Indian Journal of Chemistry Vol. 44B, November 2005, pp. Hard-soft acid-base (HSAB) principle and difference in d-orbital configurations of metals explain the regioselectivity of nucleophilic attack to a carbinol in Friedel- Crafts reaction catalyzed by Lewis and protonic acids Gautam Panda* 2 , Jitendra K Mishra a , Shagufta a , T C Dinadayalane b , G Narahari Sastry b & Devendra S Negi c a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, UP, India b Molecular Modelling Group, Indian Institute of Chemical Technology, Hyderabad 500 007, AP, India c Department of Chemistry, H N B Garhwal University, Uttaranchal 246174, India E-mail: gautam_panda@lycos.com , bapi.rm@yahoo.com Received 10 December 2004; accepted (revised) 24 June 2005 The alkylations of aromatic compounds in presence of protonic acids yield two alkylated products arising from attack of a nucleophile (hard or soft) at two different carbocation (hard or soft) centers of a single compound. Hybrid density functional theory at B3LYP/6-31G* and B3LYP/6-31G levels and semiempirical calculations are employed to explain the observed trends in Friedel-Crafts reaction. Local HSAB principle based on local softness values explains the observed experimental reactivities. Keywords: HSAB Principle, Friedel-Crafts Alkylation, Regioselectivity IPC: Int.Cl. 7 C 07 The alkylation of aromatic rings, commonly known as Friedel-Crafts (FC) alkylation, is a powerful tool for new carbon-carbon bond formation 1 . It is a reaction between an aromatic ring and substrates such as alkyl halides, olefins, alcohols and many other types of reagents in the presence of Lewis acids or protonic acids 1 . Regardless of which reagent is used, a catalyst is always required 2 . Acidic metal halides, of which AlCl 3 and AlBr 3 are the most frequently used, comprise a large number of Lewis acid catalysts for Friedel-Crafts reactions 3 . Other frequently used active metal halide catalysts include: ZnCl 2 , BF 3 , BCl 3 , BBr 3 , GaCl 3 , GaBr 3 , TiCl 4 , ZrCl 4 , SnCl 4 , SbCl 5 , BiCl 3 and FeCl 3 . Such Lewis acids possess an electron-deficient central atom, capable of accepting electrons from basic substances. A Lewis acid catalyst can interact with reagents containing a functional group having a donor atom with non-bonded pairs of electrons. Depending on the substrates, the reaction gives rise to a positively polarized complex (tight-ion pair) or carbocationic species, which then reacts with the π- donor substrate (aromatic, alkenic or alkynic hydrocarbons). Reactions that are catalysed by metal halides are also catalysed by protonic acids 4 . The most commonly used Bronsted acids are conc. H 2 SO 4 , H 3 PO 4 or PPA and HF. When a suitable Lewis acid halide and protonic acid are combined, conjugate Friedel-Crafts acids are formed, which are, indeed, superacids with a wide range of activity. Anhydrous HF-BF 3 and HCl- AlCl 3 are widely used examples of such acids 4 . The alkylations of arenes with alcohols are of considerable interest and constitute a significant part in the field of Friedel-Crafts alkylations. The relative ease of alkylation with alcohols follows the order: benzyl, allyl > tertiary > secondary > primary > methyl. This is in accord with the knowledge that carbocations rearrange in the direction of primary < secondary < tertiary < benzyl, allyl. In each case either a carbocation or a tight-ion pair is formed from the attacking reagent and the catalyst (Scheme I) 5 . In this study, density functional theory (DFT) based reactivity descriptors have been used to understand site- and regio-selective reactions 7-9 . Several studies have been reported the applicability of local hard-soft acid- base (HSAB) principle in examining the site selectivity in a molecule 9-13 . According to Li-Evans HSAB rule 9 , ROH + Cat. MX n - HX R + - OMX n-1 R + + - OMX n-1 tight ion pair carbocation ROH + Cat. H + R + + carbocation H 2 O R + OH 2 tight ion pair Scheme I