A pragmatic procedure for predicting regioselectivity in nucleophilic substitution of aromatic fluorides Magnus Liljenberg a , Tore Brinck b,⇑ , Björn Herschend c , Tobias Rein c , Glen Rockwell c , Mats Svensson d,⇑ a AstraZeneca, Sweden Operations, S-151 85 Södertälje, Sweden b Physical Chemistry, School of Chemical Science and Engineering, KTH—Royal Institute of Technology, S-100 44 Stockholm, Sweden c AstraZeneca R&D, Pharmaceutical Development, S-151 85 Södertälje, Sweden d AstraZeneca R&D, Medicinal Chemistry, S-151 85 Södertälje, Sweden article info Article history: Received 1 March 2011 Revised 29 March 2011 Accepted 8 April 2011 Available online 15 April 2011 Keywords: Nucleophilic substitution Regioselectivity Computational r-Complex DFT abstract The scope and limitations of a method for predicting the regioisomer distribution in kinetically controlled nucleophilic substitution reactions of aromatic fluorides have been investigated. This method is based on calculating the relative stabilities of the isomeric r-complex intermediates using DFT. A wide set of sub- strates and anionic nucleophiles have been investigated. Predictions from this method can be used quan- titatively—these agree to an average accuracy of ±0.5 kcal/mol with experimental observations in eleven of the twelve investigated reactions. Ó 2011 Elsevier Ltd. All rights reserved. When novel synthetic routes to a target molecule are designed, one key part of the work-flow is the prioritization of which route alternatives (‘paper routes’) to first evaluate experimentally. Pre- dictive computational methods can aid this prioritization by pro- viding an estimate of the levels of product selectivity that can be expected in key transformations. For such methods to be useful practically there has to be a suitable balance between accuracy and throughput—sufficient accuracy has to be obtainable with a reasonable amount of computational resource and minimal man- ual input. We are investigating the possibilities for using computa- tional chemistry for semi-quantitative predictions of different useful synthetic reaction types. Our computational approach is de- signed to assist the synthetic planning, on a daily basis, by answer- ing questions such as: will this reaction give predominantly the desired product, or an undesired product isomer, or is the outcome uncertain? We recently reported a method for predicting product isomer ratios in electrophilic aromatic substitution reactions. 1 In this Letter, we report how a similar approach can be applied to pre- dict the outcome of certain types of nucleophilic aromatic substitu- tion reactions. There are several mechanisms by which net nucleophilic aromatic substitution can occur. It can proceed through a unimolecular S N 1 reaction via aryl diazonium ions, 2 or via an elimination–addition mechanism that involves the formation of a benzyne (dehydrobenzene) intermediate. 3 Another possible mechanism is via transition metal catalyzed substitution, for example with copper 4 or palladium catalysts. 5,6 The mechanism can also proceed via a two-step addition–elimination mechanism, where the active nucleophile is added to a substituted aromatic carbon atom, followed by departure of the leaving group. The inter- mediate containing both the nucleophile and the leaving group is known as a Meisenheimer complex or r-complex. This is the type of nucleophilic aromatic substitution reaction, S N Ar, we have focused on in this study. 7,8 A number of theoretical studies have been carried out over the years to give reactivity indices for the different positions in sub- strates of S N Ar reactions. Among the earlier ones is the I p -repulsion theory based on calculating the fractional charge with Hückel the- ory, 9,10 and an approach based on the Frontier Molecular Orbital method. 11 More recent attempts include calculations based on Fu- kui indices, 12 local softness and hardness reactivity descriptors, 13 and dual descriptors for both electrophilicity and nucleophilicity. 14 Many of these methods are quite successful in making qualitatively correct predictions of the selectivity pattern in S N Ar reactions. However, none of these methods has proven suitable for quantita- tive predictions of isomer distributions since the structure and sol- vation of the transition state are not taken into account. One way to make quantitative predictions of the selectivity pattern in S N Ar reactions is obviously to calculate the potential energy profile in each case, including the transition states, and theoretical investiga- tions of the potential energy profile in vacuo have recently been 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.04.032 ⇑ Corresponding authors. E-mail addresses: tore@physchem.kth.se (T. Brinck), mats.a.svensson@astraze- neca.com (M. Svensson). Tetrahedron Letters 52 (2011) 3150–3153 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet