Nucleophilic Attack on a Carbonyl Group

Attempts to produce chiral cyanhydrins under phase-transfer catalytic conditions (3.3.9) using ephedrinium or cinchoninium catalysts has been singularly unsuccessful [21,22]. Optical purities varying from 0 to 60% have been recorded [22], but verification of the reproducibility of the higher values is needed. Similarly, nucleophilic attack on a carbonyl group by the trichloromethyl anion under phase-transfer catalytic conditions (see Section 7.4) in the presence of benzylquininium chloride produces a chiral product, but only with an enantiomeric excess of 5.7% [23]. The veracity of this observation has also been questioned [24],... 

A simple nucleophilic attack on a carbonyl group is shown in Figure 9-15. This process is reviewed in Chapter 2 and is further illustrated in the discussion of reactions in Chapter 10. 

Figure 3.23. Trajectory of nucleophilic attack on a carbonyl group deduced from orbital interaction...

FIGURE 6.9 The ground and vertical charge-transfer states in the VBSCD that describes a nucleophilic attack on a carbonyl group. 

The third case is in many ways the most interesting. We have seen that the alkaline hydrolysis of ethyl esters of benzoic acids (ArCC Et) has a p value of +2.6 and that this is a reasonable value for a reaction involving nucleophilic attack on a carbonyl group conjugated with the aromatic ring. The hydrolysis of the same esters in acid solution, which also involves nucleophilic attack on the same carbonyl group, has a p value of+0.1. In other words, all these esters hydrolyse at the same rate in acid solution. Neither of the previous explanations will do. We need to see the full mechanism to explain this remarkable result. 

The earliest reaction to be studied showing open-chain diastereoselectivity was nucleophilic attack on a carbonyl group, either a carbonyl group with a stereogenic centre adjacent to it or a carbonyl group like that in 4-fert-butylcyclohex-anone, where the diastereotopic surfaces are distinguished by being axial or equatorial. 

The Hammett p value shows a modest gain of electrons in the transition state. We must not ti-. the pre-equilibrium into account in this as ArCHO is not involved in that step. In fact a Hamn c p value of -f 2.5 is typical of nucleophilic attack on a carbonyl group conjugated with the arorr.i ring (see p. 1095 for an example). 

The analysis in the chapter (p. 1200 reproduced below) shows that we need the thioamide of renzoic acid (thiobenzamide available from Aldrich) and an a-bromoketone. We need these rarticular starting materials because the soft sulfur atom will displace the bromide in a frontier-orbital-controlled Sn2 reaction whilst the hard amino group will attack the ketone in a charge-controlled nucleophilic attack on a carbonyl group. 

In this chapter, as in Chapter 12, you have met a wide variety of reactions, but we hope you have again been able to see that they are all related mechanistically. Of course, we have not been exhaustive it would be impossible to cover every possible reaction of a carbonyl group, but having read Chapters 6, 9, 12, and 13 you should feel confident in writing a reasonable mechanism for any reaction involving nucleophilic attack on a carbonyl group. You could try thinking about this, for example. 

In chapter 21 we emphasise that the most reliable method of controlling one chiral centre by another in open chain compounds is by Felkin-Anh orbital control of nucleophilic attack on a carbonyl group next to a chiral centre. We shall start this discussion with that method and follow with the next most reliable - Houk control of electrophilic attack on alkenes also next to a chiral centre. These are of course both 1,2-control and we shall deal with that before discussing 1,3-, 1,4- and remote control. 

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