Nucleophilic aliphatic substitution alcohols

Kinetics of the transformations of the N-F class of fluorinating agents in water, acetonitrile, alcohols, and aqueous solutions of alkali metal hydroxides have been studied.159 Other kinetic studies include die reactions of triphenylphosphine with 3-methoxy- or 3-acctoxy-4,4,5,5-tetrasubstitutcd-1,2-dioxolanes,160 the reactions of 2-amino-5-chlorobenzophenone witii HC1 in MeOH-H20 (die aspect of nucleophilic aliphatic substitution lies in certain products arising from attack of AH2 on CH3OH there are six products in all, and rate constants are evaluated for die formation of each of them),161 and the hydrolysis of derivatives of diazidophenyhnethane.162... 

Displacement of bromine by various thiols by Sjj2 nucleophilic substitution is definitely one of the best examples of click reaction. These reactions proceed well even in the presence of other nucleophiles such as alcohols and amines, owing to the increased nucleophilicity of thiols and thiolates. 2-Mercaptoethanol and other aliphatic thiol-dialcohol molecules when added to polymers, end-functionalized by halogen atoms, result in selective thiol end-functionalization of polymer chains. 

Even polyalkoxy-s-triazines are quite prone to nucleophilic substitution. For example, 2,4,6-trimethoxy-s-triazine (320) is rapidly hydrolyzed (20°, dilute aqueous alkali) to the anion of 4,6-dimethoxy-s-triazin-2(l )-one (331). This reaction is undoubtedly an /S jvr-4r2 reaction and not an aliphatic dealkylation. The latter type occurs with anilines at much higher temperatures (150-200°) and with chloride ion in the reaction of non-basified alcohols with cyanuric chloride at reflux temperatures. The reported dealkylation with methoxide has been shown to be hydrolysis by traces of water present. Several analogous dealkylations by alkoxide ion, reported without evidence for the formation of the dialkyl ether, are all associated with the high reactivity of the alkoxy compounds which ai e, in fact, hydrolyzed by usually tolerable traces of water. Brown ... 

A heterobimetallic BINOL-Ga/Li complex 53 has been developed for the enantioselective ARO of meso-cpoxides (BINOL = l,T-bi(2-naphthol)).278 Using />-methoxyphenol as the nucleophile, this etherification reaction was observed to take place with a high level of asymmetric induction. An improved catalyst 54 has also been reported that exhibits greater stability under the reaction conditions and delivers higher yields and ee s (Equation (78)).279 A simple catalyst derived from Sc(OTf)3 and the chiral bipyridine ligand 52 has been shown to be effective for the ARO of aryl-substituted /// -epoxides with aliphatic alcohols to give high ee s (Equation (79)).280... 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

As in carboxylic esters it is possible to substitute alkoxy groups of Fischer-type carbene complexes by non-carbon nucleophiles, such as other alcohols [73,214,218], enols [219], aliphatic amines [43,64,66,220-224], aniline [79], imines [225], or pyrroles [226]. Strong nucleophiles can also lead to a dealkylation of methoxy-substituted carbene complexes (5 2 at the methyl group, [227]), in the same way as methyl esters can be cleaved by nucleophiles such as iodide. Carbon... 

Various aldehydes 184 and alcohols have been shown to be competent in the redox esterification of unsaturated aldehydes in the presence of the achiral mesityl triazo-lium pre-catalyst 186. Both aromatic and aliphatic enals participate in yields up to 99% (Table 13). Tri-substituted enals work well (entry 3), as do enals with additional olefins present in the substrate (entries 4 and 7). The nucleophile scope includes primary and secondary alcohols as well as phenols and allylic alcohols. Intramolecular esterification may also occur with the formation of a bicyclic lactone (entry 8). 

Depending on the alcohol moieties present (i.e., quality of leaving group(s), presence of an aliphatic alcohol moiety), the neutral reaction as well as reactions with soft nucleophiles (e.g. HS-, CN, see Box 13.1) may also proceed by nucleophilic substitution at a carbon atom (C-0 cleavage). This is the case for trialkyl phosphates such as trimethyl and triethyl phosphate ... 

Phenols can be etherified with resin-bound benzyl alcohols by the Mitsunobu reaction [554,555], or, alternatively, by nucleophilic substitution of resin-bound benzyl halides or sulfonates [556,557], Both reactions proceed smoothly under mild conditions. Aliphatic alcohols have been etherified with Wang resin by conversion of the latter into a trichloroacetimidate (C13CCN/DCM/DBU (15 100 1), 0°C, 40 min), fol-... 

Aliphatic alcohols do not undergo solvolysis as readily as benzylic alcohols, and are generally converted into halides under basic reaction conditions via an intermediate sulfonate. Because of the hydrophobicity of polystyrene, however, nucleophilic substitutions with halides on this support do not always proceed as readily as in solution (Table 6.3). Alternatively, phosphorus-based reagents can also be used to convert aliphatic alcohols into halides. 

Non-activated aryl bromides (but not fluorides) can be used as substrates for palla-dium(0)-catalyzed aromatic nucleophilic substitutions with aliphatic or aromatic amines. These reactions require sodium alcoholates or cesium carbonate as a base, and sterically demanding phosphines as ligands. Moreover, high reaction temperatures are often necessary to achieve complete conversion (Entries 7 and 8, Table 10.4 Experimental Procedure 10.1). Unfortunately, the choice of substituents on the amine... 

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