Aromaticity and the Novel Boron-Nitrogen Bond: A Benzene Mimic Jeremy Schifberg Liu 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 “The circulating π electrons in an aromatic molecule produce ring currents that oppose the applied magnetic field in NMR. The NMR signal of protons in the plane of an aromatic ring are shifted substantially further down-field than those on non-aromatic sp² carbons. This is an important way of detecting aromaticity” 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 I’ll let that image resonate for a while. No pun intended.

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, 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 (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 Shameless plug

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

Synthetic Scheme The following experiments were carried out: The N-ethyl substituent was chosen as it crystallizes readily (Allyl ethyl amine) Allyl ethyl amine was synthesized under nitrogen. It was allowed to warm overnight, was extracted with ether and distilled in fractions.

Synthetic Scheme The following experiments were carried out: The N-ethyl substituent was chosen as it crystallizes readily (Allyl ethyl amine) Allyl ethyl amine was synthesized under nitrogen. It was allowed to warm overnight, was extracted with ether and distilled in fractions. The T.M. reaction was challenging. The tin reagent is very air-sensitive and had to be handled in an inert atmosphere glovebox (more on this later). The reagents were combined at -78 degrees in a dry ice/acetone bath, stirred and allowed to warm to rt overnight. Then Characterized by B11 NMR. The solvent was then removed under vacuum and solids were filtered, followed by a vacuum distillation. This is a transmetalation/substitution reaction of the allyl ethyl amine (Ring-opened precursor)

Synthetic Scheme The following experiments were carried out: The N-ethyl substituent was chosen as it crystallizes readily (Allyl ethyl amine) Allyl ethyl amine was synthesized under nitrogen. It was allowed to warm overnight, was extracted with ether and distilled in fractions. The T.M. reaction was challenging. The tin reagent is very air-sensitive and had to be handled in an inert atmosphere glovebox (more on this later). The reagents were combined at -78 degrees in a dry ice/acetone bath, stirred and allowed to warm to rt overnight. Then Characterized by B11 NMR. The solvent was then removed under vacuum and solids were filtered, followed by a vacuum distillation. The RCM reaction was stirred in an inert atmosphere glovebox, the solvent was removed and it was vacuum distilled. This is a transmetalation/substitution reaction of the allyl ethyl amine (Ring-opened precursor) This is a ring-closing metathesis of the ring-opened precursor (Dashed lines indicate steps successfully carried out in the Liu lab but not yet successfully carried out myself) (Ring-closed precursor)

Synthetic Scheme (1,2-Azaborine) This is an oxidation/aromatization of the ring-closed precursor This reaction had to carried out in a sealed, air-free Schlenk flask. Thus, it had to be carried out in an explosion hood due to a possible pressure build-up. It was heated and stirred for 16 hours, after which the catalyst was filtered out, the solvent was removed under vacuum and the remaining solution was vacuum distilled.

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 This reaction had to carried out in a sealed, air-free Schlenk flask. Thus, it had to be carried out in an explosion hood due to a possible pressure build-up. It was heated and stirred for 16 hours, after which the catalyst was filtered out, the solvent was removed under vacuum and the remaining solution was vacuum distilled. Nucleophiles included butyl, vinyl, phenyl, t-butoxy and others

… --- > 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 1,2-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 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) As you can see, these reactions are the N-TBS analogs of the ones described earlier. However, the N-TBS compounds were much easier to work with than the N-ethyl compounds because they were less volatile and more cooperative. Allyl TBS amine was synthesized at 10 below. It was allowed to warm overnight, the solvent was removed and it was vacuum distilled. TM was again challenging. Had to add everything dropwise at -78 and let stir for a four hour period. It was allowed to warm to rt overnight, solvent removed, solids filtered, vac distill. 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 This reaction had to carried out in a sealed, air-free Schlenk flask. Thus, it had to be carried out in an explosion hood due to a possible pressure build-up. It was heated and stirred for 16 hours, after which the catalyst was filtered out, the solvent was removed under vacuum and the remaining solution was vacuum distilled. A chromium complex is formed

The TBDMS protecting group is removed Synthetic Scheme The TBDMS protecting group is removed

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-1,2-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

Allows for the manipulation of air-sensitive compounds Schlenk Lines Point out trap for making sure vapors don’t contaminate pump 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

Antechamber used to get items in and out of the box 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 1H http://www.pharmacy.olemiss.edu/rips/images/Varian600.JPG

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 BNCT would require new drugs, possibly azaborine-containing mimics, could selectively destroy tumor cells and leave healthy cells in-tact. Way far down the road.

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!