Alkyl halides Direct Process Reaction

Detailed investigations into the mechanism of reaction between alkyl halides and metals have concentrated primarily on systems of great practical interest the Grignard reaction, the Direct Process Reaction, and a. few others. Whereas research reported in the preceding section involved solely pure gaseous halides and pure metals as single crystals, mechanistic investigations have involved a much wider variety of substrates and reaction conditions. When a solvent is involved, solvation of the metal product... 

The formations of Grignard reagents and organolithium compounds are examples of the reduction of alkyl halides directly by metals...It is not clear whether inner- or outer-sphere processes are involved since the reactions occurring on a metal surface offer only a limited number of probes Kochi, J.K. Free Radicals John Wiley Sons, Inc. New York, 1973 663. 

When forming the enolate for an alkylation process, the choice of base is important. Hydroxide or alkoxide ions cannot be used because under those conditions (1) both the ketone and its enolate are present at equilibrium and aldol reactions will compete with alkylation and (2) some of the base is not consumed (an equilibrium will be established) and the base can attack the alkyl halide directly, providing for competing 5 2 and E2 reactions. 

The direct process is less flexible than the Grignard process and is restricted primarily to the production of the, nevertheless all-important, methyl- and phenyl-chlorosilanes. The main reason for this is that higher alkyl halides than methyl chloride decompose at the reaction temperature and give poor yields of the desired products and also the fact that the copper catalyst is only really effective with methyl chloride. 

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)... 

In all the desulphonylation reactions discussed in Sections III.B and III.C the sulphur is lost from the starting sulphone and is reduced in the process simultaneously, the former carbon-sulphur bond is either reduced to a C—H bond or is converted into a C=C bond. The reactions described in this section have the common thread that the sulphur atom is lost with reduction at sulphur, but the carbon atom is converted directly into a carbonyl group. Formally, these reactions offer a route from alkyl halides to aldehydes or ketones. 

Functionalized organozinc halides are best prepared by direct insertion of zinc dust into alkyl iodides. The insertion reaction is usually performed by addition of a concentrated solution (approx. 3 M) of the alkyl iodide in THF to a suspension of zinc dust activated with a few mol% of 1,2-dibromoethane and MeaSiCl [7]. Primary alkyl iodides react at 40 °C under these conditions, whereas secondary alkyl iodides undergo the zinc insertion process even at room temperature, while allylic bromides and benzylic bromides react under still milder conditions (0 °C to 10 °C). The amount of Wurtz homocoupling products is usually limited, but increases with increased electron density in benzylic or allylic moieties [45]. A range of poly-functional organozinc compounds, such as 69-72, can be prepared under these conditions (Scheme 2.23) [41]. 

Although there are many claims in patents to the preparation of alkylguanidines by reaction of guanidine with alkyl halides, this method, which was first studied by Schenck [ 16 5 ], has only rarely been found satisfactory. Primary and secondary alcohols in 80-85 per cent sulphuric acid react with guanidines to give the mono-and di-alkyl derivatives [166]. A process for direct alkylation of guanidine by an alkyl tosylate has been developed [95, 138, 167]. 

The catalytic cycles for reduction of alkyl and atyl halides using Ni(o), Co(i) or Pd(o) species are interrupted by added carbon dioxide and reaction between the first formed carbon-metal bond and carbon dioxide yields an alkyl or aryl car-boxylate. These catalyses reactions have the advantage of occuriiig at lower cathode potentials than the direct processes summarised in Table 4.14. Mechanisms for the Ni(o) [240] and Pd(o) [241] catalysed processes have been established. Carbon dioxide inserts into the carbon-metal bond in an intermediate. Once the carboxy-late-metal species is formed, a further electron transfer step liberates the carboxy-late ion reforming the metallic complex catalyst. 

Reaction 3, Figure 2, illustrates another variant, the reactivity of >C=0"- as a Lewis base (e.g. nucleophile) via reaction with electrophilic species. In the specific case of >C=0"- reacting with an alkyl halide (R—X), a direct nucleophilic displacement (Sw2) process was initially envisioned. However, it is now evident that these alkylations take... 

Yoshida et al. were the first to report the synthesis of carbamate esters by the direct reaction of aliphatic amines, C02 and alkyl halides [47]. The process involved the O-alkylation of intermediate alkylammonium carbamate salt, and required relatively, severe conditions (333-393 K 4MPa C02), long reaction times (1-2 days) and an excess of amine (2.5 equiv.) with respect to the alkylating agent. The method was shown to be effective only with secondary aliphatic amines which, however, were converted into organic carbamates in low to moderate yield and with modest selectivity because of significant side-formation of N-alkylation products. 

Lipshutz and colleagues presented recently palladium-catalyzed direct coupling reactions of alkyl iodides and vinyl bromides or iodides catalyzed by 1 mol% Pd(amphos)Cl2 in the presence of zinc and TMEDA in a biphasic aqueous/poly-(ethylene glycol tocopheryl sebacate) reaction medium [198], Internal olefins were obtained in 51-95% yield. For aryl-substituted (Aj-vinyl bromides, retention of double bond geometry was observed, while different degrees of isomerization occurred for (Z)-isomers, which may indicate the intervention of a radical addition process in the course of the coupling process. Alkyl-substituted (Z)-vinyl halides were transformed in contrast with retention of alkene geometry. Aryl halides also reacted [199],... 

The direct displacement of simple alkyl halides by thiolate sometimes gives complex product mixtures due to side-reactions or gives very low yields283-285. However, in the presence of electron-withdrawing groups, the yields of this process are significantly improved and are excellent in some cases284,285. 

A slightly different mechanism has been proposed by Cairncross and Sheppard (37) for the reaction of fluoroarylcopper compounds with substituted alkyl halides. Pentafluorophenylcopper can form a complex with bicyclooctyl bromide by coordination with the halogen atom. Such a complex may go directly to coupled product in a four-center process, or, depending on the nature of the group attached and the nature of the alkyl moiety, may form an ion pair which collapses to the coupled... 

Radical reactions can often be rationalized on the basis of frontier orbital considerations for intermediate radical species, the reactivity and stereochemistry of which can certainly be regulated with Lewis acid additives [21-23]. The first appearance of Lewis acids in radical reactions was in polymerization reactions resulting in alternation of copolymers different from that obtained without Lewis acids [24-26]. This concept, Lewis acid-directed radical reactions, has been applied to reductions and alkylations of organic halides or olefins, and has resulted in highly stereospecific processes. 

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