Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

Design and Discovery of Water-Soluble Benzooxaphosphole-Based Ligands for Hindered Suzuki-Miyaura Coupling Reactions with Low Catalyst Load.

We report a new class of highly effective, benzooxaphosphole-based, water-soluble ligands in the application of Suzuki-Miyaura cross-coupling reactions for sterically hindered substrates in aqueous media. The catalytic activities of the coupling reactions were greatly enhanced by the addition of catalytic amounts of organic phase transfer reagents, such as tetraglyme and tetrabutylammonium bromide. The optimized general protocol can be conducted with a low catalyst load, thereby providing a practical solution for these reactions. The viability of this new Suzuki-Miyaura protocol was demonstrated with various substrates to generate important building blocks, including heterocycles, for the synthesis of biologically active compounds.

The Design of "Neutral" Carbanions with Intramolecular Charge Compensation.

Strategies to construct zwitterionic anions from the parent anions are proposed. Two principles are employed; the cationic counterpart is (a) attached as a substituent or (b) inserted as an integral part at a remote location in the assembly. The optimized geometries reveal that a striking similarity exists between the zwitterions and the respective precursor parent anion. The computed vibrational frequencies emphasize that these novel entities are minima on their respective potential energy surfaces. A substantial HOMO-LUMO gap indicates that the proposed structures do not show instability in their respective electronic states and that the higher energy configuration states do not contribute to the ground state viability. The separation of charge between the monopoles in these zwitterions is demonstrated by moderately large nonzero dipole moments. Significant large energy barriers for rearrangement to the closely related positional isomers, demonstrated in a few cases, advocate the thermal stability (associated with spectroscopic viability) of the novel molecules. The donor capacity (basicity) of the anionic subunit in these zwitterions is comparable to that of the respective parent anions. Since the qualitative and quantitative features in the designed charged compensated complexes are conserved as anions, these molecules may perhaps be employed in synthetic organic or organometallic chemistry.

The geometry and electronic topology of higher-order charged Möbius annulenes.

Higher-order aromatic charged Möbius-type annulenes have been L(k) realized computationally. These charged species are based on strips with more than one electronic half-twist, as defined by their linking numbers. The B3LYP/6-311+G(d,p) optimized structures and properties of annulene rings with such multiple half-twists (C(12)H(12)(2+), C(12)H(12)(2-), C(14)H(14), C(18)H(18)(2+), C(18)H(18)(2-), C(21)H(21)(+), C(24)H(24)(2-), C(28)H(28)(2+), and C(28)H(28)(2-)) have the nearly equal C-C bond lengths, small dihedral angles around the circuits, stabilization energies, and nucleus-independent chemical shift values associated with aromaticity. The topology and nature of Möbius annulene systems are analyzed in terms of the torus curves defined by electron density functions (rho(r)(pi), ELF(pi)) constructed using only the occupied pi-MOs. The pi-torus subdivides into a torus knot for annulenes defined by an odd linking number (L(k) = 1, 3pi) and a torus link for those with an even linking number (L(k) = 2, 4pi). The torus topology is shown to map onto single canonical pi-MOs only for even values of L(k). Incomplete and misleading descriptions of the topology of pi-electronic Möbius systems with an odd number of half twists result when only signed orbital diagrams are considered, as is often done for the iconic single half twist system.

4n pi electrons but stable: N,N-dihydrodiazapentacenes.

Despite having 4n pi electrons, dihydrodiazapentacenes are more viable than their 4n+2 pi azapentacene counterparts. Ab inito valence bond block-localized wave function (BLW) computations reveal that despite having 4n pi electrons, dihydrodiazapentacenes are stabilized and benefit substantially from four dihydropyrazine ethenamine (enamine) conjugations. Almost all of these dihydrodiazapentacenes have large negative overall nucleus independent chemical shifts NICS(0)(pizz) values even though their dihydropyrazine rings (e.g., for 6-H(2)) are modestly antiaromatic, as their paratropic contributions are attenuated by delocalization throughout the system.

A neutral Ga(6) octahedron: synthesis, structure, and aromaticity.

Potassium graphite reduction of L:Ga(Mes)Cl(2) [L: = :C{(i-Pr)NC(Me)}(2), Mes = 2,4,6-Me(3)C(6)H(2)] (1) in hexane yields the organogallium dimer L:(Mes)(Cl)Ga-Ga(Cl)(Mes):L (2), while potassium reduction of 1 in toluene affords the neutral aromatic Ga(6) octahedron L:Ga[Ga(4)Mes(4)]Ga:L (3).

Pi and sigma-phenylethynyl radicals and their isomers o-, m-, and p-ethynylphenyl: structures, energetics, and electron affinities.

Molecular structures, energetics, vibrational frequencies, and electron affinities are predicted for the phenylethynyl radical and its isomers. Electron affinities are computed using density functional theory, -namely, the BHLYP, BLYP, B3LYP, BP86, BPW91, and B3PW91 functionals-, employing the double-zeta plus polarization DZP++ basis set; this level of theory is known to perform well for the computation of electron affinities. Furthermore, ab initio computations employing perturbation theory, coupled cluster with single and double excitations [CCSD], and the inclusion of perturbative triples [CCSD(T)] are performed to determine the relative energies of the isomers. These higher level computations are performed with the correlation consistent family of basis sets cc-pVXZ (X = D, T, Q, 5). Three electronic states are probed for the phenylethynyl radical. In C2v symmetry, the out-of-plane (2B1) radical is predicted to lie about 10 kcal/mol below the in-plane (2B2) radical by DFT methods, which becomes 9.4 kcal/mol with the consideration of the CCSD(T) method. The energy difference between the lowest pi and sigma electronic states of the phenylethynyl radical is also about 10 kcal/mol according to DFT; however, CCSD(T) with the cc-pVQZ basis set shows this energy separation to be just 1.8 kcal/mol. The theoretical electron affinities of the phenylethynyl radical are predicted to be 3.00 eV (B3LYP/DZP++) and 3.03 eV (CCSD(T)/DZP++//MP2/DZP++). The adiabatic electron affinities (EAad) of the three isomers of phenylethynyl, that is, the ortho-, meta-, and para-ethynylphenyl, are predicted to be 1.45, 1.40, and 1.43 eV, respectively. Hence, the phenylethynyl radical binds an electron far more effectively than the three other radicals studied. Thermochemical predictions, such as the bond dissociation energies of the aromatic and ethynyl C-H bonds and the proton affinities of the phenylethynyl and ethynylphenyl anions, are also reported.

The concept of protobranching and its many paradigm shifting implications for energy evaluations.

Branched alkanes like isobutane and neopentane are more stable than their straight chain isomers, n-butane and n-pentane (by 2 and 5 kcal mol(-1), respectively). Electron correlation is largely responsible. Branched alkanes have a greater number of net attractive 1,3-alkyl-alkyl group interactions, there are three such stabilizing 1,3 "protobranching" dispositions in isobutane, but only two in n-butane. Neopentane has six protobranches but n-pentane only three. Propane has one protobranch and is stabilized appreciably, by 2.8 kcal mol(-1), relative to methane and ethane. This value per protobranch also applies to the n-alkanes and cyclohexane. Consequently, energy evaluations employing alkane reference standards, for example, of small ring strain and stabilizations due to conjugation, hyperconjugation, and aromaticity, should be corrected for protobranching, for example, by employing Pople's isodesmic bond separation reaction method. This reduces the ring strain of cyclopropane to 19.2 from the conventional 27.7 kcal mol(-1), while the stabilization energies of alkenes and alkynes due to hyperconjugation (5.5 and 7.7 kcal mol(-1) for propene and propyne) and conjugation (14.8 and 27.1 kcal mol(-1) for butadiene and butadiyne) are considerably larger than the traditional estimates. Widely diverging literature evaluations of benzene resonance energy all give approximately 65 kcal mol(-1) after adjusting for conjugation, hyperconjugation, and protobranching "contaminations." The BLW (block localized wavefunction) method, which localizes pi bonds and precludes their interactions, largely confirms these stabilization estimates for hyperconjugation, conjugation, and aromaticity. Protobranching is seriously underestimated by theoretical computations at the HF and most DFT levels, which do not account for electron correlation satisfactorily. Such levels give bond separation energies, which can differ greatly from experimental values.

The existence of secondary orbital interactions.

B3LYP/6-311+G** (and MP2/6-311+G**) computations, performed for a series of Diels-Alder (DA) reactions, confirm that the endo transition states (TS) and the related Cope-TSs are favored energetically over the respective exo-TSs. Likewise, the computed magnetic properties (nucleus-independent chemical shifts and magnetic susceptibililties) of the endo- (as well as the Cope) TS's reveal their greater electron delocalization and greater aromaticity than the exo-TS's. However, Woodward and Hoffmann's original example is an exception: their endo-TS model, involving the DA reaction of a syn- with an anti-butadiene (BD), actually is disfavored energetically over the corresponding exo-TS; magnetic criteria also do not indicate the existence of SOI delocalization in either case. Instead, a strong energetic preference for endo-TSs due to SOI is found when both BDs are in the syn conformations. This is in accord with Alder and Stein's rule of "maximum accumulation of double bonds:" both the dienophile and the diene should have syn conformations. Plots along the IRC's show that the magnetic properties typically are most strongly exalted close to the energetic TS. Because of SOI, all the points along the endo reaction coordinates are more diatropic than along the corresponding exo pathways. We find weak SOI effects to be operative in the endo-TSs involved in the cycloadditions of cyclic alkenes, cyclopropene, aziridine, cyclobutene, and cyclopentene, with cyclopentadiene. While the endo-TSs are only slightly lower in energy than the respective exo-TSs, the magnetic properties of the endo-TS's are significantly exalted over those for the exo-TS's and the Natural Bond Orbitals indicate small stabilizing interactions between the methylene cycloalkene hydrogen orbitals (and lone pairs in case of aziridine) with pi-character and the diene pi MOs.

Planar tetracoordinate carbon atoms centered in bare four-membered rings of late transition metals.

Planar tetracoordinate carbons (ptC's) can be stabilized by four-membered ring perimeters composed of four bare transition metal atoms. DFT analyses of the molecular orbitals, electronic structures, energies, and magnetic properties of these CM4 species (where M represents isoelectronic combinations of Cu, Ni, Ag, and Pd) reveal striking similarities with main group metal ptC analogues (e.g., CAl2Si2, CAl4Na-, and C5Li2). While the CCu4(2+), CAg4(2+), and CNiCu3+ ions have the largest HOMO-LUMO separations, CCu4(2+) is the best candidate for detection by gas-phase photoelectron spectroscopy.

Which NICS aromaticity index for planar pi rings is best?

Five increasingly sophisticated aromaticity indexes, based on nucleus-independent chemical shifts (NICS), were evaluated against a uniform set of aromatic stabilization energies (ASE) for 75 mono- and polyheterocyclic five-membered rings. While acceptable statistical correlations were given by all of the NICS methods, the most fundamentally grounded index, NICS(0)pizz (based on the pi contribution to the out-of-plane zz tensor component), performed best statistically (cc=0.980) and in practice. The easily computable NICS(1)zz index is a useful alternative (cc=0.968).

Octahedral and tetrahedral coinage metal clusters: is three-dimensional d-orbital aromaticity viable?

The first quantitative evidence for the viability of three-dimensional aromatic clusters involving d-orbitals in pseudo-octahedral coinage metal cages M(6)Li(2) (M = Cu, Ag, Au) as well as in tetrahedral coinage metal cages M'(4)Li(4) (M' = Cu, Ag) was obtained computationally. These cages exhibit many features similar to those of their square planar M(4)Li(2) analogues. The large negative nucleus-independent chemical shifts (NICS) at the cage centers indicate three-dimensional delocalization. This diatropic character arises mostly from d-orbital delocalization combined with substantial contributions from the lowest-valence orbitals. The bonding molecular orbitals of the pseudo-octahedral clusters M(6)Li(2) (M = Cu, Ag, Au) are analogous to those in similar octahedral clusters involving p-orbital delocalization (e.g., B(6)H(6)(2-)). The M'(4)Li(4) clusters exhibit two isomeric forms: metal tetrahedral cages tetracapped by lithium cations on the outside [(M'(4)).4Li] and lithium tetrahedra on the inside capped by coinage metal atoms on each of the four faces [(Li(4)).4M]. Whereas the (M'(4)).4Li type structure is preferred for copper, gold and silver favor the (Li(4)).4M arrangement. NBO-NICS analysis shows that the large diatropic character in (M'(4)).4Li structures is due to the favorable contribution from both s- and d-orbitals, whereas the small NICS values in the center of (Li(4)).4M are due only to the diatropic contributions from the s-orbitals.

The peculiar trend of cyclic perfluoroalkane electron affinities with increasing ring size.

The adiabatic electron affinities (AEAs), vertical electron affinities (VEAs), and vertical detachment energies (VDEs) of cyclic perfluoroalkanes, c-C(n)F(2n) (n = 3-7), and their monotrifluoromethyl derivatives were computed using various pure and hybrid density functionals with DZP++ (polarization and diffuse function augmented double-zeta) basis sets. The theoretical AEA of c-C(4)F(8) at KMLYP/DZP++ is 0.70 eV, which exhibits satisfactory agreement with the 0.63 +/- 0.05 eV experimental value. The nonzero-point-corrected AEA of c-C(4)F(8) is predicted to be 0.41 eV at the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ level of theory, which shows a slight deviation of 0.11 eV from the KMLYP estimated value of 0.52 eV for the same. With the zero-point correction from the MP2/6-311G(d) [Gallup, G. A. Chem. Phys. Lett. 2004, 399, 206] level of theory combined with the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ result, the most reliable estimate of AEA of c-C(4)F(8) is 0.60 eV. c-C(3)F(6)(-), c-C(4)F(8)(-), and c-C(5)F(10)(-) are unusual in preferring planar to near planar ring structures. The ZPE-corrected AEAs of c-C(n)F(2n) increase from n = 3 (0.24 eV) to n = 5 (0.77 eV), but then dramatically fall off to 0.40 eV for both n = 6 and n = 7. All of the other functionals predict the same trend. This is due to a change in the structural preference: C(s)() c-C(6)F(12)(-) and C(1) c-C(7)F(14)(-) are predicted to favor nonplanar rings, each with an exceptionally long C-F bond. (There also is a second, higher energy D3d minimum for C(6)F(12)(-).) The SOMOs as well as the spin density plots of the c-PFA radical anions reveal that the "extra" electron is largely localized on the unique F atoms in the larger n = 6 and n = 7 rings but is delocalized in the multiatom SOMOs of the three- to five-membered ring radical anions. The computed AEAs are much larger than the corresponding VEAs; the latter are not consistent with different functionals. The AEAs are substantially larger when a c-C(n)()F(2)(n)() fluorine is replaced by a -CF(3) group. This behavior is general; PFAs with tertiary C-F bonds have large AEAs. The VDEs for all the anions are substantial, ranging from 1.89 to 3.64 eV at the KMLYP/DZP++ level.

Effects of fluorine on the structures and energetics of the propynyl and propargyl radicals and their anions.

[reaction: see text] The adiabatic electron affinity (EA(ad)) of the CH(3)-C[triple bond]C(*) radical [experiment = 2.718 +/- 0.008 eV] and the gas-phase basicity of the CH(3)-C[triple bond]C:(-) anion [experiment = 373.4 +/- 2 kcal/mol] have been compared with those of their fluorine derivatives. The latter are studied using theoretical methods. It is found that there are large effects on the electron affinities and gas-phase basicities as the H atoms of the alpha-CH(3) group in the propynyl system are substituted by F atoms. The predicted electron affinities are 3.31 eV (FCH(2)-C[triple bond]C(*)), 3.86 eV (F(2)CH-C[triple bond]C(*)), and 4.24 eV (F(3)C-C[triple bond]C(*)), and the predicted gas-phase basicities of the fluorocarbanion derivatives are 366.4 kcal/mol (FCH(2)-C[triple bond]C:(-)), 356.6 kcal/mol (F(2)CH-C[triple bond]C:(-)), and 349.8 kcal/mol (F(3)C-C[triple bond]C:(-)). It is concluded that the electron affinities of fluoropropynyl radicals increase and the gas-phase basicities decrease as F atoms sequentially replace H atoms of the alpha-CH(3) in the propynyl system. The propargyl radicals, lower in energy than the isomeric propynyl radicals, are also examined and their electron affinities are predicted to be 0.98 eV ((*)CH(2)-C[triple bond]CH), 1.18 eV ((*)CFH-C[triple bond]CH), 1.32 eV ((*)CF(2)-C[triple bond] CH), 1.71 eV ((*)CH(2)-C[triple bond]CF), 2.05 eV ((*)CFH-C[triple bond]CF), and 2.23 eV ((*)CF(2)-C[triple bond]CF).

A metallocene-complexed dibismuthene: Cp2Zr(BiR)2 (Cp = C5H5; R = C6H3-2,6-Mes2).

The zirconocene-complexed dibismuthene, Cp2Zr(BiR)2 (Cp = C5H5; R = C6H3-2,6-Mes2), was prepared by the reaction of sodium metal with Cp2ZrCl2 and RBiCl2. The air- and moisture-sensitive dark reddish/brown compound is the first organometallic compound containing Bi-Zr bonds and the only example of a ZrBi2 ring. Moreover, our computations on associated model systems offer insight into the nature of the interaction of the heaviest dipnictene with a metallocene center.