Alkyl derivatives substitution mechanics

Nucleophilic substitutions are especially important for alkyl halides, but they should not be considered to be confined to alkyl halides. Many other alkyl derivatives such as alcohols, ethers, esters, and onium ions 3 also can undergo SN reactions if conditions are appropriate. The scope of SN reactions is so broad that it is impossible to include all the various alkyl compounds and nucleophiles that react in this manner. Rather we shall approach the subject here through consideration of the mechanisms of SN reactions, and then develop the scope of the reactions in later chapters. 

The only doubtful case is the secondaiy alkyl derivative, which can react by either mechanism, though it is not very good at either. The first question you should ask when faced with a new nucleophilic substitution is Is the carbon electrophile methyl, primary, secondaiy, or tertiary This will start you off on the right foot, which is why we introduced these important structural terms in Chapter 2. 

The formation of the benzyl radical by photolysis of toluene in benzene at 4.2 and 77 K has been investigated as a function of light intensity and shown to be unimolecular and biphotonic, and to occur via the lowest excited triplet state. The gas-phase photodissociation of [2,2]paracyclophane (71) into two molecules of /7-quinodimethane and analogous dissociations of two methyl-substituted derivatives have been shown to be efficient two-photon processes.A hot molecule formed by internal conversion from the initially formed singlet electronic excited state is proposed as an intermediate, a mechanism which is completely different from that of the two-photon dissociation of (71) in low-temperature matrices, which involves a triplet state. The photolyses of [2,2]para-cylcophane and [2,2]paracyclophane-l-ene have also been studied in THF and hexane matrices at 77 K, using detection by both luminescence and absorption spectroscopy. The products from both these compounds in THF matrices included alkyl derivatives of rra/15-stilbene, and in hexane matrices alkylphenan-threnes. Cycloreversion of so-called cyclodimers of naphthalene derivatives with benzene or furan, e.g. (72), occurs efficiently upon UV irradiation. ... 

Basic carriers (Table 27.1) consist mainly of amine-based compounds such as quaternary ammonium salts (e.g., Aliquat 336), tertiary amines (e.g., tri-n-octylamine [TOA], tri-isooctylamine [TlOA]), weakly basic compounds (e.g., alkyl derivatives of pyridine N oxides), and thiadiazine derivatives (e.g., 5-(4-phenoxyphenyl)-6/f-l,3,4-thiadiazin-2-amine [FFAT]). The reason for this classification is related to the similarity in the extraction mechanism involving the carriers discussed. In the case of fully substituted quaternary ammonium compounds (e.g., Aliquat 336), the carrier reacts as an anion exchanger forming an ion-pair with another anion from the feed phase, which can be a complex metal anion. In the case of amine and other weak bases mentioned earlier, the carrier must be protonated first in order to allow anion exchange with another anion from the feed phase or with a complex metal anion. Alternatively, the carrier may react directly with a protonated complex metal anion [16]. 

Another FGI that gives carboxylic acid products is the hydrolysis of carboxylic acid derivatives, such as esters and nitriles. Such hydrolysis reactions can either be acid catalyzed (H3O+) or base promoted (1. NaOH, H2O 2. H3O ) and involve an acyl substitution mechanism (addition-elimination) that replaces any acyl leaving group with a hydroxyl group. The synthesis of carboxylic acids via nitriles is especially noteworthy since the introduction of the cyano group via Sn2 with CN involves the formation of a new C-C bond (adds one new carbon to the alkyl halide carbon chain). 

The reduction of cyanocobalamin (b, R=CN) occurs in two one-electron steps, through Bj2r cobalt(II) species which exhibits radical character, to an anionic strongly nucleophilic species. Reduction of the model cobaloxime [Co(dmgH)2Clpy] proceeds similarly. The best route to alkyl derivatives is to react (Cb) with an alkyl halide or tosylate. These (Cb) species are very strong nucleophiles to saturated carbon centres. With tosylates substitution occurs with inversion at carbon, indicating an Sj, 2 mechanism. 

The possibilities for the formation of carbon-carbon bonds involving arenes have been dramatically increased in recent years by the use of transition metal catalysis. Copper-mediated reactions to couple aryl halides in Ulknann-type reactions [12, 13] have been known for many years, and copper still remains an important catalyst [14, 15]. However, the use of metals such as palladium [16,17] to effect substitution has led to such an explosion of research that in 2011 transition metal-catalyzed processes comprised more than half of the reactions classified as aromatic substitutions in Organic Reaction Mechanisms [18]. The reactions often involve a sequence outlined in Scheme 6.6 where Ln represents ligand(s) for the palladium. Oxidative addition of the aryl halide to the paiiadium catalyst is followed by transmetalation with an aryl or alkyl derivative and by reductive elimination to give the coupled product and legeuCTate the catalyst. Part 6 of this book elaborates these and related processes. 

Suitable mechanisms have been proposed following determination of the kinetic and activation parameters for oxidation of 2-naphthol and cyclic ketones by nicotinium dichromate some a-amino acids by tripropylammonium fluorochromate " distyryl ketone by quinaldinium fluorochromate methanol by benzyltriethylammonium chlorochromate catalysed by 1,10-phenanthroline substituted benzyl alcohols by tetraethylammonium bromochromate L-cysteine by pyridinium bromochromate lactic acid and 3,5-dimethyl-2,6-diaryl piperidin-4-one oximes by pyridinium chlorochromate allyl alcohol by IDC benzophenoxime by bispyridine silver(I) dichromate and alkyl phenyl sulfides by cetyltrimethylammonium dichromate. A non-linear Hammett plot obtained for the oxidation of substituted benzyl alcohols by IDC has been attributed to the operation of substituent effect on two steps of the proposed mechanism. " Kinetic and activation parameters for oxidation of o-toluidine and of A-methyl-2,6-diphenyl piperidin-4-one oxime and its 3-alkyl derivatives by sodium dichromate have been determined and suitable mechanisms have been suggested. Micellar catalysis in the 1,10-phenanthroline-promoted chromic acid oxidation of propanol... 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

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