Document downloaded from: http://hdl.handle.net/10251/108670 This paper must be cited as: Aurell, MJ.; González-Cardenete, MA.; Zaragoza, RJ. (2018). A new mechanism for internal nucleophilic substitution reactions. Organic & Biomolecular Chemistry. 16(7):1101-1112. doi:10.1039/c7ob02994b The final publication is available at https://doi.org/10.1039/c7ob02994b Copyright The Royal Society of Chemistry Additional Information Please do not adjust margins Journal Name ARTICLE New mechanism for internal nucleophilic substitution reactions. María J. Aurell, a Miguel A. González-Cardenete, b and Ramón J. Zaragozá*,a Received 00th January 20xx, Accepted 00th January 20xx A new mechanism of the classic internal nucleophilic substitution reactions SNi by means of computational studies in gas-phase, DCM and acetonitrile is reported. Despite the importance of the SNi mechanism, since the mid- DOI: 10.1039/x0xx00000x 1990s this mechanism has remained unexplored. The study has focused mainly on the comparison between the www.rsc.org/ mechanisms postulated to date for the SNi reactions and a new mechanism suggested by us that fits better the experimental observations. The comparative study has been applied to the conversion of ethyl, neopentyl, isopropyl and tert-butyl chlorosulfites into the corresponding alkyl chlorides. This new mechanism occurs through two transition structures. For primary and secondary substrates, the first transition structure is a 6-center syn- rearrangement of the alkanesulfonyl chloride that produces the corresponding olefin by simultaneous expulsion of HCl and SO2. The olefin, HCl and SO2 form a molecular complex. The final syn addition of HCl to the olefin leads to the alkyl chloride with retention of configuration. For tertiary substrates a variation of the previous mechanism is postulated with the intervention of contact ionic pairs. It is of great importance to emphasize that the new mechanism is able to explain some experimental observations such as the presence of olefins in this type of reactions and the low reactivity of some systems such as neopentyl chlorosulfite. Our results pave the way to a new mechanistic perspective in similar reactions which will need further studies and validation. 1-Introduction O H O + A general method for converting alcohols to halides involves R OH Cl S Cl R O S Cl reactions with various halides of nonmetallic elements. Thionyl Cl - chloride, phosphorus trichloride, and phosphorus tribromide Cl 1-5 are the most common examples of this group of reagents. H O Thionyl chloride is often preferable to other reagents due to its + 4 HCl R OSOCl R O S Cl gaseous byproduct (SO2) for simplified purification. The excess of thionyl chloride can also be readily removed by distillation Path I - or evaporation. Organic bases such as pyridine are often added Cl ,SO2 Path II Path III Path IV to the reaction mixture because they provide a substantial + - concentration of chloride ion needed for the final reaction of - R Cl Cl HCl,SO2 the chlorosulfite intermediate. Recently, the use of catalysts SN1 SN2 SNi E such as titanium tetrachloride has been introduced for the stereoretentive chlorination of cyclic alcohols with thionyl R Cl R Cl R Cl chloride.6 However, the reaction also proceeds in the absence racemization inversion retention elimination of either bases or catalysts and under heating conditions. The reaction of alcohols with thionyl chloride initially results in Scheme 1 Simplified mechanism for reaction of alcohol with SOCl2 the formation of a chlorosulfite ester which is transformed 1-6 subsequently into the chloride (Scheme 1). In the first stage, - the alcohol attacks SOCl2 and after expulsion of Cl and deprotonation, a chlorosulfite is formed. The mechanism for this stage is widely accepted and proceeds with retention of a. Departamento de Química Orgánica, Universidad de Valencia, Dr. Moliner 50, 46100 Burjassot, Valencia, Spain. configuration at the carbon bearing the hydroxyl group. b. Instituto de Tecnología Química (UPV-CSIC), Universitat Politècnica de Valencia- The further course of the reaction will depend on both the Consejo Superior de Investigaciones Científicas, Avda. de los Naranjos s/n, 46022 Valencia, Spain. structure of the chlorosulfite and the reaction conditions. The E-mail: [email protected] transformation of the chlorosulfite ester into a chloride, through a nucleophilic substitution, proceeds with † Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x racemization (Path I), inversion (Path II) or retention (Path III) This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 1 Please do not adjust margins Please do not adjust margins ARTICLE Journal Name of configuration at the carbon bearing the sulfite group this mechanism which indeed has not received much 1-12 (Scheme 1). The decomposition of the chlorosulfite may also attention. For example, the SNi mechanism is not explicitly produce an alkene via an elimination mechanism (Path IV) considered in some well-known textbooks. It is also ironic that 4-7, 11 (Scheme 1). Thus, several mechanisms might account for chlorination with SOCl2 is a technique that is covered in most the variety of products formed under different reaction undergraduate organic chemistry textbooks, and is even conditions. performed in some undergraduate teaching laboratories, For example, if racemization occurs, a SN1 mechanism is without mentioning the SNi designation. normally accepted.7In the cases of inversion of configuration, The present paper reports the results of a detailed study, by 7, 9, 11 the suggested mechanism is of SN2 type which may need means of computational studies, of the main mechanistic 7, 12 the assistance of added base such as pyridine. options suggested to date for the SNi reaction (Scheme 2, paths On the other hand, the retention of configuration is achieved A/A’ and B), comparing them with a new postulated mechanistically either through a double inversion in the mechanism (Scheme 2, path C). The study has been applied to 9 presence of nucleophilic solvents or via an internal the conversion of a chlorosulfite ester into an alkyl chloride. 6, 7, 13 nucleophilic substitution (SNi). The reaction of alcohols The new mechanism is able to explain some experimental with thionyl chloride, with retention of configuration at the observations such as the presence of olefins in this type of carbon bearing the hydroxyl group, is not the only case where reactions and the low reactivity of some systems such as a possible SNi mechanism is postulated. For example, the neopentyl chlorosulfite. reactions of certain secondary alcohols with phosgene, PCl5 in liquid SO2, or dry HBr to give halides, whose configurations are the same as those of the starting alcohols, have been classified 2-Results and Discussion 7 as examples of the SNi reaction. In Scheme 2, the three studied routes for the conversion of 14 A recent work of synthesis allowed us to perform a review on alcohol 1 into the corresponding alkyl chloride 3, through a R =H 1,R2 R R 1 2 Cl SO R1 R2 + b R1=CH3,R2=H 2 HCl OH OSOCl c R1,R2=CH3 1 2 Path C Path A Path A' Path B R1 R2 O R1 R2 R1 R2 R1 R2 H S O Cl O OSOCl OSO Cl Cl S TS1 TS1' O TS3 TS2 R1 R1 R1 - - H C C + + + + 2 R CH3C ClSOO CH3C SO2 Cl + 2 HCl SO R2 R2 2 SO2 IN1 (ion pair) IN1' (ion pair) IN2 Molecular complex SO2 - Cl R1 R2 R C 1 SO SO2 2 SO2 H2C CH3C Cl Cl H R2 3 TS4 syn-addition Scheme 2 Transformation of an alcohol to the corresponding chloroalkane via a SNi mechanism. 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins Journal Name ARTICLE chlorosulfite ester 2, by a SNi mechanism with retention of studies using ethyl chlorosulfite (2a) as a primary substrate, configuration at the carbon bearing the hydroxyl group, are isopropyl chlorosulfite (2b) as a secondary substrate, and tert- shown. Path A/A' and B describe current accepted reaction butyl chlorosulfite (2c) as a tertiary substrate. To facilitate mechanisms. Path C is a new alternative suggested by us. reading this article, we use the letters a, b and c when Here, our work demonstrates that path C is a superior referring to primary substrate, secondary substrate and energetically favorable reaction path. tertiary substrate, respectively. In path A/A’, the chlorosulfite ester is converted into the ion Firstly, we make a brief description of the calculations pair IN1/IN1’. This IN1/IN1’ undergoes front-side attack of the previously made in similar systems and then, for each of the - Cl and loss of SO2 to give the alkyl chloride 3 with retention of substrates, the calculations made by us. To this end, the configuration. Lewis and Boozer1,8 proposed a multistep energy and geometry discussion is made initially on the basis ionization mechanism, with the ion-pairs IN1 and IN1’, to of data in gas-phase, and subsequently the effect of solvent is explain the formation of alkyl chloride 3. Cram7 also suggested introduced. To study this effect, the calculations have been that the SNi mechanism involves ion-pair intermediates and carried out in a solvent of high polarity such as acetonitrile that the SNi reaction differs from the SN1 reaction only in the (CH3CN) and in a solvent of medium polarity such as sense that the departing group is complex, and that the anion dichloromethane (DCM) (see 2.2 Computational methods). of the first ion-pair can decompose internally faster than an 2.1 Previous calculations. anion can react at the rear of the carbon undergoing Schreiner, Schleyer and Hill,16 using semiempirical and ab initio substitution.