RCOX

The reagent for the synthon RCO will be RCOX where X is a leaving group, such as OEt. So how would you make TM 94 ... 

Reaction of the aromatic (eg, C H ), acyl haUde (RCOX), and aluminum haUde (AIX ) Hberates hydrogen haUde and produces a complex of aromatic ketone and aluminum haUde from which the ketone is Hberated by hydrolysis ... 

Correlations with o in carboxylic acid derivative reactions have been most successful for variations in the acyl portion, R in RCOX. Variation in the alkyl portion of esters, R in RCOOR, has not led to many good correlations, although use of relative rates of alkaline and acidic reactions, as in the defining relation, can generate linear correlations. The failure to achieve satisfactory correlations with cr for such substrates may be a consequence of the different steric effects of substituents in the acyl and alkyl locations. It has been shown that solvolysis rates of some acetates are related to the pA", of the leaving group, that is, of the parent alcohol. The pK of alcohols has been correlated with but this relationship... 

Acid halide (Section 21.1) A functional group with an acyl group bonded to a halogen atom, RCOX. 

The attack of a nucleophile on a carbonyl group can result in substitution or addition (Chapter 16), though the first step of each mechanism is the same. The main factor that determines the product is the identity of the group X in RCOX. When X is alkyl or hydrogen, addition usually takes place. When X is halogen, OH, OCOR, NH2, and so on, the usual reaction is substitution. 

In contrast to such systems, substrates of the type RCOX are usually much more reactive than the corresponding RCH2X. Of course, the mechanism here is almost always the tetrahedral one. Three reasons can be given for the enhanced reactivity of RCOX (1) The carbonyl carbon has a sizable partial positive charge that makes it very attractive to nucleophiles. (2) In an Sn2 reaction a cr bond must break in the rate-determining step, which requires more energy than the shift of a pair of n electrons, which is what happens in a tetrahedral mechanism. (3) A trigonal carbon offers less steric hindrance to a nucleophile than a tetrahedral carbon. 

Nucleophilic substitution at RSO2X is similar to attack at RCOX. Many of the reactions are essentially the same, though sulfonyl halides are less reactive than halides of carboxylic acids. The mechanisms are not identical, because a tetrahedral intermediate in this case (148) would have five groups on the central atom. Though this is possible (since sulfur can accommodate up to 12 electrons in its valence shell) it seems more likely that these mechanisms more closely resemble the Sn2 mechanism, with a trigonal bipyramidal transition state (148). There are two major experimental results leading to this conclusion. 

A quite different and complimentary approach is to assume that addition of a nucleophile to an acyl derivative (RCOX) would follow the linear free energy relationship for addition of the nucleophile to the corresponding ketone (RCOR, or aldehyde if R=H) if conjugation between X and the carbonyl could be turned off, while leaving its polar effects unchanged. This can be done if one knows or can estimate the barrier to rotation about the CO-X bond, because the transition state for this rotation is expected to be in a conformation with X rotated by 90° relative to RCO. In this conformation X is no longer conjugated, so one can treat it as a pure polar substituent. Various values determined by this approach are included in the tables in this chapter. 

The rate law followed by these reactions is generally of the form, Rate = fc[RCOX][Ye]... 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

Tab. 7.6. G raphite-supported acylation of anisole (51) by use of a variety of acylating reagents (RCOX) under the action of MW irradiation3 [27, 66].

---