Aromaticity and the Novel Boron-Nitrogen Bond: A Benzene Mimic

Jeremy SchifbergLiu Group

Background: Aromaticity• Definition:

A chemical property whereby a conjugated ring exhibits a stronger-than-expected stabilization due to its electrons being free to cycle around the ring atoms. A hybrid of a single and a double bond is formed, with each bond in the ring identical to the next.

=

P Orbitals Delocalized orbitals

http://en.wikipedia.org/wiki/Aromaticity

Background: Aromaticity• Why It’s Important:– Aromatic compounds

exhibit enhanced stability

– Aromatic compounds are common in nature

• Characteristics Include:– Huckel’s Rule: (4n + 2)

∏ electrons– Characteristic NMR

Shifts– Undergoes

Electrophilic Aromatic Substitution

– Homogenized Bond Lengths and Planar Orientation

H2N CH C

CH2

OH

O

H2N CH C

CH2

OH

O

HN

Phenylalanine and tryptophan, two aromatic amino acids

Benzene: The Quintessential Aromatic Compound

• All the C-C bonds are the same length – greater than a double bond, shorter than a single bond

• The C-C bonding electrons are delocalized over the six carbons

• This aromatic delocalization gives benzene great stability

• Benzene is everywhere: from industrial solvents to pharmaceuticals to natural compounds, benzene is one of the most fundamental and ubiquitous compounds in chemistry

Introducing Our Compound of Interest: 1,2-Dihydro-1,2-Azaborine

N

B

R

R

R

R

Why 1,2-Azaborines?

Isostructural and Isoelectronic

• They are isostructural and isoelectronic with benzene, an incredibly important compound

• If they share chemical properties with benzene (i.e. aromaticity), biomimetic possibilities that utilize unique B-N chemistry could be

significant and are virtually unexplored

Theorized Electron Delocalization and Ionic Character of 1,2-Azaborines

B

N

X

Bn

B

N

X

BnN

B

X

Bn

The Nitrogen’s lone pair donates into the Boron P-orbital, creating a delocalized, aromatic system mimicking that of Benzene (below)

1,2-Azaborines have long been considered aromatic compounds because they were found to be extra stable in related polycycles, and because of this resonance picture:

However, until recently, there had been little physical evidence of electron delocalization. How does one collect evidence of the aromaticity of these compounds?

Crystallographic Analysis

• Bond Homogenization

Single bonds are shorter and double bonds are

longer in aromatic compounds when

compared to equivalent, pre-

aromatic compounds

• Ring Planarity

Aromatic compounds are planar so as to facilitate

their characteristic electron delocalization. If aromatized, puckered

compounds become planar.

X-ray crystallography can provide evidence of both of these characteristics of aromatic compounds

1,2-Azaborines Exhibit Aromatic Qualities

• Previous work in the Liu lab included the synthesis of these pre-aromatic reference heterocycles:

• The double and single bonds in the reference compounds were compared with the delocalized bonds in the corresponding 1,2-Azaborine:

• Differences in planarity were compared as well

B

N

R1

R2

B

N

R1

R2

B

N

R1

R2

B

N

R1

R2

B

N

R1

R2

(J. Am. Chem. Soc. 2008, 130, 7250)

1,2-Azaborines Exhibit Aromatic Qualities

• The work provided strong evidence for the aromaticity of 1,2-Azaborines

Previous Work in the Liu Lab

• Previous work in the Liu lab also provided synthetic strategies for greatly increasing the scope of Boron-

substitutions in 1,2-Azaborines

• With their synthetic scope expanded and the evidence of their aromaticity strengthened, 1,2-Azaborines were clearly

established as compounds of interest

Previous Work in the Liu Lab

• Previous work in the Liu lab also provided synthetic strategies for greatly increasing the scope of Boron-

substitutions in 1,2-Azaborines

• With their synthetic scope expanded and the evidence of their aromaticity strengthened, 1,2-Azaborines were clearly

established as compounds of interest

But questions still remained…

Questions Guiding My Research and Ongoing Work in the Liu Lab

1) How do Boron substituents affect aromaticity in 1,2-Azaborines?

2) How can the parent 1,2-Azaborine (1,2-Dihydro-1,2-Azaborine) be successfully isolated?

1. How do Boron substituents affect aromaticity in 1,2-Azaborines?

• The aromaticity of 1,2-Azaborines arises out of this resonance:

• However, how exocyclic (“X”) substituents affect this aromaticity is not known

• We devised and carried out synthetic schemes to test how various electron-withdrawing, electron-donating Boron and other substituents affect the aromaticity of 1,2-Azaborines

1. How do Boron substituents affect aromaticity in 1,2-Azaborines?

Hypothesis:• We postulated that, for example, electron-donating

groups might disrupt aromaticity:

• In order to test this, however, we had to synthesize and obtain crystal structures of the compounds

N

B

OR

BnN

B

OR

Bn

Synthetic Scheme

The following experiments were carried out:

NH2Br

0 C rtEt2O

HN

(Allyl ethyl amine)The N-ethyl substituent was chosen as it crystallizes readily

Synthetic Scheme

The following experiments were carried out:

NH2Br

0 C rtEt2O

HN

(Allyl ethyl amine)The N-ethyl substituent was chosen as it crystallizes readily

This is a transmetalation/substitution reaction of the allyl ethyl amine

(Ring-opened precursor)

Ph3SnBCl3

HN NEt3

NEt

BCl

-78 C rt

Pentane/CH2Cl2/Hexane

Synthetic Scheme

The following experiments were carried out:

NH2Br

0 C rtEt2O

HN

(Allyl ethyl amine)The N-ethyl substituent was chosen as it crystallizes readily

This is a transmetalation/substitution reaction of the allyl ethyl amine

(Ring-opened precursor)

Ph3SnBCl3

HN NEt3

NEt

BCl

-78 C rt

Pentane/CH2Cl2/Hexane

(Ring-closed precursor)

This is a ring-closing metathesis of the ring-opened precursor

N

Et

B

ClRu

Cl

Cl

P(Cy)3

P(Cy)3

Ph

(Grubbs 1st Generation Catalyst)N

B

Cl

Et

(Dashed lines indicate steps successfully carried out in the Liu lab but not yet successfully carried

out myself)

Synthetic Scheme

This is an oxidation/aromatization of the ring-closed precursor

(1,2-Azaborine)N

B

Cl

Et

Pd/C85 C

N

B

Cl

Et

Synthetic Scheme

This is an oxidation/aromatization of the ring-closed precursor

(1,2-Azaborine)

From here, nucleophilic substitution reactions were carried out to place various substituents on Boron, creating the compounds

for the x-ray crystallographic analysis portion of the project

N

B

Cl

Et

Pd/C85 C

N

B

Cl

Et

N

B

Cl

Et

Nu-

N

B

Nu

Et

Synthetic Scheme

X-ray crystal structures of these compounds give information regarding bond homogenization, ring planarity and structure geometry. This can then reveal the sought-after information regarding the affect of

various exocyclic substituents on aromaticity

NH3 0 C rt

DMSOHN

BrNaI

The preceding scheme was also carried out with an N-benzyl starting material, as the benzyl substituent aids in making the final products

readily crystallizable

N

B

Nu

Bn

… --->

Conclusions The results of the x-ray crystal studies offer quantitative evidence of

substituent affects on aromaticity. For example, we postulated that an electron-donating group would disrupt aromaticity:

However, x-ray crystal results didn’t exhibit this phenomenon. Although the results showed that the geometry was prime for oxygen’s lone pair to donate , no difference was seen in the B-N bond length, indicating that aromaticity, perhaps, wasn’t disrupted. Based off the crystals obtained thus far, the trend is that aromaticity is not disrupted

We are continuing to work on trying more, varied substituents to gain a more full understanding of how they affect aromaticity

N

B

OR

BnN

B

OR

Bn

Significance

The biomimetic substitution of 1,2-Azaborines has great potential but is a subject about which little is known

Understanding how different types of substituents affect the aromaticity of the compounds is crucial if they are to

maintain biochemical significance

This study could provide the information necessary to ensure these compounds retain their aromaticity and thus are able

to fulfill biochemical roles

2. How can the parent 1,2-Azaborine be successfully isolated?

• The parent 1,2-Azaborine (1,2-Dihydro-1,2-Azaborine) is of significant interest as it is the family’s core benzene analog

N

B

H

HN

B

H

H

C

C

H

H

Compare with:

• Although various B-N substituted 1,2-Azaborines had been successfully synthesized, this important parent compound had never

before been isolated!• We devised and carried out a synthetic scheme to isolate 1,2-Dihydro-

1,2-Azaborine for the first time• This project also investigated the synthetic flexibility of the parent

compound via the replacement of a TBDMS protecting group with various substituents

Synthetic Scheme

The following experiments were carried out:

(Allyl TBDMS amine)

NH2 0 C rtCH2Cl2

HN

TBDMSTBDMSCl

-1

This is a transmetalation/substitution reaction of the allyl TBDMS amine

(Ring-opened precursor)

This is a ring-closing metathesis of the ring-opened precursor

(Ring-closed precursor)

N

TBDMS

B

ClRu

Cl

Cl

P(Cy)3

P(Cy)3

Ph

(Grubbs 1st Generation Catalyst)N

B

Cl

TBDMS

Ph3SnBCl3

HN

TBDMSNEt3

NTBDMS

BCl

-78 C rt

Pentane/CH2Cl2/Hexane

Synthetic Scheme

This is an oxidation/aromatization of the ring-closed precursor

(1,2-Azaborine)N

B

Cl

TBDMS

Pd/C85 C

N

B

Cl

TBDMS

A hydrogen is substituted in place of the chlorine

A chromium complex is formed

N

B

Cl

TBDMS

LiHBEt3

N

B

H

TBDMS

Cr(CO)3

N

B

H

TBDMS

(MeCN)3Cr(CO)3

B

N

TBDMS

H

Synthetic Scheme

The TBDMS protecting group is removed

Cr(CO)3

B

N

TBDMS

HHF-pyridine

Cr(CO)3

B

N

H

H

Cr(CO)3

B

N

H

HPPh3

N

B

H

H

Synthetic Scheme

The TBDMS protecting group is removed

1,2-Dihydro-1,2-Azaborine is successfully synthesized for the first time!

Cr(CO)3

B

N

TBDMS

HHF-pyridine

Cr(CO)3

B

N

H

H

Conclusions

• Work in the Liu Group led to the first successful isolation of parent compound 1,2-Dihydro-1,2-

Azaborine, the core B-N benzene analog

• The same successful synthetic scheme can likely be used for investigations of the compound’s synthetic flexibility via replacement of the TBDMS protecting group with various substituents. This is a project

that continues to be worked on in the Liu Lab

Significance• The parent 1,2-Azaborine has the potential to

be a very important compound in furthering understanding of chemistry in a broad sense due to its relationship with benzene

• It’s successful isolation is a crucial step in furthering study of the family of compounds

• The investigations of synthetic flexibility that this project continues to further have potential biomimetic applications

Experimental Techniques

• Many of the compounds described in the preceding schemes are air and moisture sensitive

• I was trained in Schlenk line and glovebox techniques

• Most of the reaction steps were carried out in an inert atmosphere glovebox and/or using Schlenk lines

Schlenk Lines

• A dual-manifold apparatus. One manifold is used for an inert gas while the other is connected to a vacuum pump.

• Allows for the manipulation of air-sensitive compounds

Glovebox

• A sealed container that allows for the handling of compounds requiring an inert environment

• Antechamber used to get items in and out of the box

Product Purification and Characterization

• Column chromatography and, in particular, vacuum distillations were used extensively for product purification

• I was trained in the use of hands-on NMR, and 1H and 11B NMR were used for product characterization

http://www.pharmacy.olemiss.edu/rips/images/Varian600.JPG

1H11BN

B

Cl

TBDMS

Summary of Research• X-ray crystallography used to get quantitative measures of

atomic coordinates• Bond length homogenization and ring planarity used as

evidence for aromaticity of 1,2-Azaborines• Electron-donating exocyclic substitutents didn’t have

postulated aromaticity-disrupting affect – testing of other groups continues

• Parent 1,2-Dihydro-1,2-Azaborine successfully isolated for the first time and investigations of synthetic flexibility continue

• My work was chiefly in synthesizing many of the compounds needed for crystallographic study. Many of the reaction steps were run multiple times – to adjust conditions so as to maximize yields and to bring up more product– and many steps had to be conducted over multiple days

Future Directions and Possible Applications

• Continue in-depth studies of 1,2-Azaborine stability, synthetic flexibility and substitution affects by obtaining crystals with different groups

• Biomimetic applications – utilize unique 11B to track imitated biomolecules, etc.

• Boron is not common in biology, 1,2-Azaborines could help with new biochemcial explorations

• Boron-Neutron Capture Therapy: 10B nucleus + neutron 11B nuclear fission Possible future applications in cancer therapy with 10B-

containing tumor selecting drugs allowing for destruction of individual cancer cells

Acknowledgements

• Dr. Liu• My mentor: Adam Marwitz• All the helpful Liu Group members:– Ashley, Ben, Eric, Pat, Adam G.

• SPUR• Dr. O’Day

Thanks for everything!

This has been a fantastic opportunity for me and I really appreciate all your help and teaching