Nucleophilic substitution under acidic conditions

The site of nucleophilic substitution under acid conditions is also decided by the protonated specie formed. It has been proposed that with fairly strong acids the proton is associated with an imidazole nitrogen giving rise to the cationic forms 18 and 1965 in which the... 

Thiolate anions RS- are excellent nucleophiles. The substrate, a 1° alkyl halide, is a good substrate for nucleophilic substitutions under basic conditions. The product is PhSCH2CHMe2. Ethanol acts merely as a solvent in this case. It is not nearly as nucleophilic as the thiolate, nor is it acidic enough to be deprotonated by the thiolate, so it s unlikely to react with the alkyl halide. 

The reactions of these compounds have been reviewed previously <59HC(l3)i,p. 17, B-79MI22001). Cyanuric acid will be used to illustrate the reactions of the oxo-1,3,5-triazines. It is thermally stable (it is unaffected by heating in a sealed tube to 500 °C) and is not readily hydrolyzed. The oxo group undergoes nucleophilic substitutions under forcing conditions (Scheme 29). 

Phenols are C-acylated either by electrophilic substitution under acidic conditions or by nucleophilic acylation under basic conditions. Advances in the chemistry of strong acids and Lewis acids provided novel aspects to catalytic Fries rearrangement and Friedel-Crafts acylation. Effenberger and Gutermann used a catalytic amount of... 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycies containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyri-dines, quinolines, diazines, imidazoles, benzothiazoles and purines are amongst the systems that have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and y to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because A-protonation of the heterocycle... 

The reactions in this group probably mainly involve nucleophilic additions, compared with nucleophilic substitutions in compounds of the ether series, since the phenoxide involved under basic conditions can be concluded to be reacting as a carbanion. It seems most likely that from an initially formed methylol, a quinone methide results to which the carbanion, from a phenoxide, then adds to afford first the dihydroxymethane shown which then reacts again to continue the sequence (R CgHig, CgHiy). In the reaction of formaldehyde with alkylphenols as well as nucleophilic addition in alkaline media, electrophilic substitution under acidic conditions can take place leading to the same product. 

On the other hand, with less basic nucleophiles, especially under acidic conditions, the ready reversibility of carboxylate formation may permit nucleophilic addition to compete and ultimately lead to substitution through the addition-elimination mechanism. A typical example is the esterification of a carboxylic acid (Section 9-4), in which an alcohol and a carboxylic acid react to yield an ester and water. The nucleophile, an alcohol, is a weak base, and acid is present to protonate both the carbonyl oxygen, activating it toward nucleophilic addition, and the carboxy OH, converting it into a better leaving group, water. 

Alkyl groups under nonacidic conditions sterically deflect nucleophiles from C, but under acidic conditions this steric effect is to some extent offset by an electronic one the protonated oxirane opens by transition states (Scheme 40) which are even more 5Nl-like than the borderline Sn2 one of the unprotonated oxirane. Thus electronic factors favor cleavage at the more substituted carbon, which can better support a partial positive charge the steric factor is still operative, however, and even under acidic conditions the major product usually results from Cp attack. 

Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine could be easily fimc-tionalized at C-3 and C-4 in a one-pot two-step microwave-assisted process (Scheme 34) [55]. Ding and Schultz reported that nucleophilic substitution of the addition-elimination type at the C-4 position with amines and anilines smoothly occurred under acidic conditions in dioxane upon irradiation... 

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). 

It is interesting to note that the oxidation of sulphoxides by peracids is faster in alkaline than in acidic solution. This is in contrast to the oxidation of sulphides and amines with the same reagents " . The oxidation rate of ortho-substituted aryl alkyl sulphoxides with aromatic peracids is less than the corresponding meta- and para-substituted species due to steric hindrance of the incoming peracid anion nucleophiles . Steric bulk in the alkyl group also has some effect . Such hindrance is not nearly so important in the oxidation reaction carried out under acidic conditions . 

In an earlier study the authors proposed a [3.2.0] bicyclic sulfonium salt 8 as the reactive intermediate in the trimethylsilyl iodide mediated ring contraction of 4-methoxythiephane <1996T5989>. Enantiomerically pure thio-lane derivatives were synthesized via a ring contraction of a seven-membered sulfur heterocycle by nucleophilic transannular substitution <2000TA1389>. The thiepane derivative 15, derived from d-sorbitol, was converted into the dimesyl derivative 16 following deprotection under acidic conditions. Treatment of 16 with sodium azide in DMSO at 120°C yielded the corresponding thiolane as a mixture of two diastereoisomers, 17a and 17b, in a 5 1 ratio (see Scheme 1). 

Nucleophilic substitution of leaving groups is probably the most important area in pyrimidine reactivity and, in particular, the differential reactivity of C-2 and C-4 is the most investigated topic. The displacement of 2- and 4-sulfide and sulfone groups is referred to in the synthesis section. The selective hydrolysis of 4-amino-2-chloropyrimidines under acidic conditions has been studied in great detail by a process research group <06OPRD921>. 

Another quite common reaction involving nucleophilic attack at a carbon atom of the ring is the hydrolysis of hexahydro-oxazolo[3,4- ]pyridines and tetrahydro-oxazolo[3,4-tf]pyridin-l-ones. This reaction has been known for years and is best performed under acidic conditions, respectively, producing 2-hydroxymethyl-piperidines or pipe-colic acid derivatives in good yields representative examples are collected in Table 9. Ammoniolysis of tetrahydro-oxazolo[3,4-tf]pyridin-l -ones with amino acid derivatives has also been reported and produces substituted pipecolic acid amides in good yields <2003H(61)259>. 

These authors found that nucleophilic additions to the unsubstituted ring system 1 can be carried out to yield a number of 7-substituted dihydro products or, in some cases, where an oxidation can follow this addition, also 7-substituted heteroaromatic derivatives (Scheme 6). Thus, reaction of 1 with indole under acidic conditions (in trifluoroacetic acid) yields 7-(177-indol-3-yl)-7,8-dihydrotetrazolo[l,5- ][l,2,4]triazine 24 <1998ZOR450>. Reaction of 1 with 3,4-difluoroacetophenone in the presence of potassium /frt-butoxide in tetrahydrofuran followed by... 

Two substitutions are occurring here H to Br, and Br to MeO. Looking at the order of reagents, the first substitution is H to Br. Br2 is electrophilic, so the a-C of the acyl bromide must be made nucleophilic. This is done by enolization. The substitution of Br with MeO occurs by a conventional addition-elimination reaction under acidic conditions. 

The chloromethylpyrimido[5,4-( ]-l,2,4-triazine 86 is an extremely versatile starting material (see Section 10.20.7.2, Equation 12) and was synthesized from the commercially available thiol 151 as shown in Scheme 25. Thus, 6 -methylation of compound 151 gave the sulfide 152, which was nitrosated to allow access to the nitroso-thiomethyl derivative 153. Nucleophilic substitution of the thiomethyl group by hydrazine gave the cyclization precursor 154, which underwent cyclization with chloroacetaldehyde diethyl acetal under acidic conditions to give the chloro-methylpyrimido[5,4-( ]-l,2,4-triazine 86 after workup with aqueous ammonia <2003BML2895>. 

Whereas the reactive species under acidic conditions are the [H2OOH] and [HO] cations, the reactive species under alkaline conditions is the [H02]e anion. Whereas the cationic oxidation species are stronger oxidants, with oxidation potential rising with increasing acidity favoring aromatic ring hydroxylation by electrophilic substitution (3,13), the anionic species mediate a nucleophilic attack on quinones according to the scheme illustrated in Fig. 6 (3,10,11). The formation of new acidic functionality results in a rapid decline in pH. 

If the nucleophile is a neutral molecule with a lone pair of electrons (H2O, ROH), it requires an acid catalyst for nucleophilic addition reaction to occur. Under acidic conditions, the carhonyl group becomes protonated, and thus is activated towards nucleophilic acyl substitution. Attack by a weak nucleophile generates the tetrahedral intermediate. A simultaneous deprotonation and loss of the leaving group reforms the carbonyl C=0 double bond. 

In general, [M(Con)]+ 250,253 and [M(ODC)]+ 239,258 react with electrophiles at C-5 (or C-15) under mild or stoichiometric conditions, and at C-5 and C-15 under more forcing conditions. Nitration appears to be less selective. Meso substitution is more or less reversible, and the substituents may be removed under acidic conditions if they are reasonably good leaving groups (Schemes 89 and 90).253,255,259,260 For [Ni(ODC)]+, nucleophiles also react at the meso positions (Scheme 91).239258... 

Under acidic conditions, amino-substituted imidazoles and triazoles 135 (X = CH, N) underwent intramolecular nucleophilic substitution reaction to give 136 in yields depending on the C(2 ) substituent orientation <1999CAR190, 1999MI441>. Thiouridine derivative 73 (R = Me) (Scheme 12) cyclized similarly to 72 on treatment with hexamethyldisilazane(HMDS)-ammonium sulfate <1992NN603>. 

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