Nucleophilic substitution reactions of alcohols

K. Motokura, N. Nakagiri, T. Mizugaki, K. Ebitani, and K. Kaneda, Nucleophilic substitution reactions of alcohols with use of montmorillonite catalysts as solid Br0nsted acids, J. Org. Chem., 72 (2007) 6006-6015. 

Nucleophilic substitution reaction of alcohol with ammonia MOR, RHO, CHA, FAU... 

Nucleophilic Substitution of Alcohols. The use of alcohols as electrophiles instead of halides and acetate compounds is an ideal method to prevent waste salt formation (Fig. 5). However, cataljdic substitution of the hydroxyl group in alcohols is difficult due to their poor leaving ability, which requires equimolar or greater amounts of reagents. Recently, several homogeneous catalysts, such as NaAuCh, InCla, ZrCh, La, Yb, Sc, Hf triflate, BCCeFsls, BF3, and p-toluenesulfonic acid have been used for nucleophilic substitution reactions of alcohols with amides (33), 1,3-dicarbonyl compounds (34), and allylsilanes (35). However, these catalysts are often limited by low catalytic activity and selectivity, can be difficult to reuse, and require the use of halogenated solvents. 

Scheme 2 General mechanism for direct nucleophilic substitution reactions of alcohols by amines/ amides...

Nucleophilic Substitution Reactions of Alcohols Forming Alkyl Halides 483... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Alternatively, the Sn2 nucleophilic substitution reaction between alcohols (phenols) and organic halides under basic conditions is the classical Williamson ether synthesis. Recently, it was found that water-soluble calix[n]arenes (n = 4, 6, 8) containing trimethylammonium groups on the upper rim (e.g., calix[4]arene 5.2) were inverse phase-transfer catalysts for alkylation of alcohols and phenols with alkyl halides in aqueous NaOH solution to give the corresponding alkylated products in good-to-high yields.56... 

The first evidence that an elimination-addition mechanism could be important in nucleophilic substitution reactions of alkanesulfonyl derivatives was provided by the observation (Truce et al., 1964 Truce and Campbell, 1966 King and Durst, 1964, 1965) that when alkanesulfonyl chlorides RCH2S02C1 were treated in the presence of an alcohol R OD with a tertiary amine (usually Et3N) the product was a sulfonate ester RCHDS020R with exactly one atom of deuterium on the carbon alpha to the sulfonyl group. Had the ester been formed by a base-catalysed direct substitution reaction of R OD with the sulfonyl chloride there would have been no deuterium at the er-position. Had the deuterium been incorporated by a separate exchange reaction, either of the sulfonyl chloride before its reaction to form the ester, or of the ester subsequent to its formation, then the amount of deuterium incorporated would not have been uniformly one atom of D per molecule. The observed results are only consistent with the elimination-addition mechanism involving a sulfene intermediate shown in (201). Subsequent kinetic studies... 

Recently, Lewis-acid-catalyzed nucleophilic substitution reactions of propargyl alcohols have been described. In general, costly transition metals such as Ru, Re, Pd or Au are used in these transformations. At this point Bi(III) salts are believed to be a cheap and environmentally benign alternative. 

The C-2 selective nucleophilic substitution reactions of 2,3-epoxy alcohols mediated by trialkyl borates the first endo-mode epoxideopening reaction through an intramolecular metal chelate. Org. Lett. 2003, 5, 1789-1791. 381... 

Nucleophilic substitution reactions at alcoholic substrates with HX initiated by activation of the hydroxy-group by means of TPP/D4AD first developed by Kitsunobu (1) are being increasingly utilized This prin-... 

Intramolecular nucleophilic substitution reactions of chlorine " " or bromine with alco-holates lead to tetrahydropyrans. The alcoholate can be formed in situ by deprotccting an alcohol.Activated aromatic chlorides give in nucleophilic aromatic substitution reactions a six-membered heterocyclc, e.g, reaction of 1 to give 2. ... 

Nucleophilic substitution reactions of 5-chlorop5Tazoles 48 with amines and thiols under mild conditions provided 5-alkyl amino and thioether pyrazoles 49 as selective COX-2 inhibitors <03TL7629>. 4-Chloromethylpyrazoles 50 reacted readily with amides, carbamates, urea, azoles, alcohols, and thiols under neutral conditions to give substituted benzylic products 51 in moderate yields <03H(60)167>. 

Mechanistic Studies.- A number of substitution reactions of alcohols, phenols, or amines with 1,3,2-dioxaphospholans, e.g. (73), oxazaphospholans, and diazaphos-pholans have been followed by n.m.r. and shown to involve H-phosphoranes, e.g. (74). The reactions are run in toluene or without solvent, and without addition of an acidic catalyst in some systems, with 4-chlorophenol as the nucleophile, an equilibrium was established between an H-phosphorane (75) and a phosphonium salt (76), but the authors still favour (75) as the true intermediate. The equilibrium constants for a series of exchange reactions between (thio)phosphites (77) and (thio)phosphoro-dichloridites (78), and some analogous bromidites and a fluoridite, have been measured.The constants increase with increased electron donor ability of R. 

Acidic ether cleavages are typical nucleophilic substitution reactions, of the sort discussed in Chapter 11. Primary and secondary alkyl ethers react by an Sn2 mechanism, in which I" or Br" attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI, because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

Palladium-catalyzed nucleophilic substitution reactions of allylic substrates have become useful in organic synthesis. As allylic substrates, allyl alcohols, halides, carboxylates, phosphates or vinyl epoxides can be utilized. 

Aryl thionoesters (54a) may be prepared by nucleophilic substitution reactions of aryl thiocarbonyl halides with alcohols or phenols for instance, thiobenzoyl chloride (58) condenses with phenol to yield the diaryl ester (54a) (Scheme 30). 

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