Alkyl halides nucleophilic aliphatic

The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

The best-known route for making aliphatic arsonic acids is the Meyer (103) reaction, in which an alkyl halide reacts with alkaline arsenite by simple nucleophilic displacement ... 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

Anilines are generally less basic and nucleophilic than aliphatic amines, but can still be alkylated with alkyl halides under relatively mild reaction conditions under which, for instance, aliphatic alcohols will not undergo alkylation (Scheme 6.7). Monoalkylations of primary anilines with highly reactive alkylating agents can be difficult, and usually require use of excess of aniline and/or careful optimization of the reaction conditions [31-33]. 

Nucleophilic substitution reactions on unactivated alkyl halides have been known for a long time. The available mechanisms depend on the aliphatic moiety, the nucleophile, the leaving group and the reaction conditions118. Besides the polar mechanisms of nucleophilic substitution reactions (S l, S 2 and related mechanisms), several alkyl halides react with nucleophiles by an ET reaction. 

In contrast to esterification, etherification is carried out in an alkaline medium and the etherifying agents are alkyl halides. The general reaction is termed aliphatic nucleophilic substitution and, employed under normal conditions, is of the bimolecular type. 

Aromatic amines are less basic than their aliphatic counterparts. The lone pair on the nitrogen atom is delocalized over the 7t-system of the aromatic ring. Furthermore, the basicity is influenced by substituents on the aromatic ring. Thus 4-nitroaniline (4.5) is less basic than aniline. However, the aromatic amines behave as typical nucleophiles. Alkylation of the nitrogen by alkyl halides leads to the mono- and dialkylanilines. Reaction with acetic anhydride or acetyl chloride affords acetanilides. 

Although the mechanism is not understood, evidence strongly suggests this much the alkyl group R is transferred from copper, taking a pair of electrons with it, and attaches itself to the alkyl group R by pushing out halide ion (nucleophilic aliphatic substitution. Sec. 14.9). 

This duality of mechanism does not reflect exceptional behavior, but is usual for electrophilic aromatic substitution. It also fits into the usual pattern for nucleophilic aliphatic substitution (Sec. 14.16), which—from the standpoint of the alkyl halide—is the kind of reaction taking place. Furthermore, the particular halides (T and methyl) which appear to react by this second mechanism are just the ones that would have been expected to do so. 

In following sections, we shall discuss the mechanisms of nucleophilic aliphatic substitution and of elimination using alkyl halides as our examples. But we should realize that these reactions take place in exactly the same ways with a variety of other compounds compounds which, like alkyl halides, contain good leaving groups. 

We have seen that the aryl halides are characterized by very low reactivity toward the nucleophilic reagents like OH , OR, NH3, and CN" that play such an important part in the chemistry of the alkyl halides. Consequently, nucleophilic aromatic substitution is much less important in synthesis than either nucleophilic aliphatic substitution or electrophilic aromatic substitution. 

Hence the larger the n value, the stronger the nucleophile, and the smaller the [nucl]50o/o. As already pointed out earlier, the [nucl]50o/o values given in Table 2 show that in uncontaminated freshwaters, hydrolysis is by far the most important nucleophilic substitution reaction. Furthermore, since the hydrolysis of a carbon-halogen bond is generally not catalyzed by acids, one can assume that the hydrolysis rate of aliphatic halides will be independent of pH at typical ambient conditions (i.e., pH < 10). In this context it is also important to note that no catalysis of the hydrolysis of alkyl halides by solid surfaces has been observed (El-Amamy and Mill, 1984 Haag and Mill, 1988). In salty or contaminated waters, reactions of organic chemicals with nucleophiles other than water or j hydroxide ion may be important. Zafiriou (1975), for example, has demonstrated j that in seawater ([Cl ] 0.5 M), a major sink for naturally produced methyl j iodide is transformation to methyl chloride j... 

The two mechanisms for Friedel-Crafts alkylation are not dissimilar to the two mechanisms for nucleophilic aliphatic substitution. In an S,j1 mechanism, a carbocation is generated from an alkyl halide before the nucleophile attacks, but in an S 2 reaction the halide departs simultaneously with the nucleophile attacking the R group. In the Friedel-Crafts reaction, benzene behaves as the nucleophile. 

Aliphatic and aromatic nucleophilic substitution reactions are also subject to micellar effects, with results consistent with those in other reactions. In the reaction of alkyl halides with CN and S Oj in aqueous media, sodium dodecyl sulfate micelles decreased the second-order rate constants and dodecyltrimethylammonium bromide increased them (Winters, 1965 Bunton, 1968). The reactivity of methyl bromide in the cationic micellar phase was 30 to 50 times that in the bulk phase and was negligible in the anionic micellar phase a nonionic surfactant did not significantly affect the rate constant for n-pentyl bromide with S2O3-. Micellar effects on nucleophilic aromatic substitution reactions follow similar patterns. The reaction of 2, 4-dinitrochlorobenzene or 2, 4-dinitrofluorobenzene with hydroxide ion in aqueous media is catalyzed by cationic surfactants and retarded by sodium dodecyl sulfate (Bunton, 1968, 1969). Cetyltrimethylammonium bromide micelles increased the reactivity of dinitrofluorobenzene 59 times, whereas sodium dodecyl sulfate decreased it by a factor of 2.5 for dinitrochlorobenzene, the figures are 82 and 13 times, respectively. A POE nonionic surfactant had no effect. 

C-X disconnection in aliphatic compounds (ii) gives a nucleophile XH and an electrophilic carbon species usually represented by an alkyl halide, tosylate, or mesylate. These compounds can all be made from alcohols (ii) and as alcohols can be made by C-C bond formation (Chapter 10) we shall treat the alcohol as the central functional group (Table 4.2). 

Alkyl halides that show a Dn + An mechanism (Ingold terminology SnI) in nucleophilic aliphatic substitutions can be used as electrophilic reagents in C-alkyla-tions of diazoalkanes. An example is the synthesis of ethyl 2-diazopent-4-enoate (9.18) by reaction of ethyl silver diazoacetate with 3-iodoprop-l-ene (allyl bromide) (9-14, 66% Schollkopf and Rieber, 1969). 

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