Reactivity, alkyl halides with reactions

Alkylation of tosylmethylisocyanide. Tosylmethylisocyanide (4, 514-516 5,684-685) can be monoalkylated in high yield (75-95%) by primary alkyl halides (including alkyl chlorides and benzyl bromide) under phase-transfer conditions with either this quaternary salt or the less reactive benzyltriethyl-ammonium chloride. Yields are lower with secondary alkyl halides. With more reactive alkyl halides, the reaction is conducted at 0° to avoid dialkylation. 

Conjugate addition. Trialkylstannyllithium reagents prepared in ether solution undergo predominantly 1,2-addition to cyclohexenones, but solutions prepared in THF undergo conjugate addition to almost all enones, even hindered ones. The intermediate lithium enolates can be alkylated with reactive alkyl halides. These reactions are useful because secondary alkylstannanes are converted into the corresponding carbonyl compound by oxidation with Cr03-2Py. Tertiary alkylstannanes are also oxidized by CrOa-lPy, but mixtures of alcohols and products of dehydration are formed. 

The most frequently used organocuprates are those m which the alkyl group is pri mary Steric hindrance makes secondary and tertiary dialkylcuprates less reactive and they tend to decompose before they react with the alkyl halide The reaction of cuprate reagents with alkyl halides follows the usual 8 2 order CH3 > primary > secondary > tertiary and I > Br > Cl > F p Toluenesulfonates are somewhat more reactive than halides Because the alkyl halide and dialkylcuprate reagent should both be primary m order to produce satisfactory yields of coupled products the reaction is limited to the formation of RCH2—CH2R and RCH2—CH3 bonds m alkanes... 

Reactions of alcohols with hydrogen halides (Section 4.7) Alcohols react with hydrogen halides to yield alkyl halides. The reaction is useful as a synthesis of alkyl halides. The reactivity of hydrogen halides decreases in the order HI > HBr > HCI > HF. Alcohol reactivity decreases in the order tertiary > secondary > primary > methyl. 

With highly reactive alkyl halides, like allylic, benzylic or phenacyl halides, the ZjA-alkylation can be a serious side-reaction. Because of a SNl-like mechanism in those cases, the effect of enolate concentration on the reaction rate is low, and the resulting monoalkylester 5 may be more acidic than the unsubstituted starting material ... 

Horton, H. R. Koshland, D. E. Jr. Reaction with reactive alkyl halides. Methods Enzymol. 1967, 11, 556-565. 

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

A variety of alkyl halides have been reduced at room temperature, including benzyl halides, primary, secondary and tertiary alkyl halides. The reaction times depend on the halide, and vary between 20min (benzyl bromide, 0.5 mol% 28) up to several days (iodopentane, fluoropentane). The reactivity of alkyl halides decreases in the order R—Br > R—Cl > R—1 when reductions are performed in separate flasks. Several mechanistic details of the reaction have been uncovered by in situ monitoring of the reaction by NMR spectroscopy. The precatalyst 28 appeared to be activated by a rapid reduction of the coordinated acetone to PrO—SiEt3 and concomitant coordination of an alkyl halide (H Scheme 12.11). This complex represents a resting state that is in equilibrium with a o-silane... 

Chlorine or bromine reacts with alkanes in the presence of light (hv) or high temperatures to give alkyl halides. Usually, this method gives mixtures of halogenated compounds containing mono-, di-, tri- and tetra-halides. However, this reaction is an important reaction of alkanes as it is the only way to convert inert alkanes to reactive alkyl halides. The simplest example is the reaction of methane with CI2 to yield a mixture of chlorinated methane derivatives. 

An alternative general approach to 4//-pyrans has been found recently in cathodic alkylation of 2,4,6-triphenylpyrylium perchlorate224 and might be useful, especially where the Grignard reaction (Eq. 9) fails. The salt is electrolyzed (mercury electrode) in the presence of a reactive alkyl halide two-electron reduction generates pyranyl anion 197, which is alkylated with RX to 4//-pyrans 165 (11 to 36%). 

Peptidomimetics in which one amide bond is replaced by a phosphinic acid (R-P(0H)(=0)-R phosphinic peptides ) are of interest as potential protease inhibitors [17-19]. These compounds have been prepared either from orthogonally protected phosphorus-containing monomers [17,18,20], or by forming the phosphorus-containing fragments on solid phase, as sketched in Figure 11.4 [19,21], Phosphinic acids have been prepared on solid phase mainly by reaction of carbon electrophiles with monoalkylphosphinates. As carbon electrophiles, acrylates, aldehydes, reactive alkyl halides, or a, 3-unsaturated ketones can be used. 

This reaction allows the alkylation of aryl halides. The more reactive alkyl halide forms an organosodium first, and this reacts as a nucleophile with an aryl halide as the electrophile. Excess alkyl halide and sodium may be used if the symmetric coupled alkanes formed as a side product may be separated readily. 

Alkylpalladium complexes generated by oxidative addition of Pd(0) to alkyl halides with a /3 hydrogen can undergo /3-elimination to yield an alkene and a Pd-hydrido complex (as in the Heck reaction Scheme8.7). Nevertheless, this process is relatively slow compared with transmetalations and reductive eliminations, and simple alkyl halides or tosylates with /3 hydrogen can be cross-coupled with carbon nucleophiles under optimized conditions if the nucleophile is sufficiently reactive [9, 73-75] (Scheme8.6). 

Silver nitrate test The compound to be tested is treated with a few drops of 1% alcoholic silver nitrate. A white precipitate indicates a positive reaction. This could be due to either silver chloride (reaction with a reactive alkyl halide), silver alkynide (reaction with a terminal alkyne), or the silver salt of a carboxylic acid (reaction with a carboxylic acid). 

Under these conditions, the order of reactivity to nucleophilic substitution changes dramatically from that observed in the Sn2 reaction, such that tertiary alkyl halides are more reactive then secondary alkyl halides, with primary alkyl halides not reacting at all. Thus a different mechanism must be involved. For example, consider the reaction of 2-iodo-2-methylpropane with water. (Following fig.). In it, the rate of reaction depends on the concentration of the alkyl halide alone and the concentration of the attacking nucleophile has no effect. Thus, the nucleophile must present if the reaction is to occur, but it does not matter whether there is one equivalent of the nucleophile or an excess. Since the reaction rate depends only on the alkyl halide, the mechanism is called the SN1 reaction, where SN stands for substitution nucleophilic and the 1 shows that the reaction is first order or unimolecular, i.e. only one of the reactants affects the reaction rate. 

The alkyl halides that react by the S l mechanism have a relatively low reactivity toward polar nucleophilic substitution due to steric, electronic or strain factors11, as shown for several bicycloalkyl, cycloalkyl and neopentyl halides and for /-butyl chloride. In the following section the reaction of these alkyl halides with different nucleophiles will be discussed. 

Molander has also studied the Sml2-mediated double Barbier additions of alkyl dihalides to ketoesters.22,23 These impressive anionic-anionic, inter-molecular-intramolecular sequences require the use of Nil2 as an additive and irradiation with visible light and allow access to a range of bicyclic and tricyclic systems. The reactions proceed by reduction of the more reactive alkyl halide, intermolecular Barbier addition to the ketone, lactonisation and a second Barbier addition to the lactone carbonyl (Scheme 6.18).22... 

Enamines are intermediate in reactivity more reactive than an enol, but less reactive than an enolate ion. Enamine reactions occur under milder conditions than enolate reactions, so they avoid many side reactions. Enamines displace halides from reactive alkyl halides, giving alkylated iminium salts. The iminium ions are unreactive toward further alkylation or acylation. The following example shows benzyl bromide reacting with the pyrrolidine enamine of cyclohexanone. 

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