FULL PAPER DOI: 10.1002/ejoc.201000725 A Novel Approach to the Evaluation of the Importance of Steric and Electronic Effects in S N Ar Reactions: A Computational, Thermodynamic and 1 H and 13 C NMR Study of “Meisenheimer-Type” Adducts in the Benzo[b]thiophene Series Giovanni Consiglio, [a] Barbara Cosimelli, [b] Susanna Guernelli, [a] Camilla Zaira Lanza, [a] Fernando Sancassan,* [c] Domenico Spinelli,* [d] and Marco Stenta [d] Keywords: Reaction mechanisms / Aromatic substitution / Meisenheimer adducts / Sulfur heterocycles The synthetically useful nucleophilic attack on nitrobenzo- [b]thiophenes, a starting point for ring-opening/ring-closure pathways to different heterocyclic systems, has been investi- gated in detail. 3-Nitrobenzo[b]thiophene (9) and 2-nitrob- enzo[b]thiophene (10) react with sodium methoxide in either DMSO or methanol to give the relevant “Meisenheimer- type” adducts 9' and 10', identified by NMR spectroscopy. A UV study indicated that the equilibrium constants for the formation of 9' at 293 K are 10.1 and 40 700 L mol –1 in meth- anol and in DMSO, respectively. Competition reactions showed that the stability constant of 10' is lower than that of 9': accordingly, DFT [B3LYP/6-31+G(d,p)] calculations indi- cate that the formation of 9' is thermodynamically more fav- oured than that of 10' both in the gas phase and in DMSO. The reason for the opposite sequence in the stability con- stants previously found for the corresponding gem-dimeth- oxy Meisenheimer adducts 7' and 8' was therefore investi- gated in depth and appears to be a consequence of different steric interactions in the starting compounds, 2-methoxy-3- Introduction The flexible chemical behaviour of thiophene-based ring systems is an everlasting and fascinating research field. [1] In particular, nucleophilic attack on nitro-activated thiophenes and benzo[b]thiophenes can lead to ring-opening/ring-clo- sure processes affording different hetero- and homocycles with decorations hardly obtainable in a “straightforward” approach. Amine attack on 3,4-dinitrothiophene [2a,2b] leads [a] Dipartimento di Chimica Organica “A. Mangini”, via San Giacomo 11, 40126 Bologna [b] Dipartimento di Chimica Farmaceutica e Tossicologica, via Montesano 49, 80131 Napoli [c] Dipartimento di Chimica e Chimica Industriale, via Dodecaneso 31, 16146 Genova, Italy Fax: +39-0103536118 E-mail: fernando.sancassan@unige.it [d] Dipartimento di Chimica “G. Ciamician”, via Selmi 2, 40126, Bologna, Italy Fax: +39-0512099456 E-mail: domenico.spinelli@unibo.it Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201000725. Eur. J. Org. Chem. 2010, 5807–5816 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim View this journal online at wileyonlinelibrary.com 5807 nitro-(7) and 3-methoxy-2-nitrobenzo[b]thiophene (8), respectively. A study of 13 C NMR chemical shift changes ac- companying the formation of adducts 9' and 10' confirms that the formation of the adduct exhibiting the larger stability constant is accompanied by a smaller π electron density re- distribution, as we have previously found in other cases all governed by electronic effects. The opposite behaviour is ob- served in the formation of the gem-dimethoxy adducts 7' and 8', which is a consequence of the predominance of steric ef- fects. Further outcomes of more general interest deal with the aromatic character of benzo[b]thiophenes. NMR spectro- scopic data and calculated bond lengths show that in the studied reactions the benzene ring, unlike the thiophene one, is scarcely affected by methoxide addition, retaining its nearly “full” aromatic character. Benzocondensation in- creases the stability constants of σ-adducts mainly because of a marked reduction in the aromatic character of the thio- phene ring in the substrates. to ring-opening products (with extrusion of hydrogen sul- fide) exhibiting broad synthetic usefulness. [2] Conversely, 2- nitrothiophene, [2j] 3-nitrothiophene [1g] and 3-nitrobenzo[b]- thiophene [1h] react with amines in the presence of silver ni- trate to give ring-opening products with retention of the sulfur, which can easily be alkylated. In particular, the ring- opening product of 3-nitrobenzo[b]thiophene is an interest- ing building block for the synthesis of several different het- erocyclic systems, such as thiochroman S,S-dioxides, [2e] γ- lactams, [2f] indoles [2g] and pyrrolidinone oxazines. [2h] Several of the above-mentioned compounds have revealed analge- sic, anti-exudative, and anti-inflammatory activities, [3a,3b] whereas in other cases their mutagenic [3c–3e] or polaro- graphic behaviour [3f–3h] has been investigated in depth. All the synthetically useful ring-opening/ring-closure protocols starting from 3-nitrobenzo[b]thiophene exhibit as their first steps a nucleophilic attack on the fused thiophene ring. We therefore decided to investigate nucleophilic attack on nitrobenzo[b]thiophenes, through a detailed study of the relevant “Meisenheimer-type” adducts.