Crystal structures, Hirshfeld analysis, and energy framework analysis of two differently 3'-substituted 4-methylchalcones: 3'-(N=CHC6H4-p-CH3)-4-methylchalcone and 3'-(NHCOCH3)-4-methylchalcone.

Two crystal structures of chalcones, or 1,3-diarylprop-2-en-1-ones, are presented; both contain a p-methyl substitution on the 3-Ring, but differ with respect to the m-substitution on the 1-Ring. Their systematic names are (2E)-3-(4-methylphenyl)-1-(3-{[(4-methylphenyl)methylidene]amino}phenyl)prop-2-en-1-one (C24H21NO) and N-{3-[(2E)-3-(4-methylphenyl)prop-2-enoyl]phenyl}acetamide (C18H17NO2), which are abbreviated as 3'-(N=CHC6H4-p-CH3)-4-methylchalcone and 3'-(NHCOCH3)-4-methylchalcone, respectively. Both chalcones represent the first reported acetamide-substituted and imino-substituted chalcone crystal structures, adding to the robust library of chalcone structures within the Cambridge Structural Database. The crystal structure of 3'-(N=CHC6H4-p-CH3)-4-methylchalcone exhibits close contacts between the enone O atom and the substituent arene ring, in addition to C...C interactions between the substituent arene rings. The structure of 3'-(NHCOCH3)-4-methylchalcone exhibits a unique interaction between the enone O atom and the 1-Ring substituent, contributing to its antiparallel crystal packing. In addition, both structures exhibit π-stacking, which occurs between the 1-Ring and R-Ring for 3'-(N=CHC6H4-p-CH3)-4-methylchalcone, and between the 1-Ring and 3-Ring for 3'-(NHCOCH3)-4-methylchalcone.

Structural effects of halogen bonding in iodochalcones.

The structures of three iodochalcones, functionalized with fluorine or a nitro group, have been investigated to explore the impact of different molecular electrostatic distributions on the halogen bonding within each crystal structure. The strongly withdrawing nitro group presented a switch of the halogen bond from a lateral to a linear motif. Surprisingly, this appears to be influenced by a net positive shift in charge distribution around the lateral edges of the σ-hole, making the lateral I...I bonding motif less preferable. A channel of amphoteric I...I type II halogen bonds is observed for a chalcone molecule, which was not previously reported in chalcones, alongside an example of the common synthon involving extended linear chains of I...O2N donor-acceptor halogen bonds. This work shows that halogenated chalcones may be an interesting target for developing halogen bonding as a significant tool within crystal engineering, a thus far underexplored area for this common structural motif.

Crystal structures of three functionalized chalcones: 4'-di-methyl-amino-3-nitro-chalcone, 3-di-methyl-amino-3'-nitrochalcone and 3'-nitro-chalcone.

The structure of three functionalized chalcones (1,3-di-aryl-prop-2-en-1-ones), containing combinations of nitro and di-methyl-amino functional groups, are presented, namely, 1-[4-(di-methyl-amino)-phen-yl]-3-(3-nitro-phen-yl)prop-2-en-1-one, C17H16N2O3, Gp8m, 3-[3-(di-methyl-amino)-phen-yl]-1-(3-nitro-phen-yl)prop-2-en-1-one, C17H16N2O3, Hm7m and 1-(3-nitro-phen-yl)-3-phenyl-prop-2-en-1-one, C15H11NO3, Hm1-. Each of the mol-ecules contains bonding motifs seen in previously solved crystal structures of functionalized chalcones, adding to the large dataset available for these small organic mol-ecules. The structures of all three of the title compounds contain similar bonding motifs, resulting in two-dimensional planes of mol-ecules formed via C-H⋯O hydrogen-bonding inter-actions involving the nitro- and ketone groups. The structure of Hm1- is very similar to the crystal structure of a previously solved isomer [Jing (2009 ▸). Acta Cryst. E65, o2510].

Crystal structure and Hirshfeld analysis of 3'-bromo-4-methyl-chalcone and 3'-cyano-4-methyl-chalcone.

Two crystal structures of chalcones, or 1,3-di-aryl-prop-2-en-1-ones, are presented; both contain a methyl substitution on the 3-Ring, but differ on the 1-Ring, bromo versus cyano. The compounds are 3'-bromo-4-methyl-chalcone [systematic name: 1-(2-bromo-phen-yl)-3-(4-methyl-phen-yl)prop-2-en-1-one], C16H13BrO, and 3'-cyano-4-methyl-chalcone {systematic name: 2-[3-(4-methyl-phen-yl)prop-2-eno-yl]benzo-nitrile}, C17H13NO. Both chalcones meaningfully add to the large dataset of chalcone structures. The crystal structure of 3'-cyano-4-methyl-chalcone exhibits close contacts with the cyano nitro-gen that do not appear in previously reported disubstituted cyano-chalcones, namely inter-actions between the cyano nitro-gen atom and a ring hydrogen atom as well as a methyl hydrogen atom. The structure of 3'-bromo-4-methyl-chalcone exhibits a type I halogen bond, similar to that found in a previously reported structure for 4-bromo-3'-methyl-chalcone.

The solubility and stability of heterocyclic chalcones compared with trans-chalcone.

Heterocyclic chalcones are a recently explored subgroup of chalcones that have sparked interest due to their significant antibacterial and antifungal capabilities. Herein, the structure and solubility of two such compounds, (E)-1-(1H-pyrrol-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one and (E)-3-phenyl-1-(1H-pyrrol-2-yl)prop-2-en-1-one, are assessed. Single crystals of (E)-1-(1H-pyrrol-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one were grown, allowing structural comparisons between the heterocyclic chalcones and (2E)-1,3-diphenylprop-2-en-1-one, trivially known as trans-chalcone. The two heterocyclic chalcones were found to be less soluble in all solvents tested and to have higher melting points than trans-chalcone, probably due to their stronger intermolecular interactions arising from the functionalized rings. Interestingly, however, it was found that the addition of the thiophene ring in (E)-1-(1H-pyrrol-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one increased both the melting point and solubility of the sample compared with (E)-3-phenyl-1-(1H-pyrrol-2-yl)prop-2-en-1-one. This observation may be key for the future crystal engineering of heterocyclic chalcones for pharmaceutical applications.

Crystal structure and Hirshfeld surface analysis of (E)-3-(3-iodo-phen-yl)-1-(4-iodo-phen-yl)prop-2-en-1-one.

The title compound, C15H10I2O, is a halogenated chalcone formed from two iodine substituted rings, one para-substituted and the other meta-substituted, linked through a prop-2-en-1-one spacer. In the mol-ecule, the mean planes of the 3-iodo-phenyl and the 4-iodo-phenyl groups are twisted by 46.51 (15)°. The calculated electrostatic potential surfaces show the presence of σ-holes on both substituted iodines. In the crystal, the mol-ecules are linked through type II halogen bonds, forming a sheet structure parallel to the bc plane. Between the sheets, weak inter-molecular C-H⋯π inter-actions are observed. Hirshfeld surface analysis showed that the most significant contacts in the structure are C⋯H/H⋯C (31.9%), followed by H⋯H (21.4%), I⋯H/H⋯I (18.4%). I⋯I (14.5%) and O⋯H/H⋯O (8.1%).

Potential nonadiabatic reactions: ring-opening 4,6-dimethylidenebicyclo[3.1.0]hex-2-ene derivatives to aromatic reactive intermediates.

Potential singlet-triplet surface crossings for the ring opening of 4,6-dimethylidenebicyclo[3.1.0]hex-2-ene derivatives were explored using density functional theory (DFT) and complete active space self-consistent field (CASSCF) methods. Since these ring openings involve relatively high energy species that lead to relatively stable aromatic species, a good scenario for potential nonadiabatic events, we posited that the reaction paths of these ring openings might come close to or cross excited state surfaces. At the DFT level of theory, all reaction paths exhibited characteristics suggestive of singlet-triplet intersections along their paths. 6-Methylidenebicyclo[3.1.0]hex-3-en-2-one and a closely related derivative (4-methylidenebicyclo[3.1.0]hex-2-en-6-one) were explored at the CASSCF level of theory; CASSCF results were qualitatively similar to DFT results and yielded spin-orbit couplings of 1.1-1.4 cm(-1) at the singlet-triplet crossing points.

Efforts toward developing probes of protein dynamics: vibrational dephasing and relaxation of carbon-deuterium stretching modes in deuterated leucine.

The spectral position of C-D stretching absorptions in the so-called "transparent window" of protein absorption (1800-2300 cm(-1)) makes them well suited as probes of protein dynamics with high temporal and structural resolution. We have previously incorporated single deuterated amino acids into proteins to site-selectively follow protein folding and ligand binding by steady-state FT IR spectroscopy. Ultimately, our goal is to use C-D bonds as probes in time-resolved IR spectroscopy to study dynamics and intramolecular vibrational energy redistribution (IVR) in proteins. As a step toward this goal, we now present the first time-resolved experiments characterizing the population and dephasing dynamics of selectively excited C-D bonds in a deuterated amino acid. Three differently deuterated, Boc-protected leucines were selected to systematically alter the number of additional C-D bonds that may mediate IVR out of the initially populated bright C-D stretching mode. Three-pulse photon echo experiments show that the steady-state C-D absorption linewidths are broadened by both homogeneous and inhomogeneous effects, and transient grating experiments reveal that IVR occurs on a subpicosecond time scale and is nonstatistical. The results have important implications for the interpretation of steady-state C-D spectra and demonstrate the potential utility of C-D bonds as probes of dynamics and IVR within a protein.

Direct observation of structural heterogeneity in a beta-sheet.

Structural heterogeneity is thought to be inherent in many proteins and may be important for their folding and/or function. However, it is difficult to detect by conventional methods. Carbon-deuterium bonds are environmentally sensitive, nonperturbative probes of protein environments whose observation and characterization are facilitated by their unique stretching absorption frequency in an otherwise unobscured region of the IR spectrum. We demonstrate that deuterium atoms incorporated at C(alpha) backbone positions (C(alpha)-D bonds) are sensitive to the local backbone structure and thus may be used not only to detect structural heterogeneity but also to help characterize it structurally. Density functional theory calculations are used to predict that C(alpha)-D bonds of glycine are sensitive to their local structure, with the absorptions red-shifted for an extended beta-sheet relative to gamma- and alpha-helix-like turns. These predictions are confirmed using the N-terminal Src homology 3 (nSH3) domain from the human CrkII adaptor protein, whose function as a signaling domain may require structural heterogeneity. Four nSH3 variants were synthesized in which individual glycine residues were site-specifically modified with C(alpha)D(2) glycine residues. Not only were the C(alpha)-D bonds incorporated within the beta-sheet of nSH3 more red-shifted than those incorporated within loops, but the data also reveal that nSH3 populates at least two discrete beta-sheet core structures. Moreover, the data suggest that the folded core of nSH3 may be less ordered than previously believed and also that the unfolded state may be more ordered than previously thought, and both of these factors may influence the folding and function of these important signaling domains. The C-D-based IR technique should be generally useful in the characterization of structure and heterogeneity of both folded and unfolded states.

Structural and rate studies of the formation of substituted benzynes.

The key elimination step for the formation of 3-substituted and 3,6-disubstituted benzynes from 2-haloaryllithiums displays a pronounced solvent-dependent regioselectivity. All 2-haloaryllithiums with electron withdrawing groups in the 6 position are shown by 6Li and 13C NMR spectroscopic studies to be monomers in THF. DFT computational studies implicate trisolvates. Rate studies reveal that LiF eliminates via monomer-based pathways requiring THF dissociation whereas LiCl eliminates via nondissociative pathways. Elimination to form 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity that is traced to competing solvent-dissociative and nondissociative dissociative pathways for the elimination of LiCl and LiF, respectively.

Infrared line shape of an alpha-carbon deuterium-labeled amino acid.

The viability of alpha-carbon deuterated bonds (Calpha-D) as infrared (IR) probes of protein backbone dynamics was explored through a combination of experiment and theory. alpha-Carbon deuterated alanine (Ala-d1) served as a convenient model system for a comparison of experiment, density functional theory (DFT), and combined quantum mechanical/molecular mechanical (QM/MM) simulations of the Calpha-D IR line shape. In addition to the primary Calpha-D absorption, the experimental spectrum contains three features that likely result from Fermi resonances. DFT calculations supported the assignments and identified the lower frequency modes participating in the Fermi resonances. A QM/MM simulation of the Ala-d1 line shape was in qualitative agreement with the experiment, including the presence of classical analogues of Fermi resonances. These studies demonstrated that the Calpha-D line shape is sensitive, via Fermi resonances, to lower frequency collective vibrations that are expected to play a role in protein dynamics and function, and that the QM/MM approach, which is applicable to proteins, is capable of aiding in their interpretation.

Efforts toward developing direct probes of protein dynamics.

We report the first IR characterization of a single C-D bond within a protein, methyl-d1 Met80 of horse heart cytochrome c. A comparison was made to methyl-d1/d3 methionine as well as methyl-d3 Met80. We found that for methyl-d1 and the asymmetric stretches of methyl-d3, line widths/line shapes are dominated by inhomogeneous broadening, whereas the symmetric stretch of methyl-d3 has a significant homogeneous component. Vibrational energy relaxation calculations found that a significantly stronger Fermi resonance exists for the symmetric stretch than for the asymmetric stretches, thereby suggesting that a difference in intramolecular vibrational relaxation (IVR) causes the observed line width/line shape difference between the symmetric and asymmetric stretches.

Mechanistic studies on the cyclization of (Z)-1,2,4-heptatrien-6-yne in methanol: a possible nonadiabatic thermal reaction.

Myers et al. pyrolyzed (Z)-1,2,4-heptatrien-6-yne (1) in methanol at 100 degrees C and observed benzylmethyl ether (2) as a major product and 2-phenylethanol (3) as a minor product. If a biradical intermediate, such as the open-shell singlet state of alpha,3-didehydrotoluene (4), was the only intermediate generated by the cyclization, then reaction with methanol might be expected to afford 2-phenylethanol as the principal product. The question that has been of interest since its first discovery is the origin of the principal product of the title reaction, benzylmethyl ether. This report considers three mechanisms for formation of the benzylmethyl ether: direct methanol participation in the cyclization of the reactant, partial ether formation from the biradical 4, or involvement of the closed-shell zwitterionic state of alpha,3-didehydrotoluene (5). A fourth mechanism, involving a cyclic allene intermediate, has been ruled out by earlier studies. In the present work, the first two mechanisms are ruled out by experiment and/or calculation. The remaining one, involving the zwitterion, is shown to be consistent with experimental and computational data only if a component of the reaction follows a nonadiabatic course.

Access to an excited state via the thermal ring-opening of a cyclopropylidene.

[reaction: see text] Thermal generation of singlet excited states is unusual in organic chemistry. The potential energy surface for the thermal ring-opening of 4-methylene-bicyclo[3.1.0]hex-2-ene-6-ylidene (1) was calculated at the CASSCF level of theory and found to produce alpha,3-didehydrotoluene in its biradical ground state (S(0)) and/or its zwitterionic excited state (S(1)).