molecules Article Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric cis- and trans-2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies Marian Mikołajczyk 1,* , Barbara Ziemnicka 1, Jan Krzywa ´nski 1, Marek Cypryk 2,* and Bartłomiej Gosty ´nski 2 1 Department of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łód´z,Poland; [email protected] (B.Z.); [email protected] (J.K.) 2 Department of Structural Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łód´z,Poland; [email protected] * Correspondence: [email protected] (M.M.); [email protected] (M.C.); Citation: Mikołajczyk, M.; Tel.: +48-42-680-3221 (M.M.); +48-42-680-3314 (M.C.) Ziemnicka, B.; Krzywa´nski,J.; Cypryk, M.; Gosty´nski,B. Abstract: Geometrical cis- and trans- isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2- Nucleophilic Substitution at dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of Tetracoordinate Phosphorus. III Stereochemical Course and corresponding cyclic P -halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus IV Mechanisms of Nucleophilic pentachloride and (c) halogen–halogen exchange at P -halogenide. Their conformation and configu- 1 31 Displacement Reactions at ration at the C4-ring carbon and phosphorus stereocentres were studied by NMR ( H, P) methods, Phosphorus in Diastereomeric cis- X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reac- and trans-2-Halogeno-4-methyl-1,3,2- tions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown dioxaphosphorinan-2-thiones: to depend on the nature of halogen. Cyclic cis- and trans-isomers of chlorides and bromides react Experimental and DFT Studies. − − with nucleophiles (HO , CH3O , Me2NH) with inversion of configuration at phosphorus. DFT Molecules 2021, 26, 3655. https:// calculations provided evidence that alkaline hydrolysis of cyclic thiophosphoryl chlorides proceeds doi.org/10.3390/molecules26123655 according to the SN2-P mechanism with a single transition state according to the potential energy surface (PES) observed. The alkaline hydrolysis reaction of cis- and trans-fluorides afforded the Academic Editor: Vadim same mixture of the corresponding cyclic thiophosphoric acids with the thermodynamically more V. Negrebetsky stable major product. Similar DFT calculations revealed that substitution at phosphorus in fluorides Received: 9 April 2021 proceeds stepwise according to the A–E mechanism with formation of a pentacoordinate intermediate Accepted: 10 May 2021 since a PES with two transition states was observed. Published: 15 June 2021 Keywords: 2-halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones; alkaline hydrolysis; mecha- Publisher’s Note: MDPI stays neutral nism; stereochemistry; DFT calculations with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction The stereochemistry and mechanisms of nucleophilic substitution reactions at the phosphorus atom have been the major points of interest of many research groups since Copyright: © 2021 by the authors. the middle of the last century [1]. The stereochemical course of nucleophilic displacement Licensee MDPI, Basel, Switzerland. reactions at phosphorus has also been a subject of our early systematic studies, which This article is an open access article have employed, in the first stage, optically active acyclic thiophosphonic acids 1 and their distributed under the terms and derivatives, as for example the enantiomeric thiophosphonyl chlorides 2 (Figure1). conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Molecules 2021, 26, 3655. https://doi.org/10.3390/molecules26123655 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 30 Molecules 2021, 26, 3655 2 of 30 Molecules 2021, 26, x FOR PEER REVIEW 2 of 30 Figure 1. 1. StructuresStructures of ofoptically optically active active acyclic acyclic thiophosphonic thiophosphonic acid acid(1) and (1) the and corresponding the corresponding Figure 1. Structures of optically active acyclic thiophosphonic acid (1) and the corresponding thiophosphonyl chloride (2) used in studies of nucleophilicnucleophilic substitutionsubstitution atat phosphorus.phosphorus. thiophosphonyl chloride (2) used in studies of nucleophilic substitution at phosphorus. These early investigations resulted, among others, in elaborationelaboration of a Walden cyclecycle for thiophosphonic thiophosphonicThese early acids acids investigations 11 (interconversion(interconversion resulted, of of the the enantiomers enantiomers among ofothers, of 1) 1[2,3])[2, 3and ]in and inelaboratio inproviding provid- n of a Walden cycle unequivocaling unequivocal proof proof for forthe the inversion inversion of ofconf configurationiguration at at phosphorus phosphorus occurring occurring in in thethe forchloride thiophosphonic exchange reactionreaction acids betweenbetween 1 (interconversion radioactiveradioactive chloride chloride anion ofanion the ( 36(36 ClenantiomersCl−−)) and and optically of active 1) [2,3] and in providing unequivocalthiophosphonyl chloride proof 2for [4].[4]. theIt has inversion also beenbeen demonstrateddemonstrated of configuration thatthat alkalinealkaline at hydrolysishydrolysisphosphorus ofof occurring in the chlorideoptically active exchange chlorides reaction 2 proceeds between with inversion radioactive atat thethe PP atomatom chloride [[5].5]. anion (36Cl−) and optically active The secondsecond mostmost important important question question about about the the mechanisms mechanisms of displacement of displacement reac- thiophosphonylreactionstions at phosphorus at phosphorus chloride was, was, and and it 2 isit [4]. is still, still It whether, whetherhas also these these been reactions reactions demonstrated occuroccur synchronouslysynchronously that alkaline hydrolysis of opticallyaccording to active the SN 2-P2-Pchlorides mechanism 2 proceeds via a single with transition inversion state (TS) at orthe stepwise P atom by [5]. thethe addition–eliminationThe second mechanismmechanismmost important (A–E) (A–E) involving inquestionvolving formation formation about of an unstable,theof anmechanisms pentacoor-unstable, of displacement pentacoordinatedinate phosphorus phosphorus intermediate intermediate (trigonal (trigo bipyramidalnal bipyramidal intermediate, intermediate, TBPI). It TBPI). is formed It is reactionsformedin the first in reactionthe at phosphorusfirst stepreaction by addition step was, by of andaddition the nucleophilicit is of still the , nucleophilicwhether reagent (N) these reagent to the reactions electrophilic (N) to the occur synchronously phosphorusaccordingelectrophilic substrate phosphorusto the andSN substrate2-P decomposes mechanism and indecomp the second viaoses a in step single the by second the transition departure step by ofthe state the departure leaving (TS) or stepwise by the addition–eliminationofgroup the leaving (L) to the group reaction (L) to product the reactionmechanism (see Scheme product1 ). (see(A–E) Scheme in 1).volving formation of an unstable, pentacoordinate phosphorus intermediate (trigonal bipyramidal intermediate, TBPI). It is formed in the first reaction step by addition of the nucleophilic reagent (N) to the electrophilic phosphorus substrate and decomposes in the second step by the departure of the leaving group (L) to the reaction product (see Scheme 1). Scheme 1. MechanismsMechanisms of ofnucleophilic nucleophilic substitution substitution reactions reactions at phosphorus at phosphorus and andstructures structures of of possible pentacoordinate phosphorusphosphorus intermediatesintermediates (TBPI)(TBPI) formedformed byby thethe A–EA–E mechanism.mechanism. In analogy withwith thethe SSNN2 substitution at carbon, the SSNN2-P reactions also occur withwith inversion ofof configuration.configuration. However, However, the the relationship relationship between between the the stereochemistry stereochemistry and and the A–Ethe A–E mechanism mechanism is more is complicated. more complicated. It is now generallyIt is now accepted generally that accepted the stereochemical that the stereochemicaloutcome of such outcome stepwise of reactions such stepwise depends reac mainlytions depends on the disposal mainly of on the the attacking disposalN of and the attackingleaving L N groups and leaving in a short-living L groups in intermediate a short-living TBPI. intermediate Thus, the diapicalTBPI. Thus, or diequatorialthe diapical ordisposal diequatorial of N and disposal L should of leadN and to inversion L should of lead configuration to inversion at phosphorus of configuration while theat phosphorusstereochemical while outcome the stereochemical of the apical-equatorial outcome substitutionof the apical-equatorial is predicted tosubstitution be retention. is predicted to be retention. Moreover, these three different TBPIs may be formed as primary Scheme 1. Mechanisms of nucleophilic substitution reactions at phosphorus and structures of possible pentacoordinate phosphorus intermediates (TBPI) formed by the A–E mechanism. In analogy with the SN2 substitution at carbon, the SN2-P reactions also occur