Substitutions on Saturated Carbon Atoms

Alkyl Halides, Alcohols, Thiols, Ethers, Amines 

In the previous chapters we have discussed two types of reactions, isomerizations and additions. Another major class of organic chanical reactions is a substitution. A substitution in an organic molecule can occur either at the saturated or at the unsaturated carbon atom which is called the reactive center. The reaction mechanism of a substitution includes replacement of the leaving group with the incoming group. 

The incoming group can not only be a nucleophile or an electrophile which were already discussed in this book, but also other molecular species such as radicals, which are molecules with unpaired electrons. The general layout of a substitution reaction is shown in the scheme below. 

---

Nucleophilic attack on saturated carbon atom (feading to substitution... 

Simple nucleophilic substitutions at saturated carbon atoms are fundamental reactions found wherever organic chemistry is practised. They are used in industry on an enormous scale to make heavy chemicals and in pharmaceutical laboratories to make important drugs. They are worth studying for their importance and relevance,... 

Nucleophilic attack on saturated carbon atoms, leading to substitution reactions... 

Several distinct mechanisms are possible for aliphatic nucleophilic substitution reactions, depending on the substrate, nucleophile, leaving group, and reaction conditions. In all of them, however, the attacking reagent carries the electron pair with it, so that the similarities are greater than the differences. Mechanisms that occur at a saturated carbon atom are considered first. By far the most common are the SnI and Sn2 mechanisms. 

The influence of the nitro group depends on the general nature of the substrate. The presence of a nitro group is sometimes unfavorable. However, the substitution at a saturated carbon atom is strongly facilitated if the nitro group is bonded with the same carbon atom that bears a leaving group. In this case, either X or NO2 can come off (Scheme 7.66). 

Rank the following nucleophiles in order of increasing nucleophilicity with respect to nucleophilic substitution reactions at a saturated carbon atom. Comment on your choice. 

In 1959, the coordinated mercaptide ion in the gold(III) complex (4) was found to undergo rapid alkylation with methyl iodide and ethyl bromide (e.g. equation 3).9 The reaction has since been used to great effect particularly in nickel(II) (3-mercaptoamine complexes.10,11 It has been demonstrated by kinetic studies that alkylation occurs without dissociation of the sulfur atom from nickel. The binuclear nickel complex (5) underwent stepwise alkylation with methyl iodide, benzyl bromide and substituted benzyl chlorides in second order reactions (equation 4). Bridging sulfur atoms were unreactive, as would be expected. Relative rate data were consistent with SN2 attack of sulfur at the saturated carbon atoms of the alkyl halide. The mononuclear complex (6) yielded octahedral complexes on alkylation (equation 5), but the reaction was complicated by the independent reversible formation of the trinuclear complex (7). Further reactions of this type have been used to form new chelate rings (see Section 7.4.3.1). 

The labels 7a and 7d are used to denote mechanisms which approach, but fail to reach, the extremes of A and D character respectively. In the case 7d, the E-Y bond is perceptibly weakened prior to any significant bonding of Z to E, but EX is never present as a free entity. The label 7a is appropriate where there is evidence of incipient E-Z bond formation while the E-Y bond remains more or less intact. It is often impossible to decide whether a mechanism should be labelled A, 7or 7a, on the strength of the experimental evidence alone. If the intermediate Y—EX —Z is a plausible species, having a right to exist , we may tend to favour A as opposed to 7. If, on the other hand, the intermediate offends our notions about bonding and stability, we are inclined to postulate an 7 mechanism. Thus the well-known nucleophilic substitution reaction at a saturated carbon atom ... 

Substitution at certain unsaturated centers has little direct stereochemical interest, because there is no choice, e.g. substitution at aromatic, acetylenic, and carbonyl carbons must go with retention. On the other hand, stereoselection is possible at ethylenic and allenic carbon, phosphorus (P—O, P=S) and sulfur (S=0) centers. There appear to be important mechanistic differences between substitutions at unsaturated carbon and phosphorus or sulfur. All SE, SH, SN substitutions at such carbon atoms appear to proceed in at least two steps, while those at phosphorus and sulfur may go in one or more steps. For the SN process, comparative data are available here, substitution at unsaturated carbon proceeds with retention, while at phosphorus and sulfur inversion predominates. Substitution at unsaturated phosphorus and sulfur sites was sufficiently similar to other saturated centers that it was considered with them. Because of these mechanistic differences, we shall examine substitutions at unsaturated carbon more closely. 

Surprisingly, this anion is also a good soft nucleophile and attacks saturated carbon atoms through the sulfur atom. In this case attack occurs at the less substituted end of an allylic bromide to give an allylic sulfone, which we will use later on. 

The stereochemical course of nucleophilic substitution reactions is best illustrated by reference to substitution at a saturated carbon atom. The underlying principles of these reactions are fundamental to an understanding of the more complex stereochemistry of iSn reactions on steroids, carbohydrates and vinyl compounds which are considered in detail in the relevant sections below. 

---