Deuterium: From Discovery to Applications in Synthesis

Hasan Khan Monday Night Seminar January 19th, 2009 Department of University of Toronto

1 Overview

• History and Discovery of

• Deuterium in Mechanistic Studies

• Deuterium in Synthesis

2 History and Discovery of Deuterium

3 Evidence for the existence of D

• Circa 1920 – Isotopes of light elements were unknown

• 1927 –Aston determines the atomic weihight of hdhydrogen

• 1929 – 18O, 15N and 13C detected, suggesting existence of isotopes of lighter elements

Aston, F. W. Proc. Roy. Soc. (London) 1927, A115, 487; Giauque, W. F.; Johnston, H. W. Nature. 1929, 123, 318; Naudé, S. M. Phys. Rev. 1929, 34, 1498 4 Detection of deuterium

• 1932 – Isotope enrichment of liquid hydrogen via distillation – 4 L of liquid hydrogen evaporated to 1 mL at the triple point

• 1934 – Nobel Prize awarded to HldHarold Clay ton Urey

Urey, H. C. et al. Phys. Rev. 1932, 39, 165 5 Urey’s foresight

“[This work] on deuterium is only the beginning of a very interesting scientific development.”

–Harold Clayton Urey, Nobel address

Urey, H. C. Nobel Lecture. February 14th, 1935 6 Isolation of D2O

• Enrichment of isotope abundance: – Electrolysis

– Distillation of H2O/D2O

– Distillation of H2/D2

• Girdler Sulfide process, fllfollowe d by distillation

7 Epilogue

• Methods for mass producing D2O allowed for a boom in deuterium studies

• Polanyi and Eyring predict reactivity differences between isotopomers – Origin of the kinetic isotope effect

Cremer, E.; Polanyi, M. Z. physik. Chem. 1932, B19, 443; Eyring, H.; Sherman A. J. Chem. Phys. 1933, 1, 435 8 Deuterium in Mechanistic Studies

Seminal reviews: Wiberg, K. B. Chem. Rev. 1955, 55, 713 Westheimer, F. H. Chem. Rev. 1961, 61, 265 9 1° Kinetic isotope effect

Shape of potential energy curve is the same – But zero‐point energy (ZPE) for stretching vibration differs

Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry. pp. 421‐432, University Science Books (2006) 10 1° Kinetic isotope effect

Primary KIEs exist only if C – H/D cleavage occurs in the rate limiting step

C – H/D bond is partially broken in TS

11 Mechanistic studies using 1° KIEs

• Observed kinetic isotope effect suggests proton elimination is rate limiting

Westheimer, F. H.; Nicolaides, N. J. Am. Chem. Soc. 1949, 71, 25 12 Hammond‐Leffler postulate

• Boils down to: “In an elementary step, the transition state will resemble the species closest in energy.”

Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334; Leffler, J. E. Science 1952, 117, 340; Westheimer, F. H. Chem. Rev. 1961, 61, 265 13 pKa‐based TS symmetry

Dixon, J. E.; Bruice, T. C. J. Am. Chem. Soc. 1970, 92, 905 14 2° Kinetic isotope effects

Primary KIE – Differences in stretching Secondary KIE – HbiditiHybridization: bdibending – HjtiHyperconjugation

15 2° KIE and changes in hybridization sp2 Æ sp or sp3 Æ sp2 = Normal 2° KIE

sp Æ sp2 or sp2 Æ sp3 = Inverse 2° KIE

Shiner, V. J. et al. J. Am. Chem. Soc. 1968, 90, 418; 16 Do Amaral, L. et al. J. Am. Chem. Soc. 1972, 94, 7579 2° KIE and hyperconjugation

Shiner, V. J.; Jewett, J. G. J. Am. Chem. Soc. 1964, 86, 945 17 2° KIE and hyperconjugation

Shiner, V. J.; Jewett, J. G. J. Am. Chem. Soc. 1964, 86, 945 18 Quantum Tunneling

Phenomenon in which particles pass under activation barrier

‐ Ordered TS ‐ Small particle

Kwart, L. D. et al. J. Am. Chem. Soc. 1981, 103, 1232 Tunneling in enzymes: Kohen, A.; Klinman, J. P. Acc. Chem. Res. 1998, 31, 397 19 Case study ‐ SEAr

Some mechanistic details cannot be unveiled by kinetics alone

Wheland, G. W. J. Am. Chem. Soc. 1942, 64, 900; Dewar, M. J. S. J. Chem. Soc. 1946, 406, 777; Olah, G.A. Acc. Chem. Res. 1971, 4, 240 20 SEAr – Nitration of nitrobenzene

Small observed KIE suggests that electrophilic attack is rate limiting, but…

Hammond and Leffler postulate that this may not be the case.

Bonner, T. G.; Bowyer, F.; Williams, G. J. Chem. Soc. 1952, 2650 21 Simplified energy diagram

Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334; Leffler, J. E. Science 1952, 117, 340 22 The curious case of SEAr

Olah, G. S.; Kuhn, S. J.; Flood, S. F. J. Am. Chem. Soc. 1961, 83, 4571 Bonner, T. G.; Bowyer, F.; Williams, G. J. Chem. Soc. 1952, 2650; 23 Nitration of toluene

24 Nitration of nitrobenzene

25 Isotope‐labeling studies

Matsuda, T. et al. J. Am. Chem. Soc. 2007, 129, 12086 26 First labeling study ‐ results

Matsuda, T. et al. J. Am. Chem. Soc. 2007, 129, 12086 27 First labeling study ‐ proposal

Matsuda, T. et al. J. Am. Chem. Soc. 2007, 129, 12086 28 Second labeling study

29 Large 1° KIEs at natural abundance

Pascal, R. A. et al. J. Am. Chem. Soc. 1986, 108, 6477 Saunders, W. H., Jr. et al. J. Am. Chem. Soc. 1960, 82, 138 30 Small 2° KIEs at natural abundance

Singleton, D. A.; Thomas, A. A. J. Am. Chem .Soc. 1995, 117, 9357 31 Epilogue

• Kinetic isotope effects and isotope‐labeling are indispensable

• NMR techniques can measure KIEs at natural abundances, with limitations

• What if you need to make isotope‐enrihdiched compounds?

32 Deuterium in Synthesis

Comprehensive review: Atzrodt, J. et al. Angew. Chem. Int. Ed. 2007, 46, 7744 33 Classical synthesis

Shen, Z. et al. J. Am. Chem. Soc. ASAP 34 Acid‐catalyzed exchange

• Dominant method Simple Effective Inexpensive Versatile

35 High‐temperature dilute acid

• Preparation of perdeuterated arenes – Exchange occurs at aromatic C‐H bonds only

Werstiuk, N. H.; Kadai, T. Can. J. Chem. 1973, 51, 1485 36 Supercritical media

• Access to perdeuterated haloarenes

• Many challenges remain Junk,T.;Catallo,W.J.Chem. Soc. Rev. 1997, 26, 405 37 Base‐catalyzed exchange

Wähälä, K. et al. J. Labelled Compd. Radiopharm. 1995, 36, 493 38 Synthesis of labeled amino acids

Rose, J. E.; Leeson, P. D.; Gani, D. J. Chem. Soc. Perkin Trans. 1995, 157 39 Synthesis of acetone‐d6

Exchange reaction – incomplete deuteration

Must discard semiheavy

Paulsen, P. J.; Cooke, W. D. Anal. Chem. 1963, 35, 1560 40 Syntheses of CDCl3

Breuer, F. W. J. Am. Chem. Soc. 1935, 57, 2236 Paulsen, P. J.; Cooke, W. D. Anal. Chem. 1963, 35, 1560 41 Current industrial synthesis

Circa 1965

Kluger, R. J. Org. Chem. 1963, 29, 2045 42 Iridium‐catalyzed exchange

Exchange possible with a wide variety of substrates via Iridium III‐V catalysis

Yung, C. M. et al. J. Am. Chem. Soc. 2004, 126, 13033 43 Ir(III)‐Ir(V) catalytic cycle

Yung, C. M. et al. J. Am. Chem. Soc. 2004, 126, 13033 44 Synthesis of Norzoanthamine

Miyashita, M. et al. Science. 2004, 305, 495 45 Increased yield based on KIE

Miyashita, M. et al. Science. 2004, 305, 495 46 Epilogue

• Deuterium can be introduced using classical synthesis

• Acid‐, base‐ and metal‐catalyzed methods are used to make common deuterated agents

• Few but very iiinteresting examples of deuterium in total synthesis

47 Acknowledgements

Vy Dong and the Dong Lab

Prof. Kluger

Prof. Taylor

48