A Dynamic NMR Study of Nucleophilic Attack on Tetracoordinate Phosphorus

1. A Dynamic NMR Study of Nucleophilic Attack on Tetracoordinate Phosphorus Elizabeth V. Jennings Kirill V. Nikitin Declan G. Gilheany

2. Halophosphonium Salts Polar solvents Ionic Tetracoordinate Chiral Non-polar solvents Covalent Pentacoordinate Pseudorotation • Key intermediates in functional group transformations. • Relative stabilities of the pentacoordinate and tetracoordinate forms of halophosphonium salts depend on solvent. [McAuliffe, Godfrey,Dalton1997] • Diagnostic P31 NMR shifts • Appear to racemise rapidly in solution, possibly by nucleophilic substitution.

3. Nucleophilic Substitution • Carbon- mechanism well-defined. Associative and dissociative processes known. • Phosphorus- halophosphonium salts are tetrahedral and susceptible to nucleophilic attack. Mechanism?

4. Halophosphonium Salt Inversion Our calculation, DFT with B3LYP 6-31 G*

5. Measuring Barrier to Halophosphonium Salt Inversion • Phosphonium salts: 100% abundant 31P, tetrahedral (can be chiral), low barriers compared to carbon • Synthesise diastereomeric halophosphonium salts- distinct NMR signals

6. Measuring Barrier to Halophosphonium Salt Inversion • Sterics • Nucleophile and leaving group • Concentration and order • Highly strained systems

7. Measuring Barrier to Halophosphonium Salt Inversion • Diastereomeric phosphine oxides were synthesised. • Halophosphonium salts generated by reaction of oxide with oxalyl chloride or oxalyl bromide. R = Me, Et, i-Pr, t-Bu, c-Hex, o-Tol X = Cl, Br

8. s-butylethylphenylphosphine oxide Mixture of diastereomers 31P NMR

9. Halophosphonium Salts in Solution Combined room temperature 31P NMR spectra Halophosphonium salts epimerising rapidly Br PS PO: X = O- Br PS: X = Br Cl PS: X = Cl PO Cl PS PO

10. Variable Temperature NMR Tc: -14 oC Δδ : 14.80 Hz Barrier: 13.2 kcal/mol δ P CDCl3

11. Variable Temperature NMR Tc: -14 oC Δδ : 14.80 Hz Barrier: 13.2 kcal/mol 14.8 Hz δ P CDCl3

12. InversionBarriers in CDCl3

13. InversionBarriers • Sterics • Strong effect • In contrast to carbon chemistry, increasing sterics can not lead to a dissociative type pathway • Cyclic system has similar barrier to alkyl and aryl systems

14. InversionBarriers • Nucleophile and LG • Chlorophosphonium salts have lower barriers than bromophosphonium salts. • Might this be due to the polarity of the P-X bonds?

15. InversionBarriers Calculations Calculated energies of Cl PSand Br PS in both vacuum and DCM. DFT with B3LYP 6-31 G* Barriers in kcal/mol

16. InversionBarriers • Vacuum • Cl PS and Br PS pentacoordinate • Cl PS more stabilised DFT with B3LYP 6-31 G* Barriers in kcal/mol

17. InversionBarriers • DCM • Cl PS and Br PS are tetracoordinate • Br PS more stabilised DFT with B3LYP 6-31 G* Barriers in kcal/mol

18. InversionBarriers • Conclusion • Cl PS pentacoordinate more stable than • Br PS pentacoordinate. • Pentacoordinate is intermediate/ transition state for inversion. • Barrier to inversion lower for CPS.

19. Halophosphonium Salts in Benzene • Non-polar solvents promote pentacoordination • Ring strain promotes tetracoordination • Cl PS still prefer pentacoordination

20. Inversion Barriers Concentration and Order 1.28 1.25 1.22 1.19 1.16 1.13 1.10 1.07 1.04 1.01 • s-butyl t-butyl phenyl Cl PS • Cl PS more soluble than Br PS • Bulky substituent- dissociation • Barrier: 15.1 kcal/mol • Suitable for EXSY 1H NMR 30OC CDCl3

21. Inversion Barriers Exchange Spectroscopy ppm

22. Inversion Barriers Exchange Spectroscopy ppm

23. Inversion Barriers Exchange Spectroscopy ppm

24. 1 . 00 1 . 00 1 . 00 1 . 00 1 . 05 1 . 05 1 . 05 1 . 10 1 . 10 1 . 10 ) ) ) m m m 1 . 15 1 . 15 1 . 15 p p p p p p 0 . 61 ( ( ( 1 1 1 f f f 1 . 20 1 . 20 1 . 20 1 . 25 1 . 25 1 . 25 1 . 30 1 . 30 1 . 30 1 . 35 1 . 35 1 . 35 1 . 40 1 . 40 1 . 40 1 . 17 1 . 17 1 . 17 - 1 . 00 1 . 00 1 . 00 1 . 00 1 . 00 1 . 00 1 . 05 1 . 05 1 . 05 1 . 10 1 . 10 1 . 10 ) ) ) m m m 1 . 15 1 . 15 1 . 15 p p p p - 0 . 33 p p ( ( ( 1 1 1 0 . 36 f f f 1 . 20 1 . 20 1 . 20 0 . 35 1 . 25 1 . 25 1 . 25 1 . 30 1 . 30 1 . 30 1 . 35 1 . 35 1 . 35 1 . 40 1 . 40 1 . 40 1 . 17 1 . 17 1 . 17 Inversion Barriers Concentration and Order 1 . 00 - 1 . 00 0 . 62 - 0 . 64 50 mM, 100 ms 30 mM, 100 ms 100 mM, 100 ms Concentration had no measurable effect on rate Reaction has first order kinetics 100 mM, 10 ms 50 mM, 10 ms 30 mM, 10 ms

25. Inversion Barriers Degree of dissociation Contact ion pair Fully dissociated ion pair Solvent-separated ion pair

26. Inversion Barriers Degree of dissociation Contact ion pair 1st order Fully dissociated ion pair 2nd order Solvent-separated ion pair 1st order

27. Inversion Barriers Degree of dissociation X-Ray structure of a solvent-separated ion pair Ph3PCl+Cl- in DCM “Direct evidence of a multicentre halogen bond: unexpected contraction of the P–XXX–P fragment in triphenylphosphinedihalides” Chem. Commun., 2013, 49, 1434-1436

28. Bicyclic system: phobene oxides Phosphabicyclononene Phenyl lies above the 7-membered ring or the 5-membered ring For phobanes: M. Carreira, M. Charernsuk, M. Eberhard, N. Fey, R. van Ginkel, A. Hamilton, W. P. Mul, A. G. Orpen, H. Phetmung, P. G. Pringle, J. Am. Chem. Soc, 2009, 131, 3078 Peter N. Bungu, Stephanus Otto, J. Org. Met. Chem., 2007, 692, 16, 3370

29. Bicyclic system • Hydrolysis known to occur in monocyclic systems with retention at phosphorus [Kurt MislowAccChem Rev 1970] Slow 100% retention Slow 100% retention No epimerisation

30. Halophosphonium Salts InversionBarriersConclusions • Rates in range measurable by VT NMR and EXSY • Associative nucleophilic substitution process • Chloride faster than bromide • First order kinetics

31. Acknowledgements • Declan Gilheany • Adam, Bartosz, Damien, Dominic, Kamal, Kirill, Niall, Peter, Sulaiman • Yannick Ortin, school NMR technician • Science Foundation Ireland