M i l j a n i ć G r o u p M e e ti n g / L i t e r a t u r eU n i v e r s i t y o f H o u s t o n ▪ H o u s t o n , T X ▪ J a n u a r y 2 n d 2 0 0 9

Ognjen Š . Mi l janić

Azaborines from Oregon

N

BH

H

Three Papers f rom 2007 and 2008

Diversity through Isosterism:The Case of Boron-Substituted 1,2-Dihydro-1,2-azaborinesAdam, J. V. Marwitz, Eric R. Abbey, Jesse T. Jenkins, Lev N. Zakharov, Shih-Yuan LiuOrg. Lett. 2007, 9, 4905–4908.

Crystal Clear Structural Evidence for Electron Delocalization in 1,2-Dihydro-1,2-azaborinesEric R. Abbey, Lev N. Zakharov, Shih-Yuan LiuJ. Am. Chem. Soc. 2008, 130, 7250–7252.

A Hybrid Organic/Inorganic BenzeneAdam, J. V. Marwitz, Myrna H. Matus, Lev N. Zakharov, David A. Dixon, Shih-Yuan LiuAngew. Chem. Int. Ed. 2008, 47, ASAP.

Col laborative Research

Shih-Yuan Liu

Postdoc—Massachusetts Institute of Technology (2003–06, Daniel G. Nocera)PhD—Massachusetts Institute of Technology (2003, Gregory C. Fu)Diploma—Vienna University of Technology (1997)Professor at University of Oregon since 2006.

Lev N. Zakharov

Staff crystallographer at the University of Oregon (since 2004).

David A. Dixon

PhD—Harvard University (1976)BS—California Institute of Technology (1971)Professor at University of Alabama.

Oregon is Green and Pretty!

▪ Oregon is the 9 th biggest US state by area (2.5 times smaller than TX)▪ Oregon ranks as 27 th US state by population (3.7 million, 7 times smaller than TX)▪ Capital city is Salem, biggest city is Portland (600,000)▪ Moderate climate: pleasant summers and rainy (but not overly cold) winters▪ Two big universities: University of Oregon (Eugene) and Oregon State (Corvallis)▪ Well known for beer, wine, agriculture, and tourism (skiing, hiking, camping)

Boron-Conta in ing Heterocyc les are Important

Faraday, M. Philos. Trans. R. Soc. London 1825, 115, 440–466.Stock, A.; Pohland, E. Ber. Dtsch. Chem. Ges. 1926, 59, 2210–2215.

N

BH

HN

BN

B

NB

H

H

H

H

H

H

benzeneisolated by Faraday (1825)

borazinesynthesized by Stock (1926)

1,2-dihydro-1,2-azaborineunknown prior to this work

▪ Theoretically relevant in studies of aromaticity Chiavarino, B. et. al. J. Am. Chem. Soc. 1999, 121, 11204–11210.

▪ B–N bond is isoelectronic and isosteric with C=C, important for pharmaceuticalsMorin, C. Tetrahedron 1994, 50, 12521–12569.

▪ Boron neutron-capture therapy (BNCT) for cancerBarth, R. F. et. al. Clin. Cancer Res. 2005, 11, 3987–4002.

▪ Borazine is a precursor to BN ceramicsMokhtari, M. et al. Chem. Eur. J. 1996, 2, 1269–1274.

▪ Borazine is a side-product in the use of ammonia-borane in hydrogen storageMarder, T. B. Angew. Chem. Int. Ed. 2007, 46, 8116–8118.

Alkene Metathes is i s the Key Synthetic Step

Marwitz, A. J. V.; Abbey, E. R.; Jenkins, J. T.; Zakharov, L. N.; Liu, S.-Y. Org. Lett. 2007, 9, 4905–4908.

BCl2

N Et

H N Et

B Cl

N Et

B Cl

(Cy3P)2(PhCH)RuCl2

66%58%

Challenging aromatization, finally achieved with Pd black / cyclohexene:

N Et

B Cl

N Et

B Cl

oxidation

DDQ / pentane / 35 °C / 24 hPd-C / pentane / 80 °C / 16 hRu-C / cyclohexene / 80 °C / 16 hRh-Al2O3 / cyclohexene / 80 °C / 16 hPd black / cyclohexene / 80 °C / 16 hPd(PPh3)4 / benzene / 80 °C / 16 h

14 %31 %1 %27 %75 % (57 % isolated)0 %

Conditions Yield

B–Cl Bond Can be Nuc leophi l i ca l ly Substituted

Marwitz, A. J. V.; Abbey, E. R.; Jenkins, J. T.; Zakharov, L. N.; Liu, S.-Y. Org. Lett. 2007, 9, 4905–4908.

N Et

B Nu

N Et

B Cl

Nu–

Li–Bu (butyllithium)

Li–vinyl (vinyllithium)BrMg–Ph (phenylmagnesium bromide)Li–NMe2 (lithium dimethylamide)K–SCH2Ph (potassium benzylthiolate)K–OtBu (potassium t-butoxide)

79 %50 %76 %66 %80 %71 %

Nucleophile Yield

LiBEt3–H (Superhydride) 92 %

N Et

B O

N Et

B Cl OMe

O

HO OMe

ONEt385 %

Are 1 ,2-Azabor ines Aromatic?

Abbey, E. R.; Zakharov, L. N.; Liu, S.-Y. J. Am. Chem. Soc. 2008, 130, 7250–7252.

To determine this, the authors performed direct structural comparison with:

N R

B R'

N R

B R'

N R

B R'

N R

B R'

A B C D

in order to evaluate the delocalization in the fully unsaturated structure:

N R

B R'

N R

B R'

N R

B R'

N R

B R'

This study is analogous to the comparison of benzene with cyclohexadiene!

N t-Bu

B NPh2

is highly crystalline, so its analogs were used in the study.

Model Compounds Were Synthes ized Divergent ly

Abbey, E. R.; Zakharov, L. N.; Liu, S.-Y. J. Am. Chem. Soc. 2008, 130, 7250–7252.

N t-Bu

B NPh2

N t-Bu

B NPh2

N t-Bu

B NPh2

N t-Bu

B NPh2

N t-Bu

B NPh2

A B

C

D

E

10% Pd black / H2

58 %

20% Pd blackcyclohexene

17 %

4% RuCl2(PPh3)3

93 %

10% RuH(Cl)(CO)(PPh3)3

95 %

Azabor ine i s C lear ly P lanar

N R

B R'

A

N R

B R'

B

N R

B R'

C

N R

B R'

D

N R

B R'E

Abbey, E. R.; Zakharov, L. N.; Liu, S.-Y. J. Am. Chem. Soc. 2008, 130, 7250–7252.

Deloca l ization Supports Aromatic ity

N R

B R'

N R

B R'

N R

B R'

N R

B R'

A B C D

N R

B R'

E

12

34

N–B

B–C4C4–C3C3–C2C2–C1C1–N

1.4031.5841.5111.5111.5081.479

Bond Length (Å)

1.4051.5901.4931.3191.4931.477

1.4071.5591.3381.4791.5031.479

1.4171.5791.5041.4941.3191.432

1.4461.5181.3631.4121.3561.383

▪ In compounds A–D, bond between N and C is a double bond (~1.41 Å)▪ Formal double bonds in B–D lengthen upon aromatization▪ All formal single bonds shorten upon aromatization

Abbey, E. R.; Zakharov, L. N.; Liu, S.-Y. J. Am. Chem. Soc. 2008, 130, 7250–7252.

F ina l ly, the Unsubstituted Azabor ine!

Cr

BCl2

N TBS

H N TBS

B Cl

N TBS

B Cl

(Cy3P)2(PhCH)RuCl2

82%58%

N TBS

B Cl+

15 mol% Pd/C

35%

N TBS

B Cl

N TBS

B H

LiBHEt3

99%

(MeCN)3Cr(CO)3

71%B

NH

TBS

OC COCO

HF-pyridine

76%

Cr

BN

HH

OC COCO

PPh3

10% isolated yield

N H

B HMarwitz, A. J. V.; Matus, M. H.; Zakharov, L. N.; Dixon, D. A.; Liu, S.-Y.

Angew. Chem. Int. Ed. 2008, 47, ASAP.

NMR Studies Confirm Aromatic i ty

Marwitz, A. J. V.; Matus, M. H.; Zakharov, L. N.; Dixon, D. A.; Liu, S.-Y. Angew. Chem. Int. Ed. 2008, 47, ASAP.

▪ Boron S = 3/21:1:1:1 quartet

▪ Nitrogen S = 11:1:1 triplet

d(N–H)

d(B–H)NICS(0)NICS(1)RSE (kcal mol−1)DH f (kcal mol−1)

benzene

−8.76−10.39

34.120.5

8.444.9

−5.62−7.27

213.0

5.634.4

−2.02−3.0

−119.0

azaborine borazine

N–H Bond is Protic , B–H Bond i s Not Hydr id ic

CD3ODND

BH

NH

BH

H

O

no reduction

▪ The study nicely illustrates the thought process1) simple synthetic development2) fundamental structural studies3) the “holy grail” discovery

▪ Versatility in B-substitution in boron heterocycles, especially in azaborines

▪ Robustness of alkene metathesis protocols

▪ Use of Cr(CO)3 as a protecting group for the aromatic nuclei

Marwitz, A. J. V.; Matus, M. H.; Zakharov, L. N.; Dixon, D. A.; Liu, S.-Y. Angew. Chem. Int. Ed. 2008, 47, ASAP.

Notes on Prepar ing Effective S l ides▪ Design: be consistent, but rational

▪ You are presenting! Make sure the audience notices both you and the researchAvoid using laser pointer too much—it takes the focus away from you

▪ Slide Titles should be messages, not description of what you did“Compound A is Synthesized in 8 Steps” is an informative title“Synthetic Route towards Compound A” is not

▪ Use contrast to highlight differences in importanceHuman brain does not give any inherent meaning to color (except RED)

▪ Maximize “data-to-ink” ratio by minimizing “slide junk”Avoid bold arrows, borders, vignettes—they use space and convey nothing!

▪ Give credit where credit is due, preferably with pictures of peopleSmall personal details make presentation engaging (but maintain balance)

▪ Do not thank your audienceIf your presentation was any good, they should be thanking you