Aromaticity and the Novel BoronNitrogen Bond: A Benzene Mimic
Jeremy Schifberg
Liu Group
Background: Aromaticity
• Definition:
A chemical property
whereby a conjugated ring
exhibits a stronger-thanexpected 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
Phenylalanine and tryptophan, two
aromatic amino acids
• Characteristics Include:
– Huckel’s Rule: (4n + 2)
∏ electrons
– Characteristic NMR
Shifts
– Undergoes
Electrophilic Aromatic
Substitution
– Homogenized Bond
Lengths and Planar
Orientation
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
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
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:
The Nitrogen’s lone pair donates into the Boron P-orbital, creating
a delocalized, aromatic system mimicking that of Benzene (below)
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, prearomatic 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
(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 Boronsubstitutions 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 Boronsubstitutions 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 (1,2Dihydro-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
Synthetic Scheme
The following experiments were carried out:
The N-ethyl substituent was chosen as it crystallizes readily
(Allyl ethyl amine)
Synthetic Scheme
The following experiments were carried out:
The N-ethyl substituent was chosen as it crystallizes readily
This is a transmetalation/substitution reaction of the allyl
ethyl amine
(Allyl ethyl amine)
(Ring-opened precursor)
Synthetic Scheme
The following experiments were carried out:
The N-ethyl substituent was chosen as it crystallizes readily
This is a transmetalation/substitution reaction of the allyl
ethyl amine
(Allyl ethyl amine)
(Ring-opened precursor)
This is a ring-closing metathesis
of the ring-opened precursor
(Ring-closed
precursor)
(Dashed lines indicate
steps successfully carried
out in the Liu lab but not
yet successfully carried
out myself)
Synthetic Scheme
(1,2-Azaborine)
This is an oxidation/aromatization of the ring-closed precursor
Synthetic Scheme
(1,2-Azaborine)
This is an oxidation/aromatization of the ring-closed precursor
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
Synthetic Scheme
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
… --->
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
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
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 1,2Azaborine 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
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-Dihydro1,2-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)
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)
Synthetic Scheme
(1,2-Azaborine)
This is an oxidation/aromatization of the ring-closed precursor
A hydrogen is
substituted in place
of the chlorine
A chromium
complex is formed
Synthetic Scheme
The TBDMS protecting group is removed
Synthetic Scheme
The TBDMS protecting group is removed
1,2-Dihydro-1,2-Azaborine is successfully
synthesized for the first time!
Conclusions
• Work in the Liu Group led to the first successful
isolation of parent compound 1,2-Dihydro-1,2Azaborine, 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
11B
http://www.pharmacy.olemiss.edu/rips/images/Varia
n600.JPG
1H
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
This has been a fantastic opportunity
for me and I really appreciate all your
help and teaching
Thanks for everything!