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Article: Li, D. orcid.org/0000-0002-5329-4298 and Williams, N.H. (2016) The solvolysis mechanism of simple secondary tosylates in 50% aqueous TFE. Journal of Physical Organic Chemistry, 29 (12). pp. 709-717. ISSN 1099-1395 https://doi.org/10.1002/poc.3559

This is the pre-peer reviewed version of the following article: Li, D., and Williams, N. H. (2016) The solvolysis mechanism of simple secondary tosylates in 50% aqueous TFE. J. Phys. Org. Chem, which has been published in final form at http://dx.doi.org/10.1002/poc.3559. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-828039.html).

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[email protected] https://eprints.whiterose.ac.uk/ Journal of Physical Organic Chemistry

The solvolysis mechanism of simple secondary tosylates in 50% aqueous TFE

Journal:For Journal Peer of Physical Organic Review Chemistry Manuscript ID Draft

Wiley - Manuscript type: Special Issue Article

Date Submitted by the Author: n/a

Complete List of Authors: Williams, Nicholas; University of Sheffield, Chemistry Li, Dian; University of Sheffield, Chemistry

Keywords: solvolysis, Isotope exchange, , 1,2-hydride transfer

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1 1 2 3 4 The solvolysis mechanism of simple secondary 5 ✟✟✟ 6 7 tosylates in 50% aqueous TFE 8 9 10 11 12 Dian Li and Nicholas H. Williams* 13 14 Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, United Kingdom

15 * 16 E-mail: [email protected] 17 18 For Peer Review 19 20 Abstract 21 22 The solvolysis of simple secondary tosylates in 50% trifluoethanol has been investigated 23 24 using stereochemical and isotopic labels. 2-butyl, 2-pentyl and 2-octyl tosylate all solvolyse 25 26 at very similar rates (~ 1 ììì 10-5 s-1) at 30 . Slow racemization of S-2-butyl tosylate (~ 4.6 ììì 27 ℃℃℃ 28 29 10-7 s-1) was observed during solvolysis, but R-2-octyl tosylate did not show any significant 30 31 racemization. Competing rearrangement of 3-pentyl tosylate to 2-pentyl tosylate was 32 33 34 observed during solvolysis and is attributed to 1,2-hydride transfer, which occurs at a rate 35 36 sufficient to account for the difference in the rates of racemisation of 2-butyl and 2-octyl 37 38 tosylate. The stereochemistry of the product was studied for the reaction of R-2- 39 40 41 octyl tosylate by derivatizing the corresponding alcohol to 4-nitrobenzoate, and showed 42 43 high but not complete stereoselectivity (92:8 inversion:retention of configuration). 18O 44 45 46 isotope exchange at the leaving group tosylate showed that both 2-butyl and 2-octyl 47 48 tosylates exchange at similar rates (~ 1.6 ììì 10-7 s-1). Partitioning of a common intermediate 49 50 carbenium cannot account for all these data, so a series of parallel concerted 51 52 53 mechanisms (solvolysis, 1,2-hydride transfer and isotope exchange) is proposed as the best 54 55 explanation. 56 57 58 Keywords: Solvolysis; Carbocation; Isotope exchange; 1,2hydride transfer 59 60 1 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 2 of 41

2 1 2 3 4 INTRODUCTION 5 6 Whether simple secondary carbenium can be formed as intermediates in polar but weakly 7 8 9 nucleophilic or not has been the subject of debate for a long time. No clearcut 10 11 conclusion has been reached despite a series of mechanistic studies with 2propyl and 2butyl 12 13 substrates.1,2,3,4 14 15 3 4 6 16 Tidwell , Dannenberg and Farcaşiu studied the solvolysis of 2butyl tosylate in trifluoroacetic 17 18 acid (TFA). As a 1,2 hydrideFor shift Peer was observed durReviewing the reaction, these authors all agreed that 19 20 a simple secondary substrate in TFA should react by a stepwise substitution mechanism with a 21 22 23 true intermediate rather than through a concerted pathway. However, they did not reach a 24 25 consensus on whether the intermediate was a bridged cation or an “open” carbenium ion. 26 27 Furthermore, the reaction in TFA is complicated by the reversible addition of trifluoroacetate and 28 29 30 tosylate to the alkene product that also forms. 31 32 On the other hand, Dietze1 correlated the rates of reaction of 2propyl nosylate in pure 33 34 35 hexafluoroisopropanol (HFIP) with different against the same reactions with methyl 36 37 iodide. Since the second order rate constant for HFIP was on the same straight line generated by 38 39 other nucleophiles known to react by SN2 mechanisms for both substrates, the solvolysis of 2 40 41 42 propyl substrates in HFIP was proposed to follow the same mechanism. A change in mechanism 43 44 would be expected to give a positive deviation from the correlation. 45 46 Jencks and Dietze2 had previously applied the same correlation method to the solvolysis reaction 47 48 1 49 of 1(4nitrophenyl)2propyl derivatives in trifluoroethanol (TFE) and water/TFE mixtures . 50 51 Their conclusion was that these simple secondary substrates react through a concerted solvolysis 52 53 pathway, even in these weakly nucleophilic solvents, with an “open” transition state. The 54 55 56 57 58 59 60 2 http://mc.manuscriptcentral.com/poc Page 3 of 41 Journal of Physical Organic Chemistry

3 1 2 3 mechanistic pathway was described as a forced uncoupled concerted mechanism5 with a 4 5 6 transition state that has similar properties to a true carbenium intermediate. 7 8 Thus, the evidence for either mechanism is not unambiguous and compelling, so we have 9 10 11 investigated this reaction in 50% aqueous TFE by studying of the stereochemistry of both 12 7 13 starting material and solvolysis products, and through selective isotope labelling in the tosylate 14 15 group. Overall, the mechanism of solvolysis of secondary tosylates in 50% TFE is best regarded 16 17 1,2 18 as a concerted pathwayFor without forming Peer a discrete Review intermediate. The changes in 19 20 stereochemistry and labeling that apparently signal an intermediate (carbenium) species are best 21 22 explained through competing concerted pathways. 23 24 25 EXPERIMENTAL SECTION 26 27 28 General 29 30 The alkyl tosylates, 4nitrobenzoate and 18O labeled tosyl chloride were synthesized as 31 32 33 described below. All other chemicals were purchased from SigmaAldrich, Alfa Aesar, Acros 34 35 Organics or Santa Cruz Biotechnology. TFE was distilled from P2O5 and stored over 4Å 36 37 molecular sieves. UHQ water was obtained from an ELGA PURELAB Option SR 715 system. 38 39 40 All other chemicals were used directly without further purification. 41 42 1H NMR and 13C NMR spectra were recorded on Bruker AVHD 400 and AVHD 500 43 44 45 instruments. HPLC analysis to monitor reaction progress was carried out on a Waters 2690 (486 46 47 Tunable Absorbance Detector) and 2695 (2487 Dual λ Absorbance Detector) system with a 48 49 Waters C8 column and UV detection at 265 nm. A gradient elution was used, changing from 95% 50 51 52 water (containing 0.1% TFA) and 5% acetonitrile to 5% water (containing 0.1% TFA) and 95% 53 54 acetonitrile over 20 mins followed by a further 10 mins of the final eluent mixture. Chiral HPLC 55 56 analysis of the reactants and alcohol derivatives was recorded on a Gilson 805 manometric 57 58 59 60 3 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 4 of 41

4 1 2 3 model (Gilson 811B Dynamic Mixer, Gilson 305 + 306 Pump and Applied Biosystems 757 4 5 ® 6 Absorbance Detector) with a Phenomenex Cellulose2 chiral column and UV detection at 226 7 8 nm (for tosylates) and 265 nm (for 4nitrobenzoates). The eluent for tosylate substrates was 12% 9 10 11 isopropanol88% hexane with a flow rate 0.8 mL/min, except for 2octyl tosylate where 1% 12 13 isopropanol99% hexane was used with a flow rate of 1.0 mL/min. For 4nitrobenzoate, 0.3% 14 15 isopropanol99.7% hexane was used with a flow rate 1.0 mL/min. GC analysis of 2butanol, 2 16 17 18 octanol and 2octene wasFor determined Peer with a Perkin Review Elmer ARNEL Auto System XL GC model. 19 20 2butanol was analysed isothermally at 40 with a split ratio of 20. 2octanol and 2octene were 21 ℃ 22 analysed isothermally at 90 with a split ratio of 20. 23 ℃ 24 25 Syntheses 26 27 2-butyl tosylate was synthesised following a published procedure8. 0.74 g (10 mmol) 2butanol 28 29 30 was dissolved in 10 mL anhydrous pyridine in an icewater bath. 2.29 g (12 mmol) tosyl chloride 31 32 was added portion wise within 10 mins. The solution was stirred in the icewater bath for another 33 34 6 hrs before quenching with cold 3 M HCl solution (25 mL). After extracting with DCM (25 mL), 35 36 37 the organic phase was washed with another 25 mL of 3 M HCl and the water phase was extracted 38 39 with DCM (3 ì 5 mL). The combined organic phase was washed with saturated NaHCO3 and 40 41 42 dried over Na2SO4 before removing the under vacuum. The crude product was purified 43 44 by flash chromatography using hexane: ethyl acetate (4:1), yielding 1.59 g (70%) of 2-butyl 45 46 1 tosylate as a colourless oil. H NMR (400 MHz, CDCl3): 7.81 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J 47 48 49 = 8.7 Hz), 4.51 – 4.60 (1H, m), 2.48 (3H, s), 1.52 – 1.78 (2H, m), 1.35 (3H, d, J = 6.5 Hz) and 50 13 51 0.82 (3H, t, J = 7.5 Hz). CNMR (100 MHz, CDCl3): 144.37, 134.64, 129.70, 127.70, 81.79, 52 53 29.48, 21.62, 20.30 and 9.30.8,9 54 55 56 57 58 59 60 4 http://mc.manuscriptcentral.com/poc Page 5 of 41 Journal of Physical Organic Chemistry

5 1 2 3 S-2-butyl tosylate (ee 91%), 2-pentyl tosylate, 3-pentyl tosylate, 2-octyl tosylate and R-2- 4 5 8 6 octyl tosylate (ee 99.5%) were all synthesized by the same procedure and purified by flash 7 8 chromatography with the same eluent as above. 9 10 9 1 11 2-pentyl tosylate : 65% yield as a colourless oil. H NMR (400 MHz, CDCl3): 7.81 (2H, d, J = 12 13 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz), 4.59 – 4.74 (1H, m), 2.48 (3H, s), 1.51 – 1.76 (2H, m), 1.35 14 15 13 (3H, d, J = 6.6 Hz) and 0.67 (3H, t, J = 7.4 Hz). CNMR (100 MHz, CDCl3): 144.33, 134.74, 16 17 18 129.66, 127.67, 80.36,For 38.63, 21.56, Peer 20.76, 18.14 Review and 13.58. 19 10,11 1 20 3-pentyl tosylate : 50% yield as a colourless oil. H NMR (400 MHz, CDCl3): 7.81 (2H, d, J 21 22 = 8.3 Hz), 7.34 (2H, d, J = 8.2 Hz), 4.42 – 4.73 (1H, m), 2.47 (3H, s), 1.67 – 1.80 (4H, m) and 23 24 13 25 0.85 (3H, t, J = 7.4 Hz). CNMR (100 MHz, CDCl3): 144.30, 135.16, 129.66, 128.67, 66.84, 26 27 21.56, 20.26 and 11.08. 28 29 R-2-octyl tosylate12,13: 60% yield as a colourless oil. 1H NMR (400 MHz, CDCl ): 7.79 (2H, d, 30 3 31 32 J = 8.7 Hz), 7.35 (2H, d, J = 8.8 Hz), 4.52 – 4.67 (1H, m), 2.46 (3H, s), 1.65 – 1.08 (15H, m) and 33 13 34 0.85 (3H, t). CNMR (100 MHz, CDCl3): 144.33, 134.71, 129.66, 127.70, 80.67, 36.49, 31.57, 35 36 37 28.78, 24.80, 22.45, 21.57, 20.84 and 13.99. 38 39 2-octyl-4-nitrobenzoate: After the solvolysis reaction of R2octyl tosylate was complete (at 40 41 least 7 halflives), the TFE was removed under vacuum and the aqueous solution extracted with 42 43 44 30 mL diethyl ether. After washing with brine, the ether solution was concentrated under vacuum 45 46 and the residue dissolved in 10 mL DCM charged with 2 eq DMAP in a waterice bath. 1.5 47 48 equivalents of 4nitrobenzoyl chloride was added portion wise within 5 mins and the reaction 49 50 51 was kept in the ice bath for 2 hrs before slowly warming to room temperature. The mixture was 52 53 stirred at room temperature overnight before the solvent was removed under vacuum. The 54 55 residue was dissolved in 1.5 mL hexane and diluted to a suitable concentration for chiral HPLC 56 57 58 59 60 5 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 6 of 41

6 1 2 3 analysis. HPLC analysis gave two peaks with retention times of 20.2 and 22.1 minutes in a ratio 4 5 6 of 92:8 that correspond to the 4nitrobenzoate enantiomers as determined by analysis of racemic 7 8 2octyl4nitrobenzoate by the same method. 9 10 18 14 11 O-tosyl chloride was synthesis by modifying a published procedure . To a 100 mL round 12 13 bottom flask charged with 30 mL anhydrous acetonitrile, 1.86g (15 mmol) pthiocresol and 1 mL 14 15 18 H2 O (97% isotope labelled, Santa Cruz Biotechnology) was added and stirred in an icewater 16 17 18 bath for 15 mins. 4.18gFor (18 mmol) Peer trichloroisocyanu Reviewric acid was added portionwise to the 19 20 cooled solution within 15 mins and the reaction was kept at 0 for 1 h, then allowed to warm to 21 ℃ 22 room temperature and stirred overnight before removing the solvent under vacuum. 30 mL 23 24 25 diethyl ether was added and the mixture shaken violently. The solid was filtered off and washed 26 27 with 5 ì 2 mL diethyl ether; the combined filtrate was concentrated under vacuum to afford 2.86 28 29 18 18 30 g (14.7 mmol) of the O-tosyl chloride (98%). The extent of labelling by O was been 31 32 determined by GCMS which showed that the tosyl chloride contained 93.5% doubly labelled 33 34 18Otosyl chloride and 6.5% singly labelled 18Otosyl chloride. The crude 18Otosyl chloride was 35 36 37 used to synthesise the tosylate immediately it was isolated, using the same synthetic and 38 39 purification methods described above. 40 41 Kinetic analysis 42 43 44 The solvolysis reactions of all the tosylate esters were carried out under the same conditions: 5 45 46 mM tosylate, 5 mM 2,6dimethyl pyridine, 1 mM 2,6dimethyl3hydroxy pyridine (as an 47 48 internal standard) and 1 M sodium perchlorate in 50% aqueous TFE (v/v) at 30 . The solutions 49 ℃ 50 51 were immersed in a thermostated water bath, and the progress of the reactions was monitored by 52 53 analyzing aliquots of the reactions mixture using HPLC as described above for 72 hrs. The peak 54 55 56 57 58 59 60 6 http://mc.manuscriptcentral.com/poc Page 7 of 41 Journal of Physical Organic Chemistry

7 1 2 3 areas in the chromatograms were integrated and a first order equation fit to these data; in all 4 5 2 6 cases, R > 0.99. 7 8 Stereochemical analysis 9 10 S 11 2- -butyl tosylate (100 mM and 10 mM; initial ee 91%): At various time intervals, an 12 13 appropriate volume of the reaction mixture (100 or 10 mM 2Sbutyl tosylate; 1.2 equivalents 14 15 2,6dimethylpyridine; 1 M sodium perchlorate) was withdrawn and extracted with hexane. As 16 17 18 the reaction proceeded,For increasing Peer volumes of the Review solution were required to ensure sufficient 19 20 reactant was present for the analysis. The hexane layer was analyzed directly by chiral HPLC to 21 22 measure the ratio of the tosylate enantiomers, and by chiral GC to measure the ratio of the 2 23 24 25 butanol enantiomers. Solutions with varying concentrations of tosylate anion present (5 mM 2S 26 27 butyl tosylate; 6 mM 2,6dimethylpyridine; 0.1, 0.5 or 1.0 M sodium tosylate, with the total salt 28 29 concentration made up to 1 M with sodium perchlorate; 1 M 15crown5) were analysed the 30 31 32 same way. 33 34 2-R-octyl tosylate (5 mM (initial ee 99.5%); 6 mM 2,6dimethylpyridine; 1 M sodium 35 36 37 perchlorate) was analysed as above to determine the stereochemical changes in the reactant as 38 39 the reaction progressed. To monitor the stereochemical changes in the alcohol product 2Roctyl 40 41 tosylate (10 mM; 12 mM 2,6dimethylpyridine; 1 M sodium perchlorate) was allowed to proceed 42 43 44 to completion (7 half lives), and the 2octanol isolated as above and converted to 4nitrobenzoate 45 46 ester before being analyzed by chiral HPLC. 47 48 Isomerisation of 3-pentyl tosylate and 2-pentyl tosylate: At various time intervals, an 49 50 51 appropriate volume of the reaction mixture was withdrawn and extracted with hexane, which was 52 53 directly analyzed by chiral HPLC. The signals for 3pentyl tosylate and both enantiomers of 2 54 55 56 57 58 59 60 7 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 8 of 41

8 1 2 3 pentyl tosylate were completely resolved in the chromatogram, and the ratio was determined by 4 5 6 integrating these peaks. 7 8 Product analysis 9 10 13 11 The products from the solvolysis of 2butyl tosylate and 2pentyl tosylate were analyzed by C 12 13 NMR. These reactions was carried out in 1:1 TFE:D2O (v/v), with all other conditions the same 14 15 as for the kinetic measurements. The ratio of the alcohol and ether products were measured by 16 17 18 integrating peaks for theFor carbon atPeer position 2. The Review products from the solvolysis of 2octyl 19 20 tosylate were directly analyzed by GC, using authentic 2octene and 2octanol as external 21 22 standards to calibrate the yield of respective products. 2octene was observed as a mixture of E/Z 23 24 25 isomers, but 1octene was not detected. 26 27 Product stability 28 29 When 2octene was incubated under the solvolysis conditions (10 mM in 50% aqueous TFE with 30 31 32 20 mM pyridinium tosylate, 10 mM 2,6dimethyl pyridine and 1 M sodium perchlorate) for 5 33 34 days and then analysed by GC, no new peaks could be identified. When R2octanol was 35 36 37 incubated under the solvolysis conditions (10 mM in 50% aqueous TFE with 20 mM pyridinium 38 39 tosylate, 10 mM 2,6dimethyl pyridine and 1 M sodium perchlorate) for 2 weeks, then 40 41 derivatized to the 4nitrobenzoate ester, chiral HPLC analysis showed the ee had not changed. 42 43 18 7 44 O isotope exchange analysis 45 46 18 18 47 O-labelled-2-butyl tosylate (5 mmol) and O-labelled-2-octyl tosylate (5 mmol) were 48 49 individually subjected to solvolysis under the conditions described above (with an initial reactant 50 51 concentration of 10 mM). At different time intervals, an appropriate volume of solution (to be 52 53 54 able to extract about 50 mg of the unreacted tosylate) was withdrawn and extracted with diethyl 55 56 ether. The organic layer was separated and dried over Na2SO4 and the solvent removed under 57 58 59 60 8 http://mc.manuscriptcentral.com/poc Page 9 of 41 Journal of Physical Organic Chemistry

9 1 2 3 vacuum. The residues were combined and dissolved in 1 ml CDCl and analysed by 13C NMR at 4 3 5 6 125 MHz (pulse angle 45°, 10000 transients at 25 °C acquired with a 250 Hz sweep width, 8000 7 8 data points (0.031 Hz/pt) and a 16s relaxation delay time) to determine the relative 9 10 18 13 11 concentrations of tosylate esters with O in the bridging and nonbridging positions. The C 12 13 signals at the 2position were centred at 81.8 (2butyl tosylate) and 80.8 (2octyl tosylate) ppm, 14 15 respectively. The peaks were sufficiently resolved (0.045 ppm difference) to allow the ratio of 16 17 13 18 16 18 C bonded to O or ForO to be calculated Peer by integration Review of the signals. 19 20 21 RESULTS 22 23 The first order rate constants for solvolysis of 2butyl tosylate, 2pentyl tosylate and 2octyl 24 25 5 1 5 1 5 1 26 tosylate are 1.15±0.05 ì 10 s , 1.05±0.05 ì 10 s and 1.20±0.0.06 ì 10 s respectively (at 27 28 30 in 50% aqueous TFE). Within experimental error, these secondary tosylates all solvolyse at 29 ℃ 30 31 the same rate whereas 3pentyl tosylate reacts about twice as fast and has a rate constant for 32 33 solvolysis of 1.95±0.05 ì 105 s1, consistent with earlier reports.15 34 35 The substitution products from solvolysis of 2butyl tosylate are 2butanol and 2trifluoroethoxy 36 37 38 butyl ether in a ratio of 5:1. As the molar ratio of water to TFE in the reaction mixture is about 39 40 4:1, the selectivity for water over TFE is about 1.25:1, which is slightly larger than a simple 41 42 16 43 tertiary substrate solvolysis or a secondary substrate by a concerted pathway with a cationlike 44 5 45 transition state . Under our reaction conditions, potential elimination products could not be 46 47 identified with confidence due to their volatility. GC analysis of the solvolysis products of 2 48 49 50 octyl tosylate, where the potential elimination products are less volatile, showed that the ratio of 51 52 alcohol:trifluoroethyl ether:2octene is about 5:1:4. The yield of each product was deduced by 53 54 using authentic samples (2octanol and 2octene) to calibrate the instrument, and demonstrated a 55 56 57 mass balance. Thus, the solvolysis reaction under neutral condition still produced a significant 58 59 60 9 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 10 of 41

10 1 2 3 amount of elimination products. Both E and Z isomers (E:Z about 4:1) of 2octene were observed, 4 5 6 but 1octene was not detected. 7 8 During the solvolysis of 0.01 M S2butyl tosylate in 50% aqueous TFE, partial racemization of 9 10 11 the reactant occurred, with an observed first order rate constant for racemization of 4.6±0.1 ì 10 12 13 7 s1 (Figure 1A), corresponding to a first rate constant of 2.3±0.1 ì 107 s1 for the 14 15 16 interconversion of the enantiomers. 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Figure 1. A: Change in the ratio [R2butyl tosylate] / [2butyl tosylate] with reaction time when the 34 initial concentration of reactant is 0.01 M. The solid line is the best fit of the equation [R2butyl tosylate] 35 / [2butyl tosylate] = 0.5 – 0.455ekt with k = 4.6±0.1 ì 107 s1 B: Variation in observed rate constant for 36 racemization with concentration of tosylate. The solid line is the linear least squares fit, and has the 37 7 6 1 38 equation 4.2±0.1 ì 10 + 3.8±0.2 ì 10 [tosylate] s . 39 40 This could be due to reaction between the reactant and the tosylate leaving group (generated in 41 42 the course of the reaction), inverting the stereogenic centre in the reactant. To quantify its 43 44 45 significance, the tosylate anion concentration was varied from 0.1 to 0.5 M (in the presence of 1 46 47 M 15crown5 to avoid ion pairing at high concentrations). The racemization rate increased 48 49 linearly over this concentration range (Figure 1B), giving a second order rate constant of 3.8±0.2 50 51 6 1 1 52 ì 10 M s , which corresponds to a second order rate constant of for the substitution 1.9±0.1 ì 53 54 106 M1 s1 reaction. 55 56 57 58 59 60 10 http://mc.manuscriptcentral.com/poc Page 11 of 41 Journal of Physical Organic Chemistry

11 1 2 3 In contrast, R2octyl tosylate only generated ~1% S2octyl tosylate after 72 hrs reaction 4 5 8 1 6 (corresponding to a first rate constant for racemisation of ~3.9 ì 10 s ). 7 8 During the solvolysis of 3pentyl tosylate, 2pentyl tosylate appears transiently in the reaction 9 10 11 mixture. This can be explained by the occurrence of a 1,2 hydride shift mechanism (scheme 1). 12 13 By measuring the ratio of [2pentyl tosylate] : [3pentyl tosylate] at different time intervals and 14 15 using numerical integration (Berkeley Madonna®) to fit scheme 1 to these data, k‘ (the 1,2 16 H 17 7 1 18 hydride transfer rate constant)For was Peer evaluated as ~9Review ì 10 s . Scheme 1 assumes that hydride 19 20 transfer to the C3 position in 3pentyl tosylate is twice as fast as to the C2 position in 2pentyl 21 22 23 tosylate for statistical reasons. 24 25 2k'H OTs 26 27 k' 28 OTs H 29 30 k' ~2k' S 31 S 32 33 solvolysis solvolysis 34 35 36 Scheme 1 37 38 After solvolysis of R2octyl tosylate, 2octanol was isolated and derivatized to the 39 40 corresponding 4nitrobenzoate ester to allow analysis by chiral HPLC using UV detection. The 41 42 43 ratio of retention to inversion at the stereogenic carbon is 8:92. This is much greater than the 44 45 fraction of reactant inversion noted above and represents the facial selectivity in the 46 47 48 reaction. 49 18 50 During the solvolysis of O labelled 2butyl tosylate and labelled 2octyl tosylate, scrambling of 51 52 the isotopically labeled positions was detected by 13C NMR analysis of the residual reactant 53 54 55 (Figure 2). The extent of scrambling was similar in both cases (~8% after 4 half lives), indicating 56 18 57 similar O scrambling rate constants (ki Scheme 2); the ratio of the two isotopomers at various 58 59 60 11 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 12 of 41

12 1 2 3 7 1 4 time intervals is given in table 1. Fitting with a first order equation gives ki = 5.4±0.3 ì 10 s 5 7 1 6 for 2butyl tosylate, and ki = 4.2±0.2 ì 10 s for 2octyl tosylate. 7 8 18 9 18O O18 O O 10 S 2k 18 S 11 O i O 12 k R 13 R i 14 15 k'S 16 k'S R = methyl or n-pentyl 17 18 For Peer Reviewsolvolysis 19 solvolysis 20 21 Scheme 2 22 23 Table 1. Results of isotope exchange for labelled 2butyl tosylate and labelled 2octyl tosylates 24 18 16 18 16 25 Time/s C O:C O C O:C O 26 0 0:100 0:100 27 57600 1.6:98.4 1.2:98.8 28 29 144000 4.6:95.4 3.8:96.2 30 239400 8.5:91.5 6.6:93.4 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Figure 2. 13C NMR spectrum of labelled 2butyl tosylate and 2octyl tosylate recovered after 66.5 hours 53 54 55 56 57 58 59 60 12 http://mc.manuscriptcentral.com/poc Page 13 of 41 Journal of Physical Organic Chemistry

13 1 2 3 DISCUSSION 4 5 6 Classical signs of the capacity of a secondary tosylate to form a stable carbenium ion 7 8 intermediate are: the loss of stereochemical integrity at the stereogenic centre; that the non 9 10 equivalent oxygens in the tosylate group can exchange position; and that substitution of the 11 12 13 tosylate does not occur with complete inversion of configuration. These observations are all 14 15 apparent in the data reported here. The products of the reaction are stable under the reaction 16 17 conditions, and neither revert to reactant nor change their stereochemistry once formed, unlike 18 For Peer Review 19 3,4,6 20 solvolysis in TFA. Thus, these observations must be explained by the mechanistic pathway of 21 22 the solvolysis reaction. 23 24 25 Racemisation of both 2butyl and 2octyl tosylate is observed under the solvolysis conditions. It 26 27 is possible that tosylate released in the course of the reaction can act as a competitive 28 29 and invert the stereochemistry of the reactant. This process would also provide a route for 30 31 32 scrambling of the isotopic label in the alkyl tosylate. Measuring the rate of reaction between 33 34 tosylate and 2butyl tosylate gives a second order rate constant of 1.9±0.1 ì 106 M1 s1 for the 35 36 37 bimolecular substitution reaction. If this figure is combined with the rate of solvolysis, the 38 39 fraction of the minor enantiomer can be calculated from equation 1 40 41 42 [ ] ) (1) 43 [ ] = 0.5 − (−2 [ ]( − ) 44 45 in which kN is the second order rate constant for the incorporation of tosylate from solution, k‘S is 46 47 the rate constant for solvolysis, [A]0 is the initial concentration of the reactant, and ee is the 48 49 50 initial enantiomeric excess. Over 72 hours, equation 1 predicts that the remaining substrate from 51 52 10 mM R2octyl tosylate (initially 0.25% S) will contains ~0.6% S, close to the observed vaue 53 54 of ~1%. However, for 10 mM S2butyl tosylate (initially 4.5% R), the prediction is that the 55 56 57 remaining substrate will contains 4.8% R, significantly different from the observed value of ~10% 58 59 60 13 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 14 of 41

14 1 2 3 R. It is evident that a significant additional pathway for racemization is required for 2butyl 4 5 6 tosylate. 7 8 A second process that can lead to racemization is a 1,2 hydride shift, coupled with 1,2 leaving 9 10 11 group migration. In 2butyl tosylate, each migration still gives 2butyl tosylate but can lead to a 12 13 change in stereochemistry. In 2octyl tosylate, racemization requires two migrations – to the 3 14 15 position, then back to the 2 position. The rate constant for the 1,2 migration between secondary 16 17 18 centres was measured Forby studying Peer the simultaneous Review solvolysis and isomerization of 3pentyl 19 20 tosylate. As 2pentyl tosylate is significantly less reactive than 3pentyl tosylate to solvolysis, 21 22 and because the rate of isomerization to the 2pentyl tosylate is benefits from a statistical factor 23 24 25 of 2, appreciable concentrations of 2pentyl tosylate accumulate in the reaction mixture. Analysis 26 27 of this accumulation using numerical integration gives a rate constant for the 1,2 shift of 9 ì 107 28 29 1 30 s . 31 32 Considering the stereochemistry of the reaction of 2butyl tosylate, the 1,2 transfer could happen 33 34 through two transition states: cis and trans (Scheme 3). Both will contribute to the observed rate 35 36 7 1 37 constant for the 1,2 shift of 9 ì 10 s , but only the cis transition state will cause racemization. 38 39 OTs TsO H OTs TsO 40 H H H 41 H H H H H 42 H H H 43 S-2-butyl tosylate R-2-butyl tosylate S-2-butyl tosylate S-2-butyl tosylate 44 45 cis transition state trans transition state 46 47 48 Scheme 3 49 50 The ratio of the two transition states can be estimated to be about 4:1 by using cis and trans 2 51 52 butene as a model,3 leading to a predicted rate constant of 1.8 ì 107 s1 for the interconversion of 53 54 55 the 2butyl tosylate isomers through this pathway. This value is similar to the observed rate 56 57 constant for the interconversion of the 2butyl tosylate enantiomers (Figure 1). Fitting equation 2 58 59 60 14 http://mc.manuscriptcentral.com/poc Page 15 of 41 Journal of Physical Organic Chemistry

15 1 2 3 to the best fit for the 1,2 shift rate constant (k‘ ) using the independently measured rate constants 4 H 5 6 for tosylate exchange and solvolysis leads to the solid line given in figure 2, and k‘H = 2.1±0.1 ì 7 8 107 s1 in good agreement with the behavior of 3pentyl tosylate. 9 10 11 [ ] ) (2) 12 = 0.5 − (−2[] − − 2′ 13 [ ] 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 Figure 3. Racemization of 10mM S2butyl tosylate. The solid line is the best fit of equation 2, 31 accounting for racemization through tosylate anion incorporation and 1,2 shifts. 32 33 Similarly, the behavior of 2octyl tosylate due to these factors can be predicted. In this case, the 34 35 36 effect of 1,2 shifts on racemization is much reduced because (i) migration from the 3 position is 37 38 partitioned between the 2 and 4 positions and (ii) the competing rate of solvolysis in the 3 and 4 39 40 positions is faster than from the 2 position. We assume that 3octyl tosylate and 4octyl tosylate 41 42 43 undergo solvolysis two times faster than 2octyl tosylate (i.e. at the same rate as 3pentyl tosylate, 44 45 which is a conservative estimate15). Numerical modeling of scheme 4 (using Berkeley Madonna®) 46 47 was used to predict the variation in the ratio of the two enantiomers with time, with k = 0.8k‘ = 48 1 H 49 7 1 7 1 5 1 6 1 1 50 7.2 ì 10 s and k2 = 0.2k‘H. = 1.8 ì 10 s , and k‘S = 1.1 ì 10 s and kN = 2.2 ì 10 M s . 51 52 Each arrow is associated with the rate constant shown near it (i.e. forward and reverse reactions 53 54 55 have the same rate constant, shown once for clarity). This predicts that 1,2 migrations lead to 56 57 ~0.4% racemization. In contrast to 2butyl tosylate, migration away from the 2 position and more 58 59 60 15 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 16 of 41

16 1 2 3 rapid solvolysis of these isomers suppresses the observation of racemisation through the 1,2 4 5 6 migration pathway. In combination with the incorporation of tosylate formed during the 7 8 solvolysis reaction, the ~1% fraction of S2octyl tosylate observed after 72 hours is 9 10 11 satisfactorily accounted for. 12 13 solvolysis solvolysis solvolysis 14 15 k'S ~2k'S ~2k'S 16 OTs k 17 k1 1 18 For Peer Review 19 20 OTs OTs 21 k k 2 k - 2 22 - N[OTs ] k [OTs-] kN[OTs ] N 23 k 24 + 1 k OTs 25 1 k1 26 27 28 OTs OTs 29 k' k' k' 30 S ~2 S ~2 S 31 32 solvolysis solvolysis solvolysis 33 34 Scheme 4 35 36 From these data, the dominant process that competes with solvolysis to affect the structure of 2 37 38 39 butyl tosylate in dilute solution is 1,2migration. When analysed through the stereochemical 40 41 changes in the substrate, most of the migrations (~80%) are invisible as they lead to the same 42 43 enantiomer. These migrations do not affect the structure of 2octyl tosylate to any significant 44 45 46 extent. During this process, the bridging and nonbridging oxygen atoms of the tosylate can 47 48 potentially change position. Selective isotopic labeling of the nonbridging oxygens in the 49 50 reactant was used to reveal the extent of this process, and showed that both 2butyl and 2octyl 51 52 18 53 tosylates scramble the position of O introduced into the nonbridging positions to a similar 54 55 extent (7% and 9% after 72 hours, with slightly greater exchange occurring in the 2butyl 56 57 58 tosylate). Taking into account the statistical factors and assuming heavy atom isotope effects are 59 60 16 http://mc.manuscriptcentral.com/poc Page 17 of 41 Journal of Physical Organic Chemistry

17 1 2 3 7 1 4 negligible, the rate constants for isotopic exchange are 1.8±0.1 ì 10 s (2butyl tosylate) and 5 6 1.4±0.1 ì 107 s1 (2octyl tosylate). 7 8 Residual 2octyl tosylate is not significantly affected by 1,2hydride transfer or incorporation of 9 10 18 11 tosylate released during solvolysis, so O scrambling at the C2 position of labelled 2octyl 12 13 tosylate requires a pathway independent of these processes. 18O scrambling in labelled 2butyl 14 15 16 tosylate will also include this pathway, plus a possible contribution from isotope exchange 17 18 associated with 1,2migration.For Peer Review 19 20 If 1,2migration in 2butyl tosylate occurs by a pathway that selectively involves a nonbridging 21 22 23 oxygen in the tosyl group, then the rate constant for isotopic exchange through this pathway 24 25 would be the same as for 1,2 migration (~9 ì 107 s1). If migrations occur selectively through the 26 27 28 bridging oxygen, then 1,2transfer will not cause any isotope exchange. As the rate constant for 29 30 isotopic exchange in 2butyl tosylate is greater by only ~0.5 ì 107 s1 than for 2octyl tosylate, 31 32 isotopic exchange through the 1,2 migration must be strongly selective (~95%) for the bridging 33 34 35 oxygen, assuming that the contribution from direct exchange at the 2 position is similar for both 36 37 compounds. 38 39 40 The simplest detailed mechanism to potentially account for all these data is the formation of a 41 42 carbenium ion that can partition between solvolysis, reversion back to reactant and a 1,2 hydride 43 44 shift (followed by either solvolysis or reversion back to reactant for 2butyl tosylate). For 45 46 47 reversion back to reactant to be accompanied by an exchange of oxygen atoms, rotation of the 48 49 tosylate is required. This process has a rate constant of 5 ì 1010 s1,5,7 slightly slower than the 50 51 11 1 17 52 solvent reorganization rate constant of 10 s that limits solvolysis of the carbenium ion. 53 54 The 1,2hydride transfer and isotope exchange could also occur in a coupled process, with 1,2 55 56 hydride transfer accompanying isotope exchange. This must be a minor pathway, as shown by 57 58 59 60 17 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 18 of 41

18 1 2 3 the similarity in isotope scrambling rates in 2butyl and 2octyl tosylate, and is not included in 4 5 6 this mechanism (but see below). 7 8 Scheme 5 shows this proposal as applicable to the data for the isotope scrambling in the reactant. 9 10 11 For 2octyl tosylate, 1,2 hydride shift contributes to formation of products, but in 2butyl tosylate 12 13 this an identity reaction that does not affect the rate of solvolysis. The potential effect of 1,2 14 15 hydride shift on oxygen exchange is small (see above) and is not included in this scheme (see 16 17 18 below). For Peer Review 19 20 O O O O O O O O 21 k 1 S k S k 22 S Ar O R Ar O -1 S 23 Ar O Ar O 24 R k-1 R kR R k1 R 25 26 k k k 27 R kR 28 k kR 29 products R products 30 31 32 O O O O 33 k S k-1 S 34 products Ar O Ar O 35 R k R 36 1 37 38 For 2-octyl tosylate (R = n-pentyl,) k = kS + kH 39 For 2-butyl tosylate (R = methyl), k = k 40 S 41 42 Scheme 5 43 44 Scheme 6 shows this proposal as applicable to the data for racemization of 2butyl tosylate. The 45 46 47 overall rate constant for formation of the ion pair with the correct geometry is 0.2k1 based on the 48 49 different energies of the trans and gauche forms. The trans cation can also undergo 1,2 hydride 50 51 52 transfer, but this does not change the sense of the stereogenic centre. The trans cation contributes 53 54 to solvolysis and oxygen exchange, but not to racemization. We assume that hydride transfer and 55 56 ion recombination are not significantly affected by the different geometry. 57 58 59 60 18 http://mc.manuscriptcentral.com/poc Page 19 of 41 Journal of Physical Organic Chemistry

19 1 2 3 4 5 6 O O O O 7 O S k O O 0.2k1 H S 0.2k1 O 8 S O Ar O Ar O O S 9 Ar Ar 10 k-1 kH k-1 11 12 13 k k k k 0.8 1 -1 kS k -1 0.8 1 14 S 15 k k 16 O O S S O O 17 S products products S 18 Ar O For Peer Review O Ar 19 20 21 22 Scheme 6 23 24 These schemes lead to these expressions for the observed rate constant for solvolysis: 25 26 5 1 27 2butyl tosylate: kobs = k1 kS / (k1 + kS) = 1.15 ì 10 s (3) 28 29 2octyl tosylate: k = k (k + k ) / (k + k + k ) = 1.20 ì 105 s1 (4) 30 obs 1 S H 1 S H 31 32 The rate of isotope exchange is described by the expression: 33 34 [18OTs]/{[16OTs]+[18OTs]} = 2/3(1eat), where a is: 35 36 7 1 37 2butyl tosylate: 3k1kR k1/[(k1 + kS) (k1 + kS + 3kR)] = 5.4 ì 10 s (5) 38 7 1 39 2octyl tosylate: 3k1kR k1/[(k1 + kS + kH)( k1 + kS + kH + 3kR)] = 4.2 ì 10 s (6) 40 41 42 Finally, the racemization of S2butyl tosylate induced by 1,2hydride transfer is described by 43 44 the expression: 45 46 [ROTs]/{[ROTs]+[SOTs]} = 0.5 0.455ebt, where b is: 47 48 7 1 49 0.4 k1 k1 kH/[(k1 + kS)(k1 + kS + 2kH)] = 4.2 ì 10 s (7) 50 51 These equations cannot be solved with a consistent set of values for the rate constants. 52 53 10 1 5,7 54 For example, using kR = 5 ì 10 s , and assuming kS is limited to the solvent reorganization 55 11 1 17 56 rate constant of kS = 10 s if the carbenium ion is a true intermediate, we can combine 57 58 59 60 19 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 20 of 41

20 1 2 3 9 1 4 equations 3 and 5 to obtain a value for k1 of 8 ì 10 s . However, using this value and 5 11 1 6 combining 3 and 7 leads to a negative value for kH. If kS is assumed to be greater than 10 s , to 7 8 avoid this problem, the mechanism now becomes at least a preassociation enforced concerted 9 10 11 mechanism, and is not consistent with the scheme. Combining equations 3 and 4 shows that k1 12 13 must be at least 0.04kS to avoid kH being negative. If k1 approaches this limit, then kH becomes 14 15 large relative to k which is inconsistent as then 2octyl tosylate should solvolyse significantly 16 S 17 18 faster than 2butyl tosylate;For however, Peer the observed Review solvolysis rates for both substrates are 19 20 virtually the same. If k1 is comparable or much much larger than kS, then kH becomes 21 22 23 insignificant relative to kS. However, this is incompatible with the observation that oxygen 24 25 exchange is observed in a partitioning process that involves kR, which has to be comparable with 26 27 kH, and which itself is comparable to kS. Generally, these set of equations are not self consistent, 28 29 30 and so the scheme involving a common carbenium ion intermediate cannot be valid. 31 32 According to this analysis, the pathway for solvolysis of simple secondary tosylates in 50% TFE 33 34 is a true concerted mechanism without forming any intermediates. Similarly, the oxygen 35 36 37 exchange and 1,2 hydride shift must follow parallel concerted pathways. 38 39 CONCLUSION 40 41 42 The data presented here is best explained by competing concerted pathways for solvolysis, 1,2 43 44 hydride migration and oxygen exchange, rather than the formation of a carbenium ion. The 45 46 47 substitution reactions must proceed through a concerted pathway, likely an enforced concerted, 48 49 uncoupled pathway as previously suggested for similar substitution reactions. 50 51 Since 1,2hydride migration and oxygen exchange at the tosylate are observed, the transition 52 53 54 state is expected to be similar in character to a true carbenium intermediate as would be expected 55 56 in the uncoupled concerted process. The stereochemistry of the productalcohol has a significant 57 58 59 60 20 http://mc.manuscriptcentral.com/poc Page 21 of 41 Journal of Physical Organic Chemistry

21 1 2 3 level of retained configuration (8%) which requires an open transition state to allow enough 4 5 6 space for frontside attack at the substituted carbon, presumably via the solvation shell of the 7 8 leaving group, as observed in the solvolysis reaction of S1(3nitrophenyl)ethyl tosylate in 50% 9 10 5 11 TFE . An important observation is that oxygen scrambling within the reactant can be achieved 12 13 without forming an intermediate ion pair, and so isotope exchange cannot be used to infer the 14 15 presence of such an intermediate.5,18,19 Presumably the transition state resembles a true 16 17 18 carbenium ion intermediate,For but leavingPeer group depart Reviewure can be coupled with leaving group 19 20 rotation to. As this concerted exchange is slow compared with other substrates that can form 21 22 cation intermediates7, this suggests that the energy barrier for a concerted exchange is higher 23 24 25 than for the stepwise pathway. 26 27 Acknowledgements 28 29 30 We acknowledge the Department of Chemistry, The University of Sheffield for generous support 31 32 of this work. 33 34 35 REFERENCES 36 37 [1] P. E. Dietze, R. Hariri, J. Khattak, J. Org. Chem. 1989, 54, 3317. 38 39 [2] P. E. Dietze, W. P. Jencks, J. Am. Chem. Soc. 1986, 108, 4549. 40 41 42 [3] A. D. Allen, I. C. Ambidge, T. T. Tidwell, J. Org. Chem. 1983, 48, 4527. 43 44 [4] J. J. Dannenberg, J. K. Barton, B. Bunch, B. J. Goldberg, T. Kowalski, J. Org. Chem. 1983, 48, 4524. 45 46 [5] Y. Tsuji, M. M. Toteva, T. L. Amyes, J. P. Richard, Org. Lett. 2004, 6, 3633. 47 48 [6] D. Farcaşiu, J. Chem. Soc., Chem. Commun. 1994, 22, 2611. 49 50 [7] a) Y. Tsuji, T. Mori, J. P. Richard, T. L. Amyes, M. Fujio, Y. Tsuno, Org. Lett. 2001, 3, 1237. b) Y. 51 52 Tsuji, M. M. Toteva, T. L. Amyes, J. P. Richard, Org. Lett. 2004, 6, 3633. c) M. Teshima, Y. Tsuji, J. 53 54 55 P. Richard, J. Phys. Org. Chem. 2010, 23, 730. 56 57 [8] D. H. Burns, J. D. Miller, H. K. Chan, M. O. Delaney, J. Am. Chem. Soc. 1997, 119, 2125. 58 59 60 21 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 22 of 41

22 1 2 3 [9] Y. Muraki, T. Taguri, R. Yamakawa, T. Ando, J. Chem. Ecol. 2014, 40, 250 4 5 6 [10] X. Ma, Y. Zhang, Y. Zhang, C. Peng, Y. Che, J. Zhao, Adv. Mater. 2015, 27, 7746. 7 8 [11] M. Pohmakotr, W. Ieawsuwan, P. Tuchinda, P. Kongsaeree, S. Prabpai, V. Reutrakul, Org. Lett. 9 10 2004, 6, 4547 11 12 [12] Y. Nitta, Y. Arakawa, N. Ueyama, Chem. Pharm. Bull. 1986, 34, 2710. 13 14 [13] C. Chiappe, D. Pieraccini, Green Chem. 2003, 5, 193. 15 16 [14] a) H. Veisi, R. Ghorbani Vaghei, J. Mahmoodi, Bull. Korean Chem. Soc. 2011, 32, 3692. b) H. Veisi, 17 ‐ 18 For Peer Review 19 A. Sedrpoushan, S. Hemmati, D. Kordestani, Phosphorus, Sulfur, Silicon Relat. Elem. 2012, 187, 20 21 769. 22 23 [15] a) T. W. Bentley, C. T. Bowen, D. H. Morten, P. V. R. Schleyer, J. Am. Chem. Soc. 1981, 103, 5466. 24 25 b) P. E. Peterson, R. E. Kelley Jr, R. Belloli, K. A. Sipp, J. Am. Chem. Soc. 1965, 87, 5169. c) T. W. 26 27 Bentley, P. V. R. Schleyer, J. Am. Chem. Soc. 1976, 98, 7658. 28 29 [16] M. M. Toteva, J. P. Richard, J. Am. Chem. Soc. 1996, 118, 11434. 30 31 32 [17] U. Kaatze, R. Pottel, A. Schumacher, J. Phys. Chem. 1992, 96, 6017. 33 34 [18] Y. Tsuji, J. P. Richard, J. Am. Chem. Soc. 2006, 128, 17139. 35 36 [19] P. E. Dietze, M. Wojciechowski, J. Am. Chem. Soc. 1990, 112, 5240. 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 22 http://mc.manuscriptcentral.com/poc Page 23 of 41 Journal of Physical Organic Chemistry

1 1 2 3 4 Supporting Information 5 6 7 The solvolysis mechanism of simple secondary tosylates in 50% TFE 8 9 * 10 Dian Li and Nicholas H. Williams 11 12 Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, United Kingdom 13 14 *E-mail: [email protected] 15 16 Table of contents 17 18 Tables of data………For………… …Peer…………… …Review……………………………………….....S2-S3 19 20 13C NMR spectrum of 2-butanol and 2-butyl trifluoroethyl ether from 2-butyl tosylate….S3 21 22 Chiral HPLC spectrum of S-2-butyl tosylate (starting material)…………………………...S3 23 24 13C NMR spectrum of labelled 2-butyl tosylate and 2-octyl tosylate recovered after 16, 40 25 and 66.5 hours…………………………………………………………………………………..S4 26 27 Chiral HPLC spectrum of solvolysis of S-2-butyl tosylate (0.1 mol/L) after 17, 24.5, 41, 65 28 29 and 73.5 hours…...... ………………………………………………………………………S5 – S7 30 31 Chiral HPLC spectrum of solvolysis of S-2-butyl tosylate (0.01 mol/L) after 8, 24, 32, 48.5, 32 56 and 72 hours…...... ……………………………………………………………………S8 – S10 33 34 Chiral HPLC spectrum of solvolysis of S-2-butyl tosylate (0.01 mol/L) with 1 mol/L sodium 35 tosylate after 55 and 72 hours…………………………………………..…………………….S11 36 37 HPLC spectrum of 3-pentyl tosylate (starting material)………...…………………………S12 38 39 HPLC spectrum of solvolysis of 3-pentyl tosylate (0.01 mol/L) after 46, 50, 54, 70 and 78 40 hours………………………………………………………………………………..….…S12 – 41 42 S14 43 44 Chiral HPLC spectrum of R-2-octyl tosylate (starting material)………………………….S15 45 46 Chiral HPLC spectrum of solvolysis of R-2-octyl tosylate (0.01 mol/L) after 16.1, 24, 40, 48, 47 64 and 72 hours……………………………………..……..……………………………S15 – S18 48 49 Chiral HPLC spectrum of racemic 2-octyl PNB…………………………………...….…….S18 50 51 Chiral HPLC spectrum of 2-octyl PNB from R-2-octyl tosylate solvolysis…………….….S19 52 53 Chiral HPLC spectrum of 2-octyl PNB from R-2-octanol after 2 weeks under the same 54 solvolysis conditions………………………………………………...... ….S19 55 56 57 58 59 60 1 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 24 of 41

2 1 2 3 Table S1. Racemization of S-2-butyl tosylate (0.1 mol/L) in 50% TFE at different time intervals 4 5 6 Reaction time/h Peak area for S-2-butyl Peak area for R-2-butyl Ratio ([S]+[R]) / [R] 7 tosylate/mV·s tosylate/mV·s 8 0 790.416 37.143 22.28:1 9 17 605.824 35.487 18.07:1 10 24.5 526.297 36.283 15.50:1 11 41 342.526 28.671 12.95:1 12 48.5 257.423 24.804 11.38:1 13 65 128.900 14.745 9.74:1 14 15 73.5 183.281 20.816 9.6:1 16 17 18 Table S2. RacemizationFor rate of S-2-Peerbutyl tosylate Review (0.1 mol/L) against the tosylate anion presented 19 20 Concentration of toyslate anion (mol/L) ki in [R] / {[R]+[S]} = 0.5 – aexp(-ki × t) 21 0.1 0.752 × 10-6 s-1 22 0.5 2.312 × 10-6 s-1 23 1.0 -6 -1 24 5.743 × 10 s 25 26 27 Table S3. Racemization of S-2-butyl tosylate (0.01 mol/L) in 50% TFE at different time intervals 28 29 Reaction time/h Peak area for S-2-butyl Peak area for R-2-butyl Ratio ([S]+[R]) / [R] 30 tosylate/mV·s tosylate/mV·s 31 0 790.416 37.143 22.3:1 32 8 240.144 13.173 19.2:1 33 24 178.725 11.666 16.3:1 34 32 187.067 13.781 14.6:1 35 36 48.5 123.362 10.286 13.0:1 37 56 359.099 32.359 12.1:1 38 72 202.228 21.561 10.3:1 39 40 41 Table S4. Ratio of 2-pentyl tosylate to 3-pentyl tosylate under solvolysis conditions 42 43 Time/s [2-pentyl tosylate]t / [3-pentyl tosylate]t 44 0 0.00 45 46 165600 0.39 47 180000 0.56 48 194400 0.84 49 252000 1.48 50 280800 2.01 51 340200 6.98 52 53 54 55 56 57 58 59 60 2 http://mc.manuscriptcentral.com/poc Page 25 of 41 Journal of Physical Organic Chemistry

3 1 2 3 Table S5. 2-butanol generated from S-2-butyl tosylate at different time intervals by chiral GC 4 determination 5 6 7 Reaction time/h Peak area of R-2-butanol/ Peak area of S-2-butanol/ Ratio ([R] / [S]) 8 uV·s uV·s 9 17 576.41 92.97 6.2:1 10 24.5 712.39 122.79 5.9:1 11 41 910.59 150.73 6.0:1 12 48.5 922.88 146.48 6.3:1 13 65 1176.41 176.86 6.4:1 14 73.5 808.71 126.21 6.3:1 15

16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 Figure S1. 13CNMR spectrum of 2-butanol and 2-butyl trifluoroethyl ether from 2-butyl tosylate 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Figure S2. Chiral GC spectrum of 2-butanol generated from S-2-butyl tosylate 55 56 57 58 59 60 3 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 26 of 41

4 1 2 3 Figure S3. 13CNMR spectrum of labelled 2-butyl tosylate and 2-octyl tosylate recovered after 16, 4 5 40 and 66.5 hours 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 4 http://mc.manuscriptcentral.com/poc Page 27 of 41 Journal of Physical Organic Chemistry

5 1 2 3 Chiral HPLC spectrum of S-2-butyl tosylate (starting material) 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 Chiral HPLC spectrum of solvolysis of S-2-butyl tosylate (0.1 mol/L) after 17, 24.5, 41, 65 32 33 and 73.5 hours 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 28 of 41

6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 6 http://mc.manuscriptcentral.com/poc Page 29 of 41 Journal of Physical Organic Chemistry

7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 7 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 30 of 41

8 1 2 3 Chiral HPLC spectrum of solvolysis of S-2-butyl tosylate (0.01 mol/L) after 8, 24, 32, 48.5, 4 5 56 and 72 hours 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 8 http://mc.manuscriptcentral.com/poc Page 31 of 41 Journal of Physical Organic Chemistry

9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 9 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 32 of 41

10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 10 http://mc.manuscriptcentral.com/poc Page 33 of 41 Journal of Physical Organic Chemistry

11 1 2 3 Chiral HPLC spectrum of solvolysis of S-2-butyl tosylate (0.01 mol/L) with 1 mol/L sodium 4 5 tosylate after 55 and 72 hours 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 11 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 34 of 41

12 1 2 3 HPLC spectrum of 3-pentyl tosylate (starting material) 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 HPLC spectrum of solvolysis of 3-pentyl tosylate (0.01 mol/L) after 46, 50, 54, 70 and 78 32 33 hours 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 12 http://mc.manuscriptcentral.com/poc Page 35 of 41 Journal of Physical Organic Chemistry

13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 36 of 41

14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14 http://mc.manuscriptcentral.com/poc Page 37 of 41 Journal of Physical Organic Chemistry

15 1 2 3 Chiral HPLC spectrum of R-2-octyl tosylate (starting material) 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 Chiral HPLC spectrum of solvolysis of R-2-octyl tosylate (0.01 mol/L) after 16.1, 24, 40, 48, 32 33 64 and 72 hours 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 15 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 38 of 41

16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 16 http://mc.manuscriptcentral.com/poc Page 39 of 41 Journal of Physical Organic Chemistry

17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17 http://mc.manuscriptcentral.com/poc Journal of Physical Organic Chemistry Page 40 of 41

18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 Chiral HPLC spectrum of racemic 2-octyl PNB 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 18 http://mc.manuscriptcentral.com/poc Page 41 of 41 Journal of Physical Organic Chemistry

19 1 2 3 Chiral HPLC spectrum of 2-octyl PNB from R-2-octyl tosylate solvolysis 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 Chiral HPLC spectrum of 2-octyl PNB from R-2-octanol after 2 weeks under the same 32 33 solvolysis conditions 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 19 http://mc.manuscriptcentral.com/poc