Deuterium aldol condensation

The 2-methyl group of 2-methyl-3T/-azepines, e.g. 11, is surprisingly reactive and undergoes rapid deuterium exchange and, in the presence of base, aldol condensation with areneal-dehydes to yield styryl derivatives, e.g. 12.76108... 

The solid base catalysed aldol condensation of acetone was performed over a CsOH/Si02 catalyst using a H2 carrier gas. The products observed were diacetone alcohol, mesityl oxide, phorone, iso-phorone and the hydrogenated product, methyl isobutyl ketone. Deuterium tracer experiments were performed to gain an insight into the reaction mechanism. A mechanism is proposed. 

One mechanism proposed earlier was the formation of metal-bound enolate intermediate via deprotonation at C3 position. However, a recent study failed to detect a significant deuterium primary kinetic isotope effect which excludes this pathway and suggested an aldolase cleavage mechanism where deprotonation of the substrate (115) is followed by bond cleavage (116), analogous to the reversed reaction in aldose mechanism (114 113) discussed above. Cleavage is followed by reposition of the fragments (117) and aldol condensation (118) to complete the epimerization. 

Problem 21.13 (a) When acetaldehyde at fairly high concentration was allowed to undergo base-catalyzed aldol condensation in heavy water (D2O), the product was found to contain almost no deuterium bound to carbon. This finding has been taken as one piece of evidence that the slow step in this aldol condensation is formation of the carbanion. How would you justify this conclusion (b) The kinetics also supports this conclusion. What kinetics would you expect if this were the case (Remember Two molecules of acetaldehyde are involved in aldol condensation.) (c) When the experiment in part (a) was carried out at low acetaldehyde concentration, the product was found to contain considerable deuterium bound to carbon. How do you account for this (Hint See Sec. 14.20.) (d) In contrast to acetaldehyde, acetone was found to undergo base-catalyzed hydrogen-deuterium exchange much faster than aldol condensation. What is one important factor contributing to this difference in behavior ... 

The various steps in the overall sequence will here be considered individually, but only briefly, and no attempt will be made to indicate the scope of the WEH procedure which, as has already been indicated, has been widely reviewed. The aldol condensation which leads to the ions 154 is considered to be essentially reversible, a feature which has been observed in the reactions between diethyl (prop-2-enyl)phosphonate anion and aromatic aldehy-des Reversibility has also been demonstrated in a variety of other reactions that include crossover experiments, based on the system from benzaldehyde and 153 (Z = CN or COOMe) into which a more electrophilic aldehyde is added this results in the incorporation of the latter into products in such a way that the dissociation of the phospho-nate-benzaldehyde adduct must have occurred The addition of an aldehyde to a deuterium-labelled adduct in the presence of NaOEt-EtOH affords a mixture of labelled and unlabelled alkenes in the ratio of ca 1 1. The product (158) from the interaction of HO (Na2C03 in Et0H-H20) and a dialkyl (a-cyanoethenyl)phosphonate decomposes into the expected alkene, but also dissociates into a carbonyl compound together with a carbanion the latter can then be trapped by the addition of a different aldehyde or ketone (Scheme 30) ... 

The correspondence between isotope exchange and kinetic behaviour extends to the analogous aldol condensation of acetone. This is well established as a second-order reaction catalysed specifically by hydroxide ions, corresponding to /c2[SH] /c i at all values of [SH] studied. This should lead to facile isotope interchange, and in fact it was foundthat a molar solution of acetone in alkaline D2O takes up deuterium about 1000 times as quickly as it undergoes condensation. 

We find that the rate of our aldol condensation is comparable to the rate seen above for simple enolization (and deuterium exchange) of ketone 12. Thus it seems likely that the deuterium exchange was a good measure of the rate of enolization, despite the caveats expressed above. 

The ready removal of the hydrogen atom next to the carbonyl group is consistent with the expected activities of such atoms in alkaline solutions, as in the aldol condensations. Experimental evidence is provided by the observation that one carbon-bound deuterium atom is formed when tetra-0-methylglucose (45) or glucose (83) is dissolved in alkaline heavy water. 

Reaction mechanisms of acetone aldol condensation over MgO and La20s were studied using deuterium as a tracer. Analysis of the isotopic distributions of the product and reactant revealed that the slow step is involved in Step II in accordance with homogeneous systems. 

The experimental atomic ratio of deuterium to hydrogen of 0.106 corresponds closely to the ratio calculated for the aldol mechanism (0.091) on the supposition that deuterium and hydrogen atoms in the alpha position participate equally in the condensation. 

Further support comes from a study of deuterium exchange. If the condensation takes place in deuterium oxide, it is clear that every reversal of reaction (96a) will lead to the introduction of deuterium into acetaldehyde, and hence ultimately into the aldol. At high aldehyde concentrations kj SO that (96a) will rarely be reversed, but with... 

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