7248 Chem. Commun., 2011, 47, 7248–7250 This journal is c The Royal Society of Chemistry 2011 Cite this: Chem. Commun., 2011, 47, 7248–7250 Hydrogen bond assisted activation of a dinitrile towards nucleophilic attackw Maximilian N. Kopylovich, Kamran T. Mahmudov, Archana Mizar and Armando J. L. Pombeiro* Received 24th March 2011, Accepted 4th May 2011 DOI: 10.1039/c1cc11696g The possibility of tunable regioselective activation of a dinitrile towards nucleophilic attack was demonstrated. For that, a sulfo- arylhydrazone unit was introduced into malononitrile and the thus formed intramolecular hydrogen bond systems assisted specific nucleophilic attacks to the cyano moieties leading to a variety of amidines, carboxamides and iminoesters depending on the nucleophiles and conditions used. Hydrogen bonding assisted organic synthesis is a rapidly growing area of modern chemistry. 1 Usually it involves the application of enantiopure organocatalysts containing H-donor–acceptor groups which preferably accelerate the transformation of the starting materials towards one stereo- isomer. Most of the published works on the activation of molecules by hydrogen bonding follow the above line, and not much attention has been paid to other possible developments of that concept. For example, hydrogen bonding could be used for the synthesis of unsymmetrical compounds from symmetrical ones by introducing a suitable supporting group into a symmetrical molecule thus promoting a particular type of reactivity (e.g., a nucleophilic attack) at a part of the starting molecule due to stabilization of the formed unsymmetrical product by intramolecular hydrogen bonds. The asymmetrical molecule thus formed could be isolated or used for further transformations. For the development of this idea, one should choose molecules which, upon an expected reaction, could form a stable hydrogen-bonding system, such as the so-named ‘‘resonance- assisted hydrogen bonding’’ (RAHB), 2 XÁÁÁH–Y 2 YÁÁÁH–X (X, Y = N, O, S, etc.) where X and Y interact via a resonance chain [Scheme 1(a), for a 6-membered system]. Such systems involve a synergistic reinforcement of hydrogen bonds by delocalization of a p-conjugated chain connecting donor and acceptor atoms. Until now, the RAHB systems have been applied for the activation of a carbon at the a-position to a carbonyl, induced enolization in keto–enol tautomerism, controlled crystal packing or formation of bistable H-bonds in functional molecular materials, etc. 2,3 We now demonstrate the possibility to apply such systems to the regioselective transformation of a symmetrical dinitrile to a variety of unsymmetrical products. As a model substrate we have chosen malononitrile, CH 2 (CRN) 2 , an important starting material in the synthesis of many organic compounds, in particular herbicides, dyes, polymers, washing and bleaching compositions, lubricants, optical sensitizers, etc. 4 The chemistry of this dinitrile is well studied, concerning reactions such as dimerization, trimerization, hydrolysis, halogenation, reduction, carbonyl condensation, ortho-ester and ylide formation, etc., that have been thoroughly described and reviewed. 4,5 In most of the cases, both cyano groups undergo nucleophilic attack leading to the corresponding symmetric products. 4 On the other hand, the introduction of a metal ion, in particular Mn II , stabilizes the product of only one attack, leaving the other cyano group unreacted. 6 However, as referred above, RAHB systems can also be expected to be used, instead of metals, for promoting a nucleophilic attack and for product stabilization. Moreover, to our knowledge, activation of a nitrile by hydrogen bonding had not yet been reported. Thus, we have now focused on the development of a specific and tunable transformation of a nitrile (in particular malononitrile, for the above reasons) using RAHB systems. To generate the RAHB system in the proximity to the nitrile groups we have introduced a sulfo-arylhydrazo moiety to malononitrile by its reaction with 2-sulfophenyldiazonium chloride. This is a known, 7 easy and convenient way to introduce the hydrazo function to a methylene active compound. On the other hand, the arylhydrazone moiety with a sulfo-group at the ortho-position was used in view of the following perspectives: (i) although it already forms an intramolecular RAHB [Scheme 2, compound 1, (2-(2-(dicyanomethylene)hydrazinyl)benzenesulfonic acid)], the system becomes further stabilized by a second RAHB chain (see below) upon nucleophilic attack at the nearest cyano-group, thus ‘‘freezing’’ the product of only one attack; (ii) the formed products are expected to be easily separated by precipitation of their salts upon protonation (see ESIw for details). The reaction of 1 with methanol concerns the nucleophilic attack, by this protic nucleophile, at one of the cyano groups, to produce the nitrile-iminoester 2 (Scheme 2, Route I) that is stabilized by two fused 6-membered three centre RAHB Centro Quı´mica Estrutural, Complexo I, Instituto Superior Te ´cnico, TU Lisbon, Av. Rovisco Pais, 1049-001, Lisbon, Portugal. E-mail: pombeiro@ist.utl.pt; Fax: +351 218464455 w Electronic supplementary information (ESI) available. See DOI: 10.1039/c1cc11696g ChemComm Dynamic Article Links www.rsc.org/chemcomm COMMUNICATION Downloaded by Universidade Tecnica de Lisboa (UTL) on 14 June 2011 Published on 23 May 2011 on http://pubs.rsc.org | doi:10.1039/C1CC11696G View Online