Nucleophilic substitution of alcohols

Experimental observations indicate that acid strength significantly affects the reaction rate. For example, sulfuric acid promotes nucleophilic substitution of alcohols by bromide, but acetic acid does not. How would a change in acid strength affect your calculated reaction energies ... 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

Curran, D. P., Dandapani, S. Fluorous nucleophilic substitution of alcohols and reagents for use therein, specifically, perfluoroalkyl-containing phosphines and azodicarboxylates as polyfluorinated reagents for the Mitsunobu reaction, 2002-US26045 2003016246, 2003 (University of Pittsburgh, USA). 

Alcohols react with H2S in the presence of acid or base catalysts to give mercaptans. The nucleophilic substitution of alcohols by H2S occurs at around 300° C on an alumina-type catalyst impregnated with alkali metal oxides such as Na20, K2O or transition metal oxides such as WO3. Phosphotungstate alkaline salts on alumina have also been used. 

Fig. A. Nucleophilic substitution of alcohols is not favoured. Good leaving group...

Dual activation of molecules by protonic acid sites in the interlayer space of H+-mont was employed in the nucleophilic substitution of alcohols with anilines, alkylsilanes, and indoles (Scheme 6.7) [94,266]. 

A diaryl cyclopropenone (171) catalyses nucleophilic substitution of alcohols, for example, chlorination. Employing an activator such as oxalyl chloride [(COCl)2], a cyclopropenium salt (172) is generated and adds to the alcohol (to give 173), with the nucleophile then generating the product (with inversion of configuration), and regenerating the original cyclopropenone (171). The method shows considerable promise for dehydrations. ... 

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. 

The direct nucleophilic substitution of alcohols represents a valuable methodology for the preparation of a variety of derivatives, since water is the only byproduct of the transformation. In this context, Cozzi et al. have reported very recently an organocatalytic alkylation of aldehydes proceeding through an SNl-type reaction of alcohols. This very simple method to effect the enantioselective direct alkylation of a wide range of aldehydes with unfunctionalised alcohols was catalysed by MacMillan catalyst and provided good to high yields and enantioselectivities of up to 90% ee, as shown in Scheme 5.5. 

The cyclopropenium activation approach has been employed in a number of elimination reactions, such as nucleophilic substitution of alcohol, nucleophilic acyl substitution of carboxylic acid, cyclodehydration of diol, and the Beckmann rearrangement (Scheme 6.17) [45]. 

A catalytic route for nucleophilic substitution of alcohols using simple CPN 55 as a catalyst was also developed by Lambert in 2011 (Scheme 6.18a) [46]. In this reaction, oxalyl chloride acts as an activating reagent for 55. The catalytic system is also employed for the conversion of oximes and primary amides into nitriles (Scheme 6.18b) [47]. 

Notably, proline was unique for this transformation, as all the other chiral secondary amines tested failed to promote the reaction. Another well-estabhshed organo-catalyst (4), invented by MacMillan [27], and unable to form secondary interactions with electrophiles like proUne, was used in the addition of aldehydes to indolyl and other carbocations derived from alcohols. The formation of stable carbenium ions from alcohols and their compatibility with water, generated by the organocatalytic cycle (formation of enamines from the corresponding carbonyl derivatives), was estabUshed by Cozzi in a SnI nucleophilic substitution of alcohols in the presence of water [28]. The enamine formed in situ by the MacMUlan catalyst approaches the carbocation from the less hindered side and the hindrance of the incipient carboca-tion controls the stereoselectivity of the reaction (Scheme 26.2) [29]. 

Sanz R, Martinez A, Miguel D, Alvarez-Gutierrez, JM, Rodriguez F. Brpnsted acid-catalyzed nucleophilic substitution of alcohols. Atfv. Synth. Catal 2006 348 1841-1845. 

Friedel-Crafts alkylation can be conducted in water without a catalyst. Cozzi and Zoh [117] described the direct nucleophilic substitution of alcohol on water, with no use of Lewis or Bronsted adds or surfactants. Selected examples can be found in Scheme 6.24. The success of these reactions hinges on the formation of relatively stable carbocation, and they can be promoted by microwave (MW) radiation [118]. 

Scheme 6.24 Nucleophilic substitution of alcohols in water under catalyst-free conditions.

Nucleophilic Reactions. Useful nucleophilic substitutions of halothiophenes are readily achieved in copper-mediated reactions. Of particular note is the ready conversion of 3-bromoderivatives to the corresponding 3-chloroderivatives with copper(I)chloride in hot /V, /V- dim ethyl form am i de (26). High yields of alkoxythiophenes are obtained from bromo- and iodothiophenes on reaction with sodium alkoxide in the appropriate alcohol, and catalyzed by copper(II) oxide, a trace of potassium iodide, and in more recent years a phase-transfer catalyst (27). 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

Another remarkable reaction is the nucleophilic substitution of the chlorine by alkoxy or sulfido groups using the alcohol or the thiol and the weak base Na2C03 in situ. For example, in the case of ethanol, the reaction proceeds in 12 h at reflux Eq. (23), Table 3. 

The catalyst is phosphoric acid. The laboratory synthesis of alcohols is by nucleophilic substitution of haloalkanes. 

To obtain this compound the key step consisted in the epimerization of the C-5 in compound 6. This was acomplished by triflation of the alcohol 6 and nucleophilic substitution of the triflate by a large excess of tetrabutylammonium acetate in dichloromethane. A controlled (4 °C, 3 h) basic methanolysis of the enol benzoate led to the keto-ester 11" whose hydroxyl functions at C-4 and C-6 were simultaneously deprotected under acidic conditions to furnish 12. Finally a Zemplen deprotection of the 5-acetoxy group led to 13 obtained in five steps and 11% overall yield from 6 (figure 4). 

Goumont et al. exploited this kind of reactivity for the nucleophilic substitution of the hydrogen atom in position 5 by carbon nuclophiles <20030BC2192> (Scheme 18). These authors reported that 6,8-dinitrotetrazolo[l,5- ]pyr-idine 11 easily reacts with potassium nitropropenide to yield an adduct similar to those obtained with alcohols 12. This adduct when oxidized by cerium ammonium nitrate yields the nitroalkyl-substituted aromatic compound 64. 

Acetonitrile is another participating solvent, which in many cases leads to the formation of an equatorially linked glycoside [125-131], It has been proposed that these reactions proceed via an a-nitrilium ion intermediate. It is not well understood why the nitrilium ion adopts an axial orientation however, spectroscopic studies support the proposed anomeric configuration [130,131], It is known that nucleophilic substitution of the a-nitrilium ion by an alcohol leads to P-glycosidic bonds and the best P-selectivities are obtained when reactive alcohols at low reaction temperatures are employed. Unfortunately, mannosides give poor anomeric selec-tivities under these conditions. 

The nucleophilic addition of alcohols [130, 204-207], phenols [130], carboxylates [208], ammonia [130, 209], primary and secondary amines [41, 130, 205, 210, 211] and thiols [211-213] was used very early to convert several acceptor-substituted allenes 155 to products of type 158 and 159 (Scheme 7.25, Nu = OR, OAr, 02CR, NH2, NHR, NRR and SR). While the addition of alcohols, phenols and thiols is generally carried out in the presence of an auxiliary base, the reaction of allenyl ketones to give vinyl ethers of type 159 (Nu = OMe) is successful also by irradiation in pure methanol [214], Using widely varying reaction conditions, the addition of hydrogen halides (Nu= Cl, Br, I) to the allenes 155 leads to reaction products of type 158 [130, 215-220], Therefore, this transformation was also classified as a nucleophilic addition. Finally, the nucleophiles hydride (such as lithium aluminum hydride-aluminum trichloride) [211] and azide [221] could also be added to allenic esters to yield products of type 159. 

Very important compounds are the carboxylic acids and their derivatives, which can be formally obtained by exchanging the OH group for another group. In fact, derivatives of this type are formed by nucleophilic substitutions of activated intermediate compounds and the release of water (see p. 14). Carboxylic acid esters (R-O-CO-R ) arise from carboxylic acids and alcohols. This group includes the fats, for example (see p.48). Similarly, a carboxylic acid and a thiol yield a thioester (R-S-CO-R ). Thioesters play an extremely important role in carboxylic acid metabolism. The best-known compound of this type is acetyl-coenzyme A (see p. 12). 

Oxidation of 2-(trimethylsilyloxy)furan (301) with iodosobenzene in the presence of boron trifluoride etherate and alcohols or acids results in the formation of 5-substituted 2(5//)-furanones 303. The first step of this conversion gives intermediate 302, which on nucleophilic substitution by alcohols or acids affords the products (89TL3019) (Scheme 75). 

Various substituted cyclopropanes have been shown to undergo nucleophilic addition of alcoholic solvents. For example, the electron transfer reaction of phenylcyclopropane (43, R = H) with p-dicyanobenzene resulted in a ring-opened ether 44. This reaction also produced an aromatic substitution product (45, R = H) formed by coupling with the sensitizer anion. This reaction is the cyclopropane analog of the photo-NOCAS reaction, but preceded it by almost a decade. 

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