Benzyl chloride nucleophilic substitution

Step 1 The Boc protected amino acid is anchored to the resin Nucleophilic substitution of the benzylic chloride by the carboxylate anion gives an ester... 

The thenyl chlorides appear to be more reactive in nucleophilic aliphatic substitution than the benzyl analogs. Thus, 2-thenyh chloride gives, in the reaction with sodium cyanide in ethanol, a mixture of ethyl 2-thenyl ether (25% yield) and 2-thenyl cyanide (32% yield), whereas benzyl chloride gives a high 3deld of benzyl cyanide uncontaminated with benzyl ether. When 2-thenyl chloride and benzyl chloride were allowed to compete for a deficiency of sodium amyloxide, 2-thenyl chloride reacted three times faster. In acetone solution 2-thenyl cyanide is obtained smoothl. ... 

The reaction of tributyltin hydride with ring-substituted benzyl chlorides gives a Hammett p-factor of -1-0.81, confirming the "nucleophilic character of the BusSn- radical (303). 

The objective in selecting the reaction conditions for a preparative nucleophilic substitution is to enhance the mutual reactivity of the leaving group and nucleophile so that the desired substitution occurs at a convenient rate and with minimal competition from other possible reactions. The generalized order of leaving-group reactivity RSOj" I- > BF > CF pertains for most Sw2 processes. (See Section 4.2.3 of Part A for more complete data.) Mesylates, tosylates, iodides, and bromides are all widely used in synthesis. Chlorides usually react rather slowly, except in especially reactive systems, such as allyl and benzyl. 

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions of phenoxide ions by benzylic chlorides carbon alkylation occurs in water but not in nonpolar organic solvents, and it is observed only when the phenoxide has at least one methyl substituent (ortho, meta, or para). This has been discussed in Chapter 6 (Section 6.4.2). 

MAMP (Merrifield, Alpha-MethoxyPhenyl) resin 44 is an alternative to aldehyde linkers to construct TV-substituted amides [53], Nucleophilic displacement of the benzylic chloride with an amine followed by acylation yielded a secondary amide which was released upon a low ( 10%) concentration of TFA (Scheme 16). 

Nucleophilic substitutions of benzyl chloride or benzyltrimethylammonium chloride as electrophiles with Ph3P or Bu3P as nucleophiles have been performed with accurate control of the power and temperature by use of a monomode reactor. The results were carefully compared under similar conditions with microwave or A activation [85] (Eq. (30) and Tab. 3.11). 

The same phenomenon, i.e. that the secondary a-deuterium KIE is determined by the changes in only the shorter reacting bond in the SN2 transition state rather than by the nucleophile-leaving group distance, has been found in a completely different reaction system. Matsson, Westaway and co-workers (Matsson et al., 1996) used ku/k14 carbon incoming nucleophile, chlorine leaving group (Hill and Fry, 1962), and ku/ku a-carbon (Fry, 1970) KIEs to model the transition states for a series of SN2 reactions between p-substituted benzyl chlorides and labelled cyanide ion (reaction (17)). 

Table 14 The chlorine 35C1/37C1 leaving group, the incoming nucleophile nC/14C, the secondary a-deuterium, and the 12C/14C a-carbon KIEs for the SN2 reactions between p-substituted benzyl chlorides and cyanide ion in 20% aqueous DMSO at 30°C. ...

Gas-phase nucleophilic substitution reactions of Y-benzyl chlorides and X-phenoxide or X-thiophenoxide nucleophiles have been investigated by using the PM3 semiempirical MO method. The structure of the transition state was examined. The values of the gas-phase Hammett constants px and py are much greater than for the solution reactions, but a theoretical cross-interaction constant pxy (ca —0.60 for both phenoxides and thiophenoxides) agrees well with an experimental value of —0.62 for the thiophenoxide reactions in MeOH at 20 °C. Other work by the same group has involved theoretical studies of competitive gas-phase 5 n2 and E2 reactions of NCCH2CH2CI with HO and An ab initio method at the 6-31-l-G level was... 

A still different scheme is used for the preparation of the benzimidazole buterizine (74). Alkylation of benzhydrylpiperazine with substituted benzyl chloride 70 gives the intermediate 7U Nucleophilic aromatic displacement on this compound by means of ethyl amine leads to reduction of the nitro group then gives the diamine T. Treatment of that with the orthoformate ester of pentanoic acid serves to form the imidazole ring. There is thus obtained the peripheral vasodilating agent buteri zi ne (74). ... 

Alkyl halides with an electron-withdrawing group on the halogen-bearing carbon can be dimerized to olefins by treatment with bases. Z may be nitro, aryl, etc. It is likely that in most cases the mechanism451 involves nucleophilic substitution followed by elimination452 (illustrated for benzyl chloride) ... 

Figure 12.1 Reaction of benzyl chloride with water (a nucleophilic substitution reaction, see Chapter 13).

In a mechanistically similar process, the neutral palladium(II) dipyridylamine complex (24), obtained by deprotonation of complex (23), underwent reaction with benzoyl chloride to give the substituted complex (25) together with some free ligand (Scheme 8).33 This particular reaction sequence could not be generalized because of the relative instability of other metal complexes related to compound (24). However, a more extensive series of electrophilic substitutions could be carried out on the neutral complex (26), which displayed ambident nucleophilic behaviour by reaction with benzyl chloride and benzoyl chloride at nitrogen and reaction with benzenediazonium fluoroborate at carbon (Scheme 9). 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

Benzyl cyanide is the product of nucleophilic substitution by cyanide ion on benzyl bromide or benzyl chloride. The benzyl halides are prepared by free-radical halogenation of the toluene side chain. 

Benzylic electrophiles bearing electron-withdrawing groups at the arene do not always yield the expected products of nucleophilic substitution on treatment with a nucleophile. One important side reaction is the dimerization of these compounds to yield 1,2-diarylethenes (stilbenes). This dimerization does not require such highly activated systems as the example sketched in Scheme 4.28, but can even occur with, for example, 2- or 4-nitrobenzyl chloride [120, 121]. The latter compounds are converted into the corresponding stilbenes by treatment with KOH in ethanol [120]. Di-arylmethyl halides behave similarly and can yield tetraarylethenes on treatment with a base. These reactions presumably proceed via the mechanism sketched in Scheme 4.27, in which the amphiphilic character of the nitro group plays a decisive role (metalated nitroalkanes or 4-nitrobenzyl derivatives can act as nucleophiles and as electrophiles). 

If the activated aromatic compound reacts with a mixture of formalin, concentrated hydrochloric acid, and ZnCl2, the result is a so-called chloromethylation (Figure 5.29). The stable reaction product is a primary benzyl chloride. This reaction is initiated by an electrophilic substitution by protonated formaldehyde it is terminated by an SN1 reaction in which a chloride ion acts as the nucleophile. 

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