Organic & Biomolecular Chemistry Blog

Amino acids form the fundamental building blocks of proteins and peptides and largely control the biochemical and biophysical properties of a living organism. Incorporation of fluorine in amino acids has been an area of wide interest, because replacement of a hydrogen atom with a fluorine atom leads to a significant change in the electronic properties of a substrate and could potentially lead to a wide variation in its biological activity. The most common functional group introduced in this regard is the trifluoromethyl (-CF₃) group, which provides an alternative to the -CH₃ group in terms of its electronic properties. One very commonly available source of the -CF₃ group is ethyl 3,3,3-trifluoromethyl pyruvate, which was utilized very elegantly by Professor Mario Waser and his group in their recent report published from the Johannes Kepler University, Linz to form α-trifluoromethylated proline derivatives, which are potentially very interesting surrogates for naturally occurring proline.

Scheme 1: Diastereoselective formal (3+2) cyclization to form α-CF₃ proline derivatives

Benzyl imine derived from ethyl 3,3,3-trifluoromethyl pyruvate was treated with benzylidene indanedione (1) in the presence of LiOH to form the spirocyclic α-trifluoromethyl proline derivative 3 as the sole diastereomer (Scheme 1). It was observed that simple ammonium salts used as phase transfer catalysts could improve the conversion drastically and benzyl triethylammonium bromide (TEBAB) was found to be the best reagent for the same. This transformation exhibits a wide substrate scope with different acceptors and donors alike, while maintaining very good diastereoselectivities.

Mechanistically, the transformation is driven by the formation of the stable 2-azaallyl carbanions (4 and 4’), which by virtue of its two resonating forms could form the two different spirocyclic regioisomers 3 and 5 (Scheme 2). It was observed that the α-nucleophilic attack on the Michael acceptor 1 proceeded exclusively and there was no trace of the γ-adduct for any of the substrates. The remarkable levels of diastereoselectivity of the α-adducts adds to the ingenuity of the method.

Scheme 2: Formal (3+2) cyclization modes leading to α-CF₃ proline derivatives

This is indeed a very useful and efficient method for the construction of an unprecedented class of α-trifluoromethylated proline derivatives which can easily be incorporated in peptide chains for biological studies. There is however, room for improvement in this methodology, as the efforts towards enantioselective formation of the trifluoromethylated proline derivatives were unfortunately met with failures. The authors used cinchona alkaloid derived chiral phase transfer catalysts, which resulted in unsatisfactory enantioselectivities. A successful enantioselective protocol towards the formation of fluorinated amino acids would drive this field of research even further in future.

About the blog writer: Satrajit Indu is a recent PhD graduate from Indian Institute of Technology Bombay. His doctoral work in the group of Prof. Krishna P. Kaliappan was mainly focused on the total synthesis of complex natural products and development of new catalytic methods aimed for achieving interesting chemical transformations. A keen interest in organic chemistry coupled with an urge to communicate with the scientific community has driven him to take up blog writing.

Polycyclic aromatic hydrocarbons (PAHs) containing heteroatoms have recently been grabbing the attention of scientists as they exhibit intriguing photophysical properties and can be widely used as building blocks for π-conjugated materials due to the effect of heteroatoms on the electronic properties of the system.

PAHs are often employed in OLEDs. Over the last few years, these PAHs have been synthesized in several different ways. Kawashima et.al synthesized different acene-like π-extended dibenzoborines such as compound B which show fascinating photophysical properties. More recently, Hatakeyama et.al have reported the synthesis of various PAHs that contain multiple 1,4-azaborine rings, such as compound C, which show excellent thermally activated delayed fluorescence. By investigating these types of molecules in more detail, their electronic properties can be improved to make better OLEDs.

a) Representative examples of previously reported dibenzoazaborine-based pi-conjugated compounds and b) planarized B,N-phenylated dibenzoazaborine 1 together with reference compounds 2-4

a) UV-vis absorption and b) fluorescence spectra of 1 (red), 2 (blue), 3 (green) and 4 (orange) in THF.

In their recent OBC publication, Professor Shigehiro Yamaguchi of the Institute of Transformative Bio- Molecules, Nagoya University et al. explored in detail the relation between the structure of materials and their electronic structures. They mainly focused on the correlation between the ring-fusion mode, where two cyclic rings fused in a planar manner, and the degree of structural constraint within the dibenzoazaborine skeleton. As constraining molecules into a planar fashion can extend π-conjugation and increase chemical stability, Shigehiro planarized the B-, N- phenyl groups in dibenzoazaborine to synthesize a new family of planarized triarylboranes with a carbazole substructure, confirming this structure by single-crystal X-ray diffraction analysis. They studied the photophysical properties of 1 and compared it with compunds 2-4. Compound 1 showed an intense absorption band at λ_abs= 402 nm unlike compounds 2-4 which showed λ_abs at 389 and 371, 400, 404 and 387 nm respectively. The fluorescence spectra of compound 1 showed an intense deep blue emission with a full width at half maximum (FWHM) of 27 nm which is due to its rigid structure. The optimized structure of 1 with respect to DFT calculations matched with the experimentally determined crystal structure. They report the time dependent DFT calculations which prove compound 1 to have the highest oscillator strength (f) amongst compounds 1-4, resulting in the largest molar absorption coefficient (ε). This clearly represents that it absorbs light strongly at the given wavelength. They also studied the electrochemical properties of 1-4 using cyclic voltammetry which resulted in one reversible reduction wave irrespective of the structural constraint showing that there are no electronic effects imposed on the structural constraint.

In conclusion, Shigehiro et al. succeeded in synthesizing structurally constrained, planarized dibenzoazaborines and investigating their photophysical and electronic effects.

Read their full article at https://rsc.li/2Xw8uoA.

Blog writer description: I am A. Vamshi Krishna, pursuing a PhD in organic chemistry with Prof. D. B. Ramachary at the University of Hyderabad. My research mainly focuses on asymmetric supramolecular-organocatalysis where we synthesise highly functionalized biologically active novel scaffolds with excellent selectivity and yields. I am passionate about scientific writing.