I, and under equilibrium conditions (when stabilized ylides are used) the E-alkene product is favoured (Scheme 4.24). However, kinetic control conditions, which appear to dominate when non-stabilized ylides are used, would lead to Z-alkene. 

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