Reactivity, alkyl halides with solvent polarity

SN1 versus S There are two different mechanisms involved in the nucleophilic substitution of alkyl halides. When polar aprotic solvents are used, the SN2 mechanism is preferred. Primary alkyl halides react more quickly than secondary alkyl halides, with tertiary alkyl halides hardly reacting at all. Under protic solvent conditions with non-basic nucleophiles (e.g. dissolving the alkyl halide in water or alcohol), the SN1 mechanism is preferred and the order of reactivity is reversed. Tertiary alkyl halides are more reactive than secondary alkyl halides and primary alkyl halides do not react at all. 

Danusso s conclusion that the monomer is only weakly polarized in the complex must certainly be true for the stereospecific coordinated anionic catalysts, such as AlR3/TiCl3, which are used for a-olefin polymerization. If it were not so, then rapid termination would take place through hydride abstraction by the strongly polarized monomer. This appears to be the case when strongly acidic alkyl metal chlorides are used in catalysts. For example, low molecular weight polypropylene oils are obtained with RAlCl2/TiCla catalyst (308) and polyethylene oils are obtained with RjA Cla/TiC catalysts in reactive alkyl halide solvents (309). 

Rapid and nearly complete alkylation of carboxylate salts with reactive organic halides has been demonstrated in nonpolar and polar solvents. With less reactive alkyl halides, the use of dipolar aprotic solvents for alkylation has been marginally successful. The rate of alkylation of potassium 2-methyl-2-propylpentanoate with 1-chlorohexane in four dipolar aprotic solvents at 60 °C decreased in the order HMPA > iV-methylpyrrolidone > DMSO > DMF. ... 

Sulfonium salts are compounds containing a tricoordinate, positively charged sulfur atom. Sulfonium salts (1) are prepared by the reaction of alkyl halides on dialkyl sulfides, the latter functioning as nucleophiles (l).1 The reaction is facilitated by the use of polar solvents like methanol. Methyl iodide is the most reactive alkyl halide, and in the alkyl iodides the reactivity decreases with increasing chain length. 

Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents45 or with crown ether catalysts.46 The reactivity order for carboxylate salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due to both high solubility and minimal ion pairing with the anion 47 Acetone is a good solvent for reaction of carboxylate anions with alkyl iodides48 Cesium fluoride in DMF is another useful... 

Generally, smaller particles are obtained with polar, more highly solvating solvents. However, these solvents do not necessarily yield the most active metal slurries. The reactivities vary, and the metal slurries can be fine tuned somewhat for use in specific types of reactions. For example, nickel particles from pentane are very active as hydrogenation catalysts, whereas nickel particles from THF are not active as hydrogenation catalysts but are very active in alkyl halide reactions. 

The susceptibility of the mercaptide groups in these Schiff base complexes to ligand reaction was evaluated by treating these compounds with methyl iodide and benzyl bromide in chloroform solution. The pure compounds isolated from these reaction mixtures were of the composition NiL.2RX, where L represents the tetradendate Schiff base and RX represents the alkyl halide added. These reactions proceed smoothly and the stoichiometry of the products implies that both sufur atoms are reactive. The products are monomeric in dichloroethane. They exhibit magnetic moments consistent with octahedral structures, and they behave as di-univalent electrolytes in coordinating, polar solvents. 

A number of reactivity studies have been performed on 6 and 8 and indicate a strongly polar (if not ionic) Mn—E bond Mn "—E,+ (E = In, Tl). Thus heterolytic bond dissociation occurs in polar ligating solvents such as MeCN or DMF, and halogens, hydrogen halides, and alkyl halides readily add across the metal-metal bond in a manner consistent with the polarity described above (13,13a,18). In the thallium example, however, the reactions are generally more complicated and result in T1(I) salts [e.g., Eq. (3)], and metal exchange reactions are also more facile, e.g., the synthesis of 6 from 8 and indium metal. In general, therefore, the chemistry of 6 and 8 is consistent with predominantly ionic behavior. 

The O-alkylation of carboxylates is a useful alternative to the acid-catalyzed esterification of carboxylic acids with alcohols. Carboxylates are weak, hard nucleophiles which are alkylated quickly by carbocations and by highly reactive, carbocation-like electrophiles (e.g. trityl or some benzhydryl halides). Suitable procedures include treatment of carboxylic acids with alcohols under the conditions of the Mitsunobu reaction [122], or with diazoalkanes. With soft electrophiles, such as alkyl iodides, alkylation of carboxylic acid salts proceeds more slowly, but in polar aprotic solvents, such as DMF, or with non-coordinating cations acceptable rates can still be achieved. Alkylating agents with a high tendency to O-alkylate carboxylates include a-halo ketones [42], dimethyl sulfate [100,123], and benzyl halides (Scheme 6.31). 

Extractive alkylation has a reaction scheme identical with that for the previous procedure. The substrate with a carboxyl group reacts in an aqueous solution with a quaternary base and is extracted in the form of an ion pair into a polar solvent of low solvation capacity (dichloromethane) that contains alkyl halide. Low solvation of the anion of the acid and high solvation of the reaction product lead to increased reactivity of the anion and to a rapid reaction with the alkylation agent in the organic phase. Methyl iodide [27] is used to prepare methyl esters and pentafluorobenzyl bromide [28] is used for the preparation of esters providing a high ECD response. 

Direct Reaction of Zn with Alkyl Halides. The direct insertion see Insertion) reaction of Zn metal into alkyl halides - alkyl iodides being the ideal snbstrates - is a nseful reaction to prepare simple or polyfunctional organozinc halide compounds (equation 1). With primary alkyl iodides, the reaction requires an excess of Zn dnst (ca. 3 eqniv), previonsly treated with few mol % of 1,2-dibromoethane and TMSCl, and a temperature of 40 °C in THF. In these conditions, secondary alkyl iodides react at room temperatnre and benzylic and allylic bromides at 0 °C. The insertion see Insertion) into less activated C-X bonds may reqnire more reactive forms of zinc (Riecke zinc), higher temperatures, or the use of polar see Polar Compounds) solvent or cosolvent. 

DMl/THF solvent mixture. Then, by simply increasing the proportion of DM1 in the reaction medium from 1 2 to 2 1 DMl/THF, the C j—Cl bond was coupled with the second alkylzinc halide. Taking advantage of this solvent polarity trigger and the high reactivity of 27 in alkyl-alkyl coupling, a variety of functionalized alkanes were prepared in moderate to excellent yields at room temperature (Scheme 30). 

In the absence of strongly polar co-solvents 2-lithiothiophene displays moderate reactivity in alkylations and the reactions have to be carried out at elevated temperatures in the region of 50 °C. Careful control of the temperature is therefore not necessary if the reaction is carried out on a modest scale. The reactivity of 2-lithiothiophene in alkylations can be enhanced enormously by addition of a small amount of HMPT (5-10vol.%) in this case the reaction with butyl bromide proceeds smoothly at 20 °C and is complete within 15 minutes. The organometallic derivative can also be rendered more reactive by adding an equivalent amount of /-BuOK dissolved in THF. Subsequent reaction with butyl bromide proceeds smoothly at —10 to 0 °C. The procedure below can also be applied to prepare other non-volatile alkylthiophenes. We expect secondary alkyl halides to react much less easily dehydrohalogenation may be an important side-reaction, or even the dominant process. 

The alkylation, with the more reactive of alkyl halides, of the sodium salts of monoes-terified phosphonothioic acids (equation 22) (see also Scheme 11) or of the disodium salts 107 results in preferential S-alkylation, and the same situation obtains for the salts of phosphinothioic acid " methylation can also be carried out with dimethyl sulphate. Alkylations may also be performed under phase-transfer conditions. From both practical and theoretical perspectives, the subject is more complex, since the course of alkylation reactions depends on the nature of the alkylating agent, on the polarity of solvent and whether this is protic or non-protic and on the concentrations of reactants a study of these features has been the subject of two reports In non-polar or weakly polar aprotic media, or in EtOH, alkylation occurs almost exclusively on sulphur, but in dipolar aprotic solvents, O-alkylation also takes place. The relative yields of sulphur- and oxygen-substituted derivatives, [Qs/Qol depends, for a given solvent, on the nature of substituents on phosphorus, i.e. essentially, whether the substrate is a thiophosphoric, thiophosphonic or thiophosphinic acid. With alkyl tosylates as alkylating agents at 0.02 m in hmpt, the alkylation of sodium 0,0-dialkyl or diphenyl phosphorothioates results in 100% overall conversions with [Qs/Qo] 5 the overall yields for sodium diphenyl- or diisopropyl-phosphinothioates are lower (50-100%) with [Qs/Qo] 1 ... 

In the conversion of 66 to 67, we saw that HMPA was used as an additive. Another useful ingredient in many alkylation reactions is hexamethylphosphorus triamide [HMPT, (Me2N)3P], which coordinates with the enolate anion, diminishing the aggregate state and increasing reactivity. This additive also enhances the polarity of the solvent and thereby enhances the facility of the Sn2 alkylation step (sec. 2.7.A.i). The use of an additive such as HMPA or HMPT is very common when the enolate anion reacts slowly and/or the halide is relatively unreactive. Other acid derivatives such as lactones can react with LDA to give an enolate anion, which then reacts with alkyl halides in the usual manner. 

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