Deuterium: From Discovery to Applications in Synthesis
Hasan KhanMonday Night SeminarJanuary 19th, 2009
Department of ChemistryUniversity of Toronto
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OverviewOverview
• History and Discovery of DeuteriumHistory and Discovery of Deuterium
• Deuterium in Mechanistic Studies
• Deuterium in Synthesis
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Evidence for the existence of DEvidence for the existence of D
• Circa 1920 – Isotopes of light elements wereCirca 1920 Isotopes of light elements were unknown
• 1927 – Aston determines the atomici h f h dweight of hydrogen
• 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 deuteriumDetection of deuterium
• 1932 – Isotope enrichment of liquid1932 Isotope enrichment of liquidhydrogen via distillation– 4 L of liquid hydrogen evaporated– 4 L of liquid hydrogen evaporatedto 1 mL at the triple point
• 1934 – Nobel Prize awarded to H ld Cl t UHarold Clayton Urey
Urey, H. C. et al. Phys. Rev. 1932, 39, 1655
Urey’s foresightUrey s foresight
“[This work] on deuterium[This work] on deuteriumis only the beginning of
a very interesting scientifica very interesting scientific development.”
– Harold Clayton Urey,
Nobel addressNobel address
Urey, H. C. Nobel Lecture. February 14th, 19356
Isolation of D2OIsolation of D2O
• Enrichment of isotope abundance:Enrichment of isotope abundance:– Electrolysis
Distillation of H O/D O– Distillation of H2O/D2O
– Distillation of H2/D2
• Girdler Sulfide f ll dprocess, followed
by distillation
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EpilogueEpilogue
• Methods for mass producing D2O allowed forMethods for mass producing D2O allowed for a boom in deuterium studies
• Polanyi and Eyring predict reactivity differences between isotopomersdifferences between isotopomers– Origin of the kinetic isotope effect
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Cremer, E.; Polanyi, M. Z. physik. Chem. 1932, B19, 443; Eyring, H.; Sherman A. J. Chem. Phys. 1933, 1, 435
Deuterium in Mechanistic Studies
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Seminal reviews: Wiberg, K. B. Chem. Rev. 1955, 55, 713Westheimer, F. H. Chem. Rev. 1961, 61, 265
1° Kinetic isotope effect1 Kinetic isotope effect
Shape of potential energy curve is the sameShape of potential energy curve is the same– But zero‐point energy (ZPE) for stretching vibration differsvibration differs
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry. pp. 421‐432, University Science Books (2006) 10
1° Kinetic isotope effect1 Kinetic isotope effect
Primary KIEs exist only if C – H/D cleavagePrimary KIEs exist only if C H/D cleavage occurs in the rate limiting step
C – H/D bond is /partially broken in TS
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Mechanistic studies using 1° KIEsMechanistic studies using 1 KIEs
• Observed kinetic isotope effect suggests proton elimination is rate limiting
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Westheimer, F. H.; Nicolaides, N. J. Am. Chem. Soc. 1949, 71, 25
Hammond‐Leffler postulateHammond Leffler postulate
• Boils down to:Boils down to:“In an elementary step, the transition state will resemble the species closest in energy”resemble the species closest in energy.
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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
pKa‐based TS symmetrypKa based TS symmetry
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Dixon, J. E.; Bruice, T. C. J. Am. Chem. Soc. 1970, 92, 905
2° Kinetic isotope effects2 Kinetic isotope effects
Primary KIE – Differences in stretchingPrimary KIE Differences in stretching
Secondary KIEH b idi ti b di H j ti– Hybridization: bending – Hyperconjugation
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2° KIE and changes in hybridization2 KIE and changes in hybridizationsp2 sp or sp3 sp2 = Normal 2° KIE
sp sp2 or sp2 sp3 = Inverse 2° KIE
16Shiner, V. J. et al. J. Am. Chem. Soc. 1968, 90, 418; Do Amaral, L. et al. J. Am. Chem. Soc. 1972, 94, 7579
2° KIE and hyperconjugation2 KIE and hyperconjugation
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Shiner, V. J.; Jewett, J. G. J. Am. Chem. Soc. 1964, 86, 945
2° KIE and hyperconjugation2 KIE and hyperconjugation
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Shiner, V. J.; Jewett, J. G. J. Am. Chem. Soc. 1964, 86, 945
Quantum TunnelingQuantum Tunneling
Phenomenon in which particles pass underPhenomenon in which particles pass under activation barrier
‐ Ordered TS ‐ Small particle
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Kwart, L. D. et al. J. Am. Chem. Soc. 1981, 103, 1232Tunneling in enzymes: Kohen, A.; Klinman, J. P. Acc. Chem. Res. 1998, 31, 397
Case study ‐ SEArCase study SEAr
Some mechanistic details cannot be unveiled by kinetics aloneSome mechanistic details cannot be unveiled by kinetics alone
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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
SEAr – Nitration of nitrobenzeneSEAr Nitration of nitrobenzene
Small observed KIE suggests that electrophilic attack is rate limiting, but…gg p g,
Hammond and Leffler postulate that this may not be the case.
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Bonner, T. G.; Bowyer, F.; Williams, G. J. Chem. Soc. 1952, 2650
Simplified energy diagramSimplified energy diagram
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Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334; Leffler, J. E. Science 1952, 117, 340
The curious case of SEArThe curious case of SEAr
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Olah, G. S.; Kuhn, S. J.; Flood, S. F. J. Am. Chem. Soc. 1961, 83, 4571Bonner, T. G.; Bowyer, F.; Williams, G. J. Chem. Soc. 1952, 2650;
Isotope‐labeling studiesIsotope labeling studies
26Matsuda, T. et al. J. Am. Chem. Soc. 2007, 129, 12086
First labeling study ‐ resultsFirst labeling study results
27Matsuda, T. et al. J. Am. Chem. Soc. 2007, 129, 12086
First labeling study ‐ proposalFirst labeling study proposal
28Matsuda, T. et al. J. Am. Chem. Soc. 2007, 129, 12086
Large 1° KIEs at natural abundanceLarge 1 KIEs at natural abundance
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Pascal, R. A. et al. J. Am. Chem. Soc. 1986, 108, 6477Saunders, W. H., Jr. et al. J. Am. Chem. Soc. 1960, 82, 138
Small 2° KIEs at natural abundanceSmall 2 KIEs at natural abundance
31Singleton, D. A.; Thomas, A. A. J. Am. Chem .Soc. 1995, 117, 9357
EpilogueEpilogue
• Kinetic isotope effects and isotope‐labelingKinetic isotope effects and isotope labelingare indispensable
• NMR techniques can measure KIEs at natural abundances with limitationsabundances, with limitations
Wh if d k i i h d• What if you need to make isotope‐enriched compounds?
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Deuterium in Synthesis
33Comprehensive review: Atzrodt, J. et al. Angew. Chem. Int. Ed. 2007, 46, 7744
Acid‐catalyzed exchangeAcid catalyzed exchange
• Dominant methodDominant methodSimple Effective Inexpensive Versatile
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High‐temperature dilute acidHigh temperature dilute acid
• Preparation of perdeuterated arenesPreparation of perdeuterated arenes– Exchange occurs at aromatic C‐H bonds only
Werstiuk, N. H.; Kadai, T. Can. J. Chem. 1973, 51, 148536
Supercritical mediaSupercritical media
• Access to perdeuterated haloarenesAccess to perdeuterated haloarenes
• Many challenges remain• Many challenges remainJunk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26, 405
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Base‐catalyzed exchangeBase catalyzed exchange
38Wähälä, K. et al. J. Labelled Compd. Radiopharm. 1995, 36, 493
Synthesis of labeled amino acidsSynthesis of labeled amino acids
39Rose, J. E.; Leeson, P. D.; Gani, D. J. Chem. Soc. Perkin Trans. 1995, 157
Synthesis of acetone‐d6Synthesis of acetone d6
Exchange reaction – incomplete deuteration
Must discard semiheavy water
Paulsen, P. J.; Cooke, W. D. Anal. Chem. 1963, 35, 156040
Syntheses of CDCl3Syntheses of CDCl3
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Breuer, F. W. J. Am. Chem. Soc. 1935, 57, 2236Paulsen, P. J.; Cooke, W. D. Anal. Chem. 1963, 35, 1560
Current industrial synthesisCurrent industrial synthesis
Circa 1965
42Kluger, R. J. Org. Chem. 1963, 29, 2045
Iridium‐catalyzed exchangeIridium catalyzed exchange
Exchange possible with a wide variety ofExchange possible with a wide variety of substrates via Iridium III‐V catalysis
43Yung, C. M. et al. J. Am. Chem. Soc. 2004, 126, 13033
Ir(III)‐Ir(V) catalytic cycleIr(III) Ir(V) catalytic cycle
44Yung, C. M. et al. J. Am. Chem. Soc. 2004, 126, 13033
Synthesis of NorzoanthamineSynthesis of Norzoanthamine
45Miyashita, M. et al. Science. 2004, 305, 495
Increased yield based on KIEIncreased yield based on KIE
46Miyashita, M. et al. Science. 2004, 305, 495
EpilogueEpilogue
• Deuterium can be introduced using classicalDeuterium can be introduced using classical synthesis
• Acid‐, base‐ and metal‐catalyzed methods are used to make common deuterated agentsused to make common deuterated agents
F b i i l f• Few but very interesting examples of deuterium in total synthesis
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