Reactivity of Carbonyl Compounds toward Addition

SECTION 8.4. REACTIVITY OF CARBONYL COMPOUNDS TOWARD ADDITION 

The reaction is second-order overall, with the rate given by A [R2C=0][NaBH4]. The interpretation of the rate data is complicated slightly by the fact that the alkoxyborohy-drides produced by the first addition can also function as reducing agents, but this has httle apparent effect on the relative reactivity of the carbonyl compounds. Table 8.3 presents some of the rate data obtained fi om these studies. 

The borohydride reduction rate data are paralleled by the rate data for many other carbonyl addition reactions. In fact, for a series of ketones, most of which are cyclic, a linear free-energy correlation of the form 

This equation implies that the relative reactivity is independent of the specific nucleophile and that relative reactivity is insensitive to changes in position of the transition state. Table 8.4 lists the B values for some representative ketones. The parameter B indicates relative reactivity on a log scale. Cyclohexanone is seen to be a particularly reactive ketone, being almost as reactive as cyclobutanone and more than 10 times as reactive as acetone. 

The same structural factors come into play in determining the position of equilibria in reversible additions to carbonyl compounds. The best studied of such equilibrium processes is probably addition of cyanide to give cyanohydrins. 

Considering the various equilibrium constants shows that the protonated imine is present in sufficient concentration to be the dominant reactive species. Although the protonated aldehyde would be even more reactive, its concentration is very low. On the other hand, even though the aldehyde may be present in greater concentration than the protonated imine, its reactivity is sufficiently less so that the iminium ion is the major reactant. 

The reaction is second order overall, with rate = fc[RCR][BH4 ], and complicated only slightly by the fact that borohydride ion is converted to alkoxyborohydrides during the course of the reaction. The rate-determining step is addition of hydride to the carbonyl carbon this allows relative reactivities to be directly determined. Table 8.2 presents some of the rate data obtained from these studies. 

Among the cyclic ketones, the reactivity of cyclobutanone is enhanced because of the decrease in angle strain in going from the ground state to the transition state. 

At this point we consider some general relationships concerning the reactivity of carbonyl compounds toward addition of nucleophiles. Several factors influence the overall rate of a reaction under various conditions. Among the cmcial factors are (1) structural features of the carbonyl compound (2) the role of protons or other Lewis acids in activating the carbonyl group toward nucleophilic attack (3) the reactivity of the nucleophilic species and its influence on subsequent steps and (4) the stability of the tetrahedral intermediate and the extent to which it proceeds to product rather than reverting to starting material. 

We focus first on the inherent reactivity of the carbonyl compound itself. An irreversible processes in which the addition product is stable is the most direct means of comparing the reactivity of carbonyl compounds. In these circumstances, the relative rate of reaction of different carbonyl compounds can be directly compared. One such reaction is hydride reduction. In particular, reductions by sodium borohydride in protic 

Among the cyclic ketones shown in Table 7.1, the reactivity of cyclobutanone is enhanced because of the strain of the four-membered ring, which is decreased on going from sp to sp hybridization. The higher reactivity of cyclohexanone compared to cyclopentanone is quite general for carbonyl addition reactions. The major factor responsible for the difference in this case is the change in torsional strain as addition occurs. As the hybridization goes from sp to the torsional strain is increased in cyclopentanone. The opposite is true for cyclohexanone. The 

Addition, Condensation and Substitution Reactions of Carbonyl Compounds 

The addition-elimination reactions just described, because of their mechanistic complexities, do not permit an easy assessment of the relative reactivity of various carbonyl compounds. Such information can be obtained more directly by studying the rates of reactions of nucleophiles that form stable addition products with carbonyl compounds. The hydride reducing agents, in particular sodium borohy-dride, provide a convenient system for such studies  

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

Finiels and P. Geneste, J. Org. Chem. 44, 1577 (1979) reactivity relative to cyclohexanone as a standard. 

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