Formaldehyde, lithium enolates

Fig. 2.6. Free-energy profile (B3LYP/6-31 + G with ZPE correction) for intermediates and transition structures for Wadsworth-Emmons reactions between the lithium enolate of trimethyl phosphonoacetate anion and formaldehyde in the gas phase and in tetrahydrofuran or ethanol. Adapted from J. Org. Chem., 63, 1280 (1998), by permission of the American Chemical Society.

The excellent agreement with the experimental and calculated isotope effect (calculated for formaldehyde, 3.22, and for acetaldehyde, 3.3 experimental value 2.9) supports the computational approach. This suggests that the computed transition structure for hydride transfer in the reaction of the lithium enolate of acetone with acetaldehyde (Figure 30) is realistic. 

The aldol reaction is an addition of metal enolates to aldehydes or ketones to form P-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.1). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2... 

SCHEME 107. Relative energies and geometries for the O- and C-addition transition state calculated for the addition of formaldehyde to the lithium enolate of acetaldehyde and the preferred conformations of aldol535... 

Formaldehyde is not available as a pure monomer because itfomis trimers and tetramers in the pure state (Chapter 52). The aqueous solution formalin used to preserve biological specimens is available—it is 37% formaldehyde and mostly consists of the hydrate CH2(OH)2 see Chapter 6. A pure dry polymer paraformaldehyde is also available and was mentioned in Chapter 9. Neither of these is particularly useful in aldol reactions. The aqueous solution is used in the Mannich reaction that we describe shortly. It is possible to make the short-lived monomer and capture it with a lithium enolate, but this is not trivial experimentally. 

They even react cleanly with formaldehyde, thus solving the problem that the Mannich reaction is not applicable to esters. The synthesis of the exo-methylene lactone 80 can be accomplished this way. Enone disconnection13 reveals formaldehyde as the electrophilic component in a crossed aldol reaction, realised with a lithium enolate 82.14 The mono-adduct 83 of formaldehyde and the lactone 81 can be isolated and the cautious dehydration step is to avoid migration of the double bond into the ring. 

The reactions of enolates bearing chiral auxiliaries with formaldehyde or symmetrical ketones can be stereoselective. After removal of the auxiliary, nonra-cemic primary or tertiary alcohols are obtained. The reaction of lithium enolates of Schollkopfs lactim ethers 1.114 with symmetrical carbonyl compounds are highly stereoselective, as are the reactions of enolates of Seebach s imidazolidinone S.39 (R = Ph). In both cases, the enolate reacts from its least hindered face [154, 261] (Figure 6.11). After acidic hydrolysis, P-hydroxy-a-aminoacids are obtained with a high enantiomeric excess. However, when R = H, some unwanted epimerization can take place. 

Houk et al. have made calculations for the reactions of lithium enolate and enol borinate of acetaldehyde with formaldehyde at the 3-21G level [125j. In the first case. 

The reaction of the lithium enolate (219) with formaldehyde-ZnCla provided the 17a-hydroxymethyl-20-oxopregnane (220) directly. Reaction of the... 

DFT and Car-Parrinello molecular dynamics simulations have been used to study aggregation effects in model aldols, using the lithium enolates of acetaldehyde and acetone, with formaldehyde and acetone as electrophiles. The core of the aggregates is Li 0 ... 

Calculated reaction pathway for addition of acetaldehyde lithium enolate to formaldehyde. 

Even if a particular enolate vith a distinct geometry is reacted vith an aldehyde, the question vhether the transition state is closed or open cannot be ans vered by simple either-or . More recent discussions have, instead, led to an as vell as , because the role of the counter-ion becomes more evident. Thus, ab-initio calculations of Houk and co vorkers [92] predict an open-transition-state structure for metal-free, naked enoiates and closed transition states for lithium enoiates. For addition of acetaldehyde lithium enolate to formaldehyde, the lo vest-energy reaction path vay (sho vn in Scheme 1.13) has been studied on the basis of on ab-initio (3-21 G) calculations [93]. 

TABLE 6. Computed reaction and activation energies and corresponding isotope effects for the sequence of reactions between lithium vinyloxide (LiEn) and formaldehyde and between the hthium enolate of acetone (AcCH2Li) and acetaldehyde. Reproduced with permission from Reference 29. Copyright 1998 American Chemical Society... 

TABLE 13. Computed reaction and activation energies (kcalmoD ) and corresponding kinetic (KIE) and equilibrium (ElE) isotope effects a reaction sequence between lithium acetaldehyde enolate (Lien) and formaldehyde... 

Icetene VII from doing so Besides the molecular diffusion that would reduce the local concentration of methoxy, no other nucleophile, least of all the bulky lithium base, would be available to compete for this ketene. Furthermore, the incorporation of methoxy would result in a new ester enolate XI whose addition to formaldehyde would yield II (see Scheme 36.3). 

The beauty of this reaction lies in the fact that nearly all the facts needed to elucidate the mechanism are, in one way or another, in the products. Although the formation of 11 might seem somewhat tantalizing at first, a second glance will reveal that simply isomerization of I will suffice to account for it. A rather unusual isomerization, however, because activation of the a carbon of the ester as a nucleophile and introduction of formaldehyde (from where ) at this carbon need justification. The first argument may be reformulated as the formation of an ester enolate, which is made possible by the advent of lithium amide superbases such as lithium diisopropyl amide (LDA) in aptotic tetrahydrofuran (THF)-hexamethyl-phosphoramide (HMPA) solvent mixtures.2 The participation of an ester enolate is emphasized by the formation of condensed diester IV. 

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