Abstract:Alkylation of pi-rich heteroaromatics such as pyrroles and furans by the standard Friedel-Crafts approach is impractical because the acid catalysts employed (Brønsted or Lewis) induce polyalkylation, ring opening, and polymerization. The present study describes the facile benzylation of pi-excessive heteroaromatics using the nitrosoamide approach, which generates nitrogen-separated carbocation-counterion ion-pairs as the alkylating agent with no catalyst being required. N-Nitrosoamides are favorable sources of… Show more
“…The partitioning of the benzyl carbocation, generated from the decomposition of N -benzyl- N -nitrosobenzamide or the protonation of phenyldiazomethane by benzoic acid, between nucleophilic addition of solvent and trapping by benzoate ion within an ion pair results in a higher yield of the solvent adduct in a solvent of pyrrole than in a solvent of methanol . This observation is in qualitative agreement with the results reported here that pyrrole is more reactive than the hydroxylic solvent water toward 1 + .…”
The following selectivities are reported for partitioning of the R-(N,N-dimethylthiocarbamoyl)-4methoxybenzyl carbocation 1 + between nucleophilic addition of π-nucleophiles and a solvent of 50:50 (v:v) acetonitrile/water at 25°C (nucleophile, k Nu /k s ): pyrrole, 23 M -1 ; 2-methoxythiophene, ≈2 M -1 . No nucleophile adducts (<2% of total products) were detected from the reaction of this carbocation in the same solvent containing the following carbon nucleophiles: thiophene (0.10 M), furan (0.10 M), ethyl 1-propenyl ether (0.10 M), amd 1-cyclohexenyl trimethylsilyl ether (0.01 M). These results show that only π-nucleophiles with Mayr nucleophilicity parameters greater than N ≈ 6 are sufficiently reactive to compete with nucleophilic aqueous solvents for addition to 1 + , and they provide support for a simple relationship between the Ritchie N + scale of nucleophilicity in water and the Mayr N scale of nucleophilicity in weakly polar nonnucleophilic solvents. 2,3 Our data require a large effective molarity for the intramolecular addition of a trisubstituted alkene to an allylic carbocation.In recent years there have been many determinations of rate constants for the addition of nucleophiles to carbocations in a variety of solvents, including weakly polar, aprotic, nonnucleophilic solvents such as dichloromethane; 2,3 polar, aprotic, and weakly nucleophilic solvents such as acetonitrile; 4 polar, protic, and weakly nucleophilic solvents such as 1,1,1,3,3,3-hexafluoro-2-propanol; 5,6 and polar, protic, and strongly nucleophilic solvents such as water. 7,8 An important conclusion from this work is that there are large decreases in the reactivity of anionic nucleophiles 4,9 and neutral amines 10 with increasing stabilization of the nucleophilic reagent by hydrogen bonding to solvent. This results from the requirement for the loss of these stabilizing hydrogen-bonding interactions on proceeding to the transition state for the nucleophile addition reaction.The effect of polar protic solvents on the nucleophilic reactivity of alkenes and other π-nucleophiles has not been investigated in detail, but the lack of data in aqueous solvents might suggest that π-nucleophiles are simply too weakly nucleophilic to compete with nucleophilic solvents for addition to unstable carbocations. However, recent studies of photolytically generated ring-substituted diarylmethyl carbocations in acetonitrile have shown that the second-order rate constants for the addition of activated alkenes, such as vinyl ethers and silyl enol ethers, are significantly larger than that for addition of water. 11 These results suggest that it should be possible to study the addition of strongly activated nucleophilic alkenes to carbocations in an aqueous solvent, but we are not aware of any reports of such studies in the chemical literature.We recently reported that the π-nucleophile 2 is 70 000-fold more reactive than a solvent of 50:50 (v:v) methanol/water toward the R-(N,N-dimethylthiocarbamoyl)-4-methoxybenzyl carbocation 1 + (k alk , Scheme 1), 12 g...
“…The partitioning of the benzyl carbocation, generated from the decomposition of N -benzyl- N -nitrosobenzamide or the protonation of phenyldiazomethane by benzoic acid, between nucleophilic addition of solvent and trapping by benzoate ion within an ion pair results in a higher yield of the solvent adduct in a solvent of pyrrole than in a solvent of methanol . This observation is in qualitative agreement with the results reported here that pyrrole is more reactive than the hydroxylic solvent water toward 1 + .…”
The following selectivities are reported for partitioning of the R-(N,N-dimethylthiocarbamoyl)-4methoxybenzyl carbocation 1 + between nucleophilic addition of π-nucleophiles and a solvent of 50:50 (v:v) acetonitrile/water at 25°C (nucleophile, k Nu /k s ): pyrrole, 23 M -1 ; 2-methoxythiophene, ≈2 M -1 . No nucleophile adducts (<2% of total products) were detected from the reaction of this carbocation in the same solvent containing the following carbon nucleophiles: thiophene (0.10 M), furan (0.10 M), ethyl 1-propenyl ether (0.10 M), amd 1-cyclohexenyl trimethylsilyl ether (0.01 M). These results show that only π-nucleophiles with Mayr nucleophilicity parameters greater than N ≈ 6 are sufficiently reactive to compete with nucleophilic aqueous solvents for addition to 1 + , and they provide support for a simple relationship between the Ritchie N + scale of nucleophilicity in water and the Mayr N scale of nucleophilicity in weakly polar nonnucleophilic solvents. 2,3 Our data require a large effective molarity for the intramolecular addition of a trisubstituted alkene to an allylic carbocation.In recent years there have been many determinations of rate constants for the addition of nucleophiles to carbocations in a variety of solvents, including weakly polar, aprotic, nonnucleophilic solvents such as dichloromethane; 2,3 polar, aprotic, and weakly nucleophilic solvents such as acetonitrile; 4 polar, protic, and weakly nucleophilic solvents such as 1,1,1,3,3,3-hexafluoro-2-propanol; 5,6 and polar, protic, and strongly nucleophilic solvents such as water. 7,8 An important conclusion from this work is that there are large decreases in the reactivity of anionic nucleophiles 4,9 and neutral amines 10 with increasing stabilization of the nucleophilic reagent by hydrogen bonding to solvent. This results from the requirement for the loss of these stabilizing hydrogen-bonding interactions on proceeding to the transition state for the nucleophile addition reaction.The effect of polar protic solvents on the nucleophilic reactivity of alkenes and other π-nucleophiles has not been investigated in detail, but the lack of data in aqueous solvents might suggest that π-nucleophiles are simply too weakly nucleophilic to compete with nucleophilic solvents for addition to unstable carbocations. However, recent studies of photolytically generated ring-substituted diarylmethyl carbocations in acetonitrile have shown that the second-order rate constants for the addition of activated alkenes, such as vinyl ethers and silyl enol ethers, are significantly larger than that for addition of water. 11 These results suggest that it should be possible to study the addition of strongly activated nucleophilic alkenes to carbocations in an aqueous solvent, but we are not aware of any reports of such studies in the chemical literature.We recently reported that the π-nucleophile 2 is 70 000-fold more reactive than a solvent of 50:50 (v:v) methanol/water toward the R-(N,N-dimethylthiocarbamoyl)-4-methoxybenzyl carbocation 1 + (k alk , Scheme 1), 12 g...
“…Benzylamine was used as nucleophile and 1b instead of 1a was used as substrate. Both 1 H NMR and 13 C NMR spectra of the product correspond to literature spectra of N-benzylbenzamide, [32][33][34] corroborating the view that nucleophilic substitution did indeed take place. Reaction between 1b and phenylamine in benzene was shown to yield N-phenylbenzamide.…”
General-base catalysed hydrolysis and nucleophilic substitution of activated amides in aqueous solutions Buurma, NJ; Blandamer, MJ; Engberts, Jan; Buurma, Niklaas J. Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. ABSTRACT: The reactivity of 1-benzoyl-3-phenyl-1,2,4-triazole (1a) was studied in the presence of a range of weak bases in aqueous solution. A change in mechanism is observed from general-base catalysed hydrolysis to nucleophilic substitution and general-base catalysed nucleophilic substitution. A slight tendency is also observed for the more hydrophobic general bases to show higher reactivity towards 1a. Aspartame is an effective nucleophile, possibly because nucleophilic substitution is subject to intramolecular general-base catalysis. A general conclusion derived from the present results is that unexpected rate effects can only be rationalised provided that the detailed reaction mechanisms are well understood. Copyright 2003 John Wiley & Sons, Ltd.KEYWORDS: hydrolysis; changes in mechanism; general-base catalysis; general-acid catalysis; nucleophilic substitution
INTRODUCTIONThe hydrolysis reaction of the activated amide 1-benzoyl-3-phenyl-1,2,4-triazole (1a) is general-base catalysed (Scheme 1).
1In highly aqueous solutions, the concentration of water is sufficiently high for water to act (detectably) as both a general base and a nucleophile. Hence, in the absence of other general bases, the water-catalysed (i.e. pHindependent) hydrolysis is the sole reaction. In the presence of sufficiently basic cosolutes, the watercatalysed reaction is unimportant. More basic cosolutes are much more effective catalysts for hydrolysis than water. Consequently, despite the relatively low molality of added general bases, the general-base catalysed hydrolysis pathway competes with the water-catalysed pathway. It is stressed that even though in the watercatalysed reaction the second water molecule in the activated complex (i.e. B = H 2 O, Scheme 1) acts as a general base, a distinction is drawn between the watercatalysed reaction and general-base catalysed reaction.Increased basicity of cosolutes usually leads to a concomitant increase in nucleophilicity. This increase in nucleophilicity provides an alternative reaction pathway: nucleophilic attack on the carbonyl functionality, followed by loss of the (substituted) 1,2,4-triazole leaving group (Scheme 2).In this mechanism, the nucleophilic water molecule is replaced by a stronge...
“…We earlier reported that carbocations formed from alkyldiazonium carboxylate ion pairs are highly reactive species that have the capability of alkylating most organic molecules of which a solvent cage could be comprised − (eq 1). …”
The protonation of heterocyclic diazotates (attachment adjacent to a nitrogen atom) yields ring-centered heterocyclic carbocations that are
highly reactive. The carbocations were found to alkylate aromatic and heterocyclic compounds, such as benzene, N-methylpyrrole, and
2-aminopyridine, in reactions that are synthetically useful. This carbocation involvement may serve as a paradigm for the cross-linking of DNA
by nitrous acid and the anticancer activity of heterocyclic diazotates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
