Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1103 113

18. Nucleophilic attack on compounds containing CDC, CDO or CDN groups 1115

potentials determined by PES varied with the approach distance, confirming that such an approach can be used to probe the nucleophilic addition of an amine to an alkene.

A comprehensive analysis of nucleophilic attack on carbon double bonds has appeared42. Using GAUSSIAN 80 and 82 the transition states for attack of nucleophiles on alkenes and carbonyls has been determined, as shown in Figure 5. Charged nucleophiles attack alkenes and alkynes with angles between 115° and 130°, as shown by hydride attacking 16 (ethyne) and 17 (propene). The deformation from this angle can occur about

126° 123°

(16)

(17)

−

−

(18)

Li

Li

120°

94°

FIGURE 5. The transition states for attack of nucleophiles on alkenes and carbonyls, determined using GAUSSIAN 80 and 82. Reproduced with permission from Reference 42. Copyright (1986) American Association for the Advancement of Science

one-half as easily as the bending of a normal C C C or H C C angle43. As thebond becomes more unsymmetrical the angle of attack decreases, as shown by 18, the attack of methoxide ion on methanal. The double-bond component is always bent towards the geometry of the product in the transition state. For alkenes and alkynes, as the substituent(s) on the carbon attacked go beneath the plane of the reactant molecule, the substituent(s) at the other carbon rise above the plane44. The addition of organolithiums or metal hydrides involve four-centre transition states, that is, the metal coordinates with the nucleophile and the system. This leads to smaller angles of attack45,46.

Frontier Molecular Orbital Theory can be used to describe qualitatively the trajectory of a nucleophile when it attacks a centre. Two sets of first-order interactions are considered. Firstly the stabilizing interaction of the HOMO of the nucleophile with the LUMO ( Ł and Ł orbitals) of the system and secondly the destabilizing interaction of the HOMO of the nucleophile with the HOMO ( and molecular orbitals) of the system, as shown in Figure 6.

The angle of attack is derived by maximizing the stabilizing interactions and minimizing the destabilizing interactions. Using such an approach Houk and coworkers found that when is greater than 90° the destabilization is reduced since the overlap between the two HOMOs is reduced42. At the same time, the stabilizing interaction between the nucleophiles HOMO and the double bonds LUMO is increased since the overlap integrals between the nucleophile HOMO and the p orbitals at C1 and C2 that make up the LUMO are of opposite sign.

stabilizing

+

−−

Nucleophilic

interaction

FIGURE 6. Stabilizing interaction between the HOMO of the nucleophile and the LUMO of the system and the destabilizing interaction between the HOMO of the nucleophile and the HOMO of thesystem. Reprinted with permission from Reference 42. Copyright (1986) American Association for the Advancement of Science

18. Nucleophilic attack on compounds containing CDC, CDO or CDN groups 1117

Nucleophilic attack on a symmetrical alkene (Scheme 6) occurs with a larger angle than attack at a carbonyl, since an electron-withdrawing substituent on carbon or an electronegative element makes the coefficient of C1 in the Ł molecular orbital the larger of the two. Since pyramidalization also occurs, the attack angle should approach 109.5° for an unsymmetrical double bond42. Liotta and collaborators found that, for carbonyls, as the energy of the frontier molecular orbital of the nucleophile (HOMO) becomes less negative, the angle approaches 90°. Thus, since hard nucleophiles have low-lying HOMOs, they will approach at a larger angle than soft nucleophiles that have higher-lying HOMOs47.

Symmetrical

alkene

SCHEME 6

Baldwin and coworkers have developed a set of rules that describe the trajectory of nucleophiles when they attack systems48 51 (Scheme 7):

Nu

C O

Nu

X

SCHEME 7

(i)The angle is about 110° when the nucleophile is derived from a first-row element.

(ii)The angle is determined by the resultant of the vector addition of the trajectories for the main resonance forms, where the magnitude of the vector reflects the relative

contribution of the resonance forms.

Thus the angle becomes greater in the series of carbonyl compounds ketone, amide, ester and carboxylate anion.

When the nucleophile involved a second-row element, the angle was smaller, possibly as a result of 3d back-bonding. This means that, as Figure 7 shows, 3- to 7-exo-trig ring closures are favoured, as are 6- to 7-endo-trig, but 3- to 5-endo-trig ring closures are disfavoured. Although the rules are generally applicable, there have been many examples where these rules appear to break down52. However, as Johnson points out in a recent review of this area, ‘a great deal may still be learnt from the rules, as much in their breach as in their observance’53. For example, the disallowed 5-endo-trig reaction (Scheme 8) does not occur in base but does take place in acid. Whilst this seems to contradict Baldwin’s rules, it has been shown that reaction proceeds with a 5-exo-trig mechanism via, after protonation, 1954 or, more likely, 2055. This was confirmed by examining the substituent effects of aryl substituents. Electron-donating groups would be expected to slow down the corresponding conjugate additions of enones; however, a rate increase was observed, as a result of stabilization of the intermediate 19 or 20.

Carbon sulphur double bonds also undergo nucleophilic attack in a similar fashion to carbon oxygen double bonds except in the cases of thiophilic addition, where the nucleophile selectively attacks the sulphur56 (Scheme 9).

SCHEME 9

18. Nucleophilic attack on compounds containing CDC, CDO or CDN groups 1119

IV. STEREOSELECTIVITY IN NUCLEOPHILIC ATTACK OF DOUBLE BONDS

The direction of approach of the nucleophile on the carbonyl coupled with steric and electronic interactions between the nucleophilic molecule and the substrate lead to stereoselective reactions which have been well studied and for which a number of predictive rules and explanations have been developed.

A difference of only 1.8 kcal mol 1 between the free energies of activation of two stereoisomeric transition states leads to a product ratio of 96:4; for enantiomeric transition states this corresponds to an ee of 92%42. A difference of more than 2.8 kcal mol 1 will give a ratio of greater than 100:1 (ee>99%).

A. Diastereoselective Approach of the Nucleophile on the Double Bond

Calculations have shown that nucleophiles with groups attached, such as a methyl anion, take up a staggered arrangement with respect to the sp2 centre they are attacking42. Based on such an approach of the nucleophile, Bassindale, Taylor and collaborators have proposed an empirical model (Scheme 10) for the nucleophilic addition of prochiral carbanions to prochiral carbonyls in the absence of chelation control57.

The carbanion C-SML approaches the carbonyl S1L1CO, where S, M and L represent small, medium and large groups, respectively, such that the smallest group on the carbanion is disposed between S1 and L1. The most favoured arrangement of the other groups is with L and S1 and M and L1 gauche. Other independent studies are in agreement with this predictive model58,59. This model assumes no chelation; however, in the presence of chelation other factors influence the stereochemistry of the interaction of the nucleophile with the double bond. For example, analysis of the relative energies of the chair-like transition states involving carbonyls or imines can usually explain the observed diastereoselectivity60,61. The presence of chiral auxiliaries can also control the stereochemistry of addition of an achiral organolithium to an aldehyde or unsymmetrical ketone, leading predominantly to one enantiomer62. A recent example is the addition of organolithium reagents to imines, which can be made stereoselective (80 90% ee) by the addition of C2-symmetric ligands such as 21 and 2263.

B. Stereoselectivity as a Result of a Chiral Centre a to a Carbon Double Bond in the Substrate

A number of models have been developed to predict the stereochemical outcome of the addition of a nucleophile to a carbonyl with a chiral ˛ carbon. One of the first was Cram’s rule which was developed on an empirical basis64. The generalization is shown in Figure 8a, where L, M and S represent large-, mediumand small-sized groups, respectively, attached to the chiral ˛ carbon. The molecule is imagined to be oriented so

that the carbonyl group is flanked by the two smaller groups, M and S, with the large group L eclipsed with the alkyl on the other side of the carbonyl. The nucleophile then approaches from the face of the carbonyl with the smallest substituent S. If one of the groups on the chiral ˛ carbon and the carbonyl oxygen are capable of forming a chelate with a metal ion, then a cyclic model has been invoked in which the carbonyl oxygen and the ˛-heteroatom are held in a coplanar arrangement and attack occurs from the side of the smaller of the remaining ˛-substituents (Figure 8b). If one of the ˛-substituents is a dipolar group such as a halogen or an oxyanion, a third possibility has been proposed in which the dipoles of the carbonyl and the ˛ C X bond arrange themselves to point in opposite directions (Figure 8c)65. Again attack occurs from the side of the smaller of the remaining ˛-substituents.

Felkin’s group has developed an alternative approach based on a staggered transition state similar to Figure 8d66 68. Here the largest group, L, on the chiral ˛ carbon is placed antiperiplanar to the forming bond The medium-sized group then occupies the sterically

FIGURE 8. Models for predicting the stereochemical outcome of the addition of a nucleophile to a carbonyl with a chiral ˛ carbon