safety moment · 2015-07-02 · chemistry nobel prize 2010 •discovering and developing highly...

Safety Moment:Distillation Station Information

Seechurn, C. C. C. J.; Kitching, M. O.; Coalacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062-5085.

Chiller Too Cold?• Dioxane (m.p. 12oC)

• Cyclohexane (m.p. 6.5oC)

• Benzene (m.p. 5.5oC)

• p-Xylene (m.p. 13oC)

• t-BuOH (m.p. 26oC)

• Cyclopentadiene dimer (m.p. 33oC)

_________________________

• Some chillers don’t temperature regulate

• Always check before going home

• Always set to an appropriate temperature

Never heat a closed system!!

Never heat a closed system!!

Buchwald-Hartwig Cross-Coupling: History and seminal developments

Tyler Lab Group Meeting : 2015/07/01

Alexander J. Kendall

Seechurn, C. C. C. J.; Kitching, M. O.; Coalacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062-5085.

Outline• I. A Brief History of Everything: Cross-Coupling for Dummies

• What is cross-coupling• Homocoupling• Cross-coupling• Early catalysis

• II. Early Catalytic Cross-Coupling• Heck, Negishi, and Suzuki• Catalytic transformations• Generalizations about cross-coupling reactions

• III. A Walk Across the Periodic Table: C-C to C-N Coupling Reactions

• Buchwald, Hartwig, and Fu• Phosphine ligands• Current state

• IV. State of the Union: C-N Bond Forming Catalysis

Disclaimer/Caveat • Lots of cross-

coupling reactions

• Focus on:• Seminal

discoveries

• Key players

• General conditions

• Mechanistic detail

Seechurn, C. C. C. J.; Kitching, M. O.; Coalacot, T. J.; Snieckus, V.

Angew. Chem. Int. Ed. 2012, 51, 5062-5085.

http://www.Wikipedia.org/crosscoupling

I. A Brief History of Everything:Cross-Coupling for Dummies

What is Cross-Coupling?• General formula:

• Combining two different organic fragments

• Metal mediated or catalyzed

• Catalytic work pioneered in the 1970’s

Why is Cross-Coupling Difficult?• Homocoupling

Wurtz, A. Ann. Chim. Phys. 1855, 44, 275-312.

Lampman, G. M; Aumiller, J. C. Org. Synth. 1971, 51, 55.


Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422-424.Baeyer, A. Berichte Dtsch. Chem. Ges. 1882, 15 (1), 50–56.


Baeyer, A. Berichte Dtsch. Chem. Ges. 1882, 15 (1), 50–56.


Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174-2185.

Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64 (2), 670–674.


• Isomerization

• Functional group intolerance

• Narrow substrate scope

• Stoichiometric metals

• Harsh reaction conditions

The First Cross-Coupling Catalysts• Job (1923)

• Studying Ni(II)Cl2, PhMgBr, and miscellaneous gasses• H2

• CO

• C2H4

• “Briefly, we believe that we have made progress by introducing catalysis into the field of organometallics.”

Job, A.; Reich, R. C. R. Hebd. Seances Acad. Sci. 1924, 179, 330-332.

The First Cross-Coupling Catalysts• Meerwein (1939)

• Homo and cross-coupling

• Non-selective

Meerwein, H.; Buchner, E.; van Emster, K. J. Prakt. Chem. 1939, 152, 237-266.

The First Cross-Coupling Catalysts• Kharasch (1941-1943)

• Homo and cross-coupling

• Non-selective Kharasch, M. S.; Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316-2320.

The First Selective Cross-Couplings• Cadiot-Chodkiewicz (1957)

• Castro-Stephens (1963)

Chodkiewicz, W.; Cadiot, P. Hebd. Seances Acad. Sci. 1955, 241, 1055-1057. : Chodkiewicz, W. Ann. Chim. Paris 1957, 2, 819-869. : Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163.

Palladium: A trash to treasure story• Discovered by Wollaston (1802)

• Considered a chemical novelty

• Upon his death in 1828, 97% of his Pd stock remained unsold

• Typically Ni and Pt preferred due to high activity

• Exceptions include:• Pd/C

• Lindlar’s catalyst

• Post WWII Europe Develops the Wacker Process (1959)

Wollaston, W. H. Philos. Trans. R. Soc. London 1805, 95, 316-330. : Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Kojer, H.; Ruttinger, R. Angew. Chem. 1959, 71, 176-182.

II. Early Catalytic Cross-Coupling

Chemistry Nobel Prize 2010• Discovering and developing highly practical

methodologies for C-C bond construction.

• Richard Heck• Developed Pd-catalyzed vinyl cross-coupling

• Worked on Wacker oxidation mechanism

• Ei-ichi Negishi• Developed Ni- and Pd-catalyzed organoaluminum and organozinc

cross-coupling

• Fleshed out transmetalation preferences in cross-coupling (including organoboron)

• Akira Suzuki• Developed Pd-catalyzed organoboron cross-coupling

• The most commonly used cross-coupling reaction

http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/

Contributions from Heck• Henry (1966)

• Heck (1966)

Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Kojer, H.; Ruttinger, R.

Angew. Chem. 1959, 71, 176-182. : Heck, R. F. Synlett 2006, 2855-2860.

The Catalytic Heck Reaction

• Heck (1968)

• Mizoroki (1971)

• Heck (1972)

Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518-5526. : Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. : Heck, R.

F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37, 2320-2322.

Heck Mechanism

Hartwig, J. Organotransition Metal Chemistry; University Science Books: Sausalito,

CA, 2010.

Contributions from Negishi

• Organoaluminum and organozinc coupling partners

• Negishi (1976)

• Negishi (1977)

Negishi, E.; Baba, S. J. Chem. Soc. Chem. Commun. 1976, 596b-597b. : Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977,

42, 1821-1823. : King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc. Chem. Commun. 1977, 683-684.

Contributions from Negishi

• Negishi (1977)

• Explored coupling partners (not just unsaturated hydrocarbons)

Suzuki

Hiyama

Stille

Kumada

Negishi

Negishi

Negishi, E. Aspects of Mechanism and Organometallic

Chemistry; Plenum: New York, NY, 1978.

By Any Other Name Would be as Simple

• General mechanism for most* Pd-catalyzed cross-couplings

• Named reactions:

• M = MgX, Kumada (1972)

• M = Zn, Negishi (1977)

• M = SnR3, Stille (1978)

• M = B(OR)2, Suzuki (1979)

• M = SiR3, Hiyama (1988)

*Notable exceptions are: Heck (olefins), Buchwald-Hartwig (amines), and phosphorus cross-coupling

Contributions by Suzuki• Cross-coupling for the common chemist

• Worked for H. C. Brown as post-doc in 1977-1978

• Based on a stoichiometric organoboron study by Heck (1975)

• Persue Negishi’s “hit” of organoboron cross-coupling (1977)• easily handled: air and water stability

• mild reaction conditions

• virtually non-toxic byproducts

• Suzuki & Miyaura (1979)

Miyaura, N.; Suzuki, A. J. Chem. Soc. Chem. Commun. 1979, 866-867.

Suzuki’s Legacy• Dependent on base used for reactivity

Uenishi, J.-I.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756-4758.

Hartwig, J. Organotransition Metal Chemistry; University Science Books: Sausalito, CA, 2010.


Kishi (1987)

Uenishi, J.-I.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756-4758.



Kishi (1987)

Palytoxin, 1994

Y. Kishi, Harvard U.

Suh, E. M.; Kishi, Y. J. Am. Chem. Soc. 1994, 116, 11205-11206.


Kishi (1987)

Palytoxin, 1994

Y. Kishi, Harvard U.

Suh, E. M.; Kishi, Y. J. Am. Chem. Soc. 1994, 116, 11205-11206.

Palythoa toxica

Some Generalizations

• M must be more electropositive than Pd for T/M step

• R can’t have β-hydrogens (tertiary, vinyl, aryl, etc.)

• Aryl:• electron rich Aryls undergo O/A slower and R/E faster

• electron poor Aryls undergo O/A faster and R/E slower

• X: I > OTf > OTs > Br >> Cl

• L:• electron rich L = O/A faster and R/E slower

• electron poor L = O/A slower and R/E faster

• Sterically large L = O/A slower and R/E faster

• Base needs appropriate pKa, can coordinate


Some Generalizations Hartwig, J. Organotransition Metal Chemistry;

University Science Books: Sausalito, CA, 2010.

III. A Walk Across the Periodic Table:C-C to C-N Coupling Reactions

I II III

Seechurn, C. C. C. J.; Kitching,

M. O.; Coalacot, T. J.; Snieckus,

V. Angew. Chem. Int. Ed. 2012,

51, 5062-5085.

Nitrogen Throws its Hat in the Ring• Seminal report by Migita (1983)

Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927-928.

Buchwald and Hartwig Take Note• Buchwald (1994)

• Hartwig (1995)

• Buchwald (1995)

Guram, A. S.; Rennels, R. A.; Buchwald,

S. L. Angew. Chem. 1995, 107, 1456-

1459.

Louie, J.; Hartwig, J. F.

Tetrahedron Lett. 1995, 36, 3609-

3612.

Guram, A. S.; Buchwald, S. L. J.

Am. Chem. Soc. 1994, 116,

7901-7902.

Buchwald-Hartwig Mechanism (simple)


A Ligand, a Ligand, My Kingdom for a Ligand!• Buchwald (1995)

• o-Biphenyl, dialkyl phosphine

• DavePhos (1995)

• S-Phos (2005)

• Hartwig (1996)• Bulky heteroleptic phosphines

• Adamantyl (1996)

• Q-Phos (2005)

• Fu (1998)• Bulky, e- rich phosphines

• Used for Ar-Cl cross-coupling

http://www.sigmaaldrich.com

S. Buchwald’s Contributions• Fine-tuned ligand effects

• Suzuki

• Buchwald-Hartwig

• C-O bond formation

• C-F bond formation

• “Ammonia” cross-coupling

• LiN(TMS)2

• LiNH2

Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417-3419. : Martin, R.; Buchwald, S. L. Acc. Chem. Rev. 2008, 11, 1461-1473. : Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338-6361.

J. Hartwig’s Contributions• Mechanistic details

• Cross-coupling kinetics

• Individual rate constants (k1, k2, etc.)

Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 12905-12906.

J. Hartwig’s Contributions• Active species

• Pd(I) dimer

Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem. 2002, 114, 4940-4942.

G. Fu’s Contributions

• Ar-Cl Activation• Focused on bulky and e- rich phosphines

• Largely pragmatic solutions to synthesis

• Extreme Biaryl Coupling• Sterically demanding

• Exotic substrates

• Electronically demanding

• Typically Works on Suzuki Coupling• Many of his ligands are used for Buch.-Hart. amminations

Fu, G. C. Acc. Chem. Res. 2008, 41, 1555-1564.

IV. State of the Union: C-N Bond Forming Catalysis

Summary• Cross-coupling is a powerful tool for bond formation

• Typically Pd, Ni, or Pt mediated

• Used for aryl-R bond formation (R= alkyl, vinyl, aryl, BR2, NR2, OR, F)

• Very mild conditions can be used thanks to metals being chemoselective

Crabtree, R. H. Chem. Rev. 2015, 115, 127-150.

• Relies on organometallic mechanisms

• Understanding these steps leads to major advances

• Convoluted mechanisms often arise from simple models

• Subtle influences on TS’s have major effects

• Major advances currently being made in ligand design and influence

• The (cross-coupling) world is your oyster

Are You Not Entertained?!• Very e- rich aryl chlorides still difficult

• ex) grisofulvan

• O/A typically rate-limiting step• Better ligands mean faster catalysis• 1 vs 2 e- processes - Pd(I) vs Pd(II) - lend selectivity to

catalysis

• Kinetics not well explored for most systems• Namely Buchwald-type• Structure-function studies lacking

• β-hydride elimination and primary amines are still problematic

• Ligands determine reactivity in modern systems

__________________________

• It’s still voodoo in most cases

"GLADIATOR [Director's cut] (15)". British Board of Film Classification. 2005-08-05

QUESTIONS

safety moment · 2015-07-02 · chemistry nobel prize 2010 •discovering and developing highly...

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