Synthesis and the influence of intramolecular H-bonding in NMR spectra of novel analogs of dendrodoine: Diaminothiazoloylbenzothiazoles

2-(4-Amino-2-arylaminothiazol-5-oyl)benzothiazoles, as the novel analogs of the cytotoxic marine alkaloid dendrodoine, are synthesized and characterized by elemental analysis, IR, NMR and mass spectral data. The thiourea derivatives provide four ring atoms for the thiazole ring construction and thus act as [C–N–C–S] synthons. The remaining carbon of the thiazole is sourced from 2-(2-bromoacetyl)benzothiazoles. This [4+1] heterocyclization reaction is adopted for the synthesis of novel benzothiazole derivatives. The presence of two signals in the ¹H NMR spectrum arising from the NH₂ hydrogens shows that the two hydrogens are not exchanging rapidly on the chemical shift time scale and they are in two different chemical environments due to H-bonding.     

Stereoelectronic effects on 1H nuclear magnetic resonance chemical shifts in methoxybenzenes

Investigation of all O-methyl ethers of 1,2,3-benzenetriol and 4-methyl-1,2,3-benzenetriol (3-16) by 1H NMR spectroscopy and density-functional calculations disclosed practically useful conformational effects on 1H NMR chemical shifts in the aromatic ring. While the conversion of phenol (2) to anisole (1) causes only small positive changes of 1H NMR chemical shifts (Delta delta < 0.08 ppm) that decrease in the order Hortho > Hmeta > Hpara, the experimental O-methylation induced shifts in ortho-disubstituted phenols are largest for Hpara, Delta delta equals; 0.19 +/- 0.02 ppm (n = 11). The differences are due to different conformational behavior of the OH and OCH3 groups; while the ortho-disubstituted OH group remains planar in polyphenols due to hydrogen bonding and conjugative stabilization, the steric congestion in ortho-disubstituted anisoles outweighs the conjugative effects and forces the Ar-OCH3 torsion out of the ring plane, resulting in large stereoelectronic effects on the chemical shift of Hpara. Conformational searches and geometry optimizations for 3-16 at the B3LYP/6-31G** level, followed by B3LYP/6-311++G(2d,2p) calculations for all low-energy conformers, gave excellent correlation between computed and observed 1H NMR chemical shifts, including agreement between computed and observed chemical shift changes caused by O-methylation. The observed regularities can aid structure elucidation of partly O-methylated polyphenols, including many natural products and drugs, and are useful in connection with chemical shift predictions by desktop computer programs.     

How the oxazole fragment influences the conformation of the tetraoxazocane ring in a cyclohexanespiro‐3′‐(1,2,4,5,7‐tetraoxazocane): single‐crystal X‐ray and theoretical study

Single crystals of (2S,5R)‐2‐isopropyl‐5‐methyl‐7‐(5‐methylisoxazol‐3‐yl)cyclohexanespiro‐3′‐(1,2,4,5,7‐tetraoxazocane), C₁₆H₂₆N₂O₅, have been studied via X‐ray diffraction. The tetraoxazocane ring adopts a boat–chair conformation in the crystalline state, which is due to intramolecular interactions. Conformational analysis of the tetraoxazocane fragment performed at the B3LYP/6‐31G(d,2p) level of theory showed that there are three minima on the potential energy surface, one of which corresponds to the conformation realized in the solid state, but not to a global minimum. Analysis of the geometry and the topological parameters of the electron density at the (3,?1) bond critical points (BCPs), and the charge transfer in the tetraoxazocane ring indicated that there are stereoelectronic effects in the O—C—O and N—C—O fragments. There is a two‐cross hyperconjugation in the N—C—O fragment between the lone electron pair of the N atom (lpN) and the antibonding orbital of a C—O bond (σ*_C—O) and vice versa between lpO and σ*_C—N. The oxazole substituent has a considerable effect on the geometry and the topological parameters of the electron density at the (3,?1) BCPs of the tetraoxazocane ring. The crystal structure is stabilized via intermolecular C—H…N and C—H…O hydrogen bonds, which is unambiguously confirmed with PIXEL calculations, a quantum theory of atoms in molecules (QTAIM) topological analysis of the electron density at the (3,?1) BCPs and a Hirshfeld analysis of the electrostatic potential. The molecules form zigzag chains in the crystal due to intermolecular C—H…N interactions being electrostatic in origin. The molecules are further stacked due to C—H…O hydrogen bonds. The dispersion component in the total stabilization energy of the crystal lattice is 68.09%.     

Thuggacins, macrolide antibiotics active against Mycobacterium tuberculosis: isolation from myxobacteria, structure elucidation, conformation analysis and biosynthesis

Two novel antibiotics, thuggacin A (1) and B (2), were isolated from the myxobacterium Sorangium cellulosum. 1 and 2 are unique thiazole-containing macrolides with side chains on both sides of the lactone group. Upon standing in solution, thuggacin A (1) rearranges by acyl migration of the lactone group to give a mixture with thuggacins B (2) and C (3). NOEs and vicinal coupling constants within the lactone ring provided distinct data for the generation of a structure model by PM3 calculations, which allowed an analysis of the conformation in solution and the relative configuration of six asymmetric centres. A minor sorangium metabolite was identified as 13-methyl-thuggacin A (4). Furthermore, two natural thuggacin variants, 5 and 6, were found in another myxobacterium, Chondromyces crocatus. In these variants, one side chain is replaced by a methyl group and a hydroxy group is repositioned to give a primary alcohol at the former methyl site, in an alpha position with respect to the thiazole ring. 1 proved to be active against clinical isolates and reference strains of Mycobacterium tuberculosis. Preliminary studies on the mechanism of action indicate inhibition of the cellular electron-transport chain.     

Temporary anion states and dissociative electron attachment to isothiocyanates

The temporary anion states of isothiocyanates CH3CH2=C=S (and CH3CH2N=C=O for comparison), C6H5CH2N=C=S, and C6H5N=C=S are characterized experimentally in the gas phase for the first time by means of electron transmission spectroscopy (ETS). The measured vertical electron attachment energies (VAEs) are compared with the virtual orbital energies of the neutral-state molecules supplied by MP2 and B3LYP calculations with the 6-31G* basis set. The calculated energies, scaled with empirical equations, reproduce satisfactorily the experimental VAEs. The first VAE is also closely reproduced as the total energy difference between the anion and neutral states calculated at the B3LYP/6-31+G* level. Due to mixing between the ring and N=C=S pi-systems, C6H5N=C=S possesses the best electron-acceptor properties, and its lowest-lying anion state is largely localized at the benzene ring. The anion states with mainly pi*C=S and pi*N=C character lie at higher energy than the corresponding anion states of noncumulated pi-systems. However, the electron-acceptor properties of isothiocyanates are found to be notably larger than those of the corresponding oxygen analogues (isocyanates). The dissociative electron attachment (DEA) spectra show peaks close to zero energy and at 0.6 eV, essentially due to NCS- negative fragments. In spite of the energy proximity of the first anion state in phenyl isothiocyanate to the DEA peak, the zero-energy anion current in the benzyl derivative is about 1 order of magnitude larger.     

1,2和1,3-缩水内醚糖衍生物的制备, 构象及其糖苷化反应

吡喃糖的1,2-及1,3-缩水内醚苄醚由相应的吡喃糖的C-2氧负离子(对1,3-缩水内醚是C-3氧负离子)与连有氯原子的C-1经分子内关环反应而制备, 而有些吡喃糖的1,2-缩水内醚苄醚是由相应的吡喃糖的C-1氧负离子与连有对甲苯磺酰氧基的C-2经分子内关环(倒关环)反应而得。呋喃糖的1,2-缩水内醚苄醚只能用倒关环法合成。1,2-(或1,3-)缩水内醚糖的开环反应通常给出1,2-反式连接(对1,3缩水内醚是1,3反式连接)的糖苷键。1,2-及1,3-缩水内醚糖的构象分析是通过^1H NMR测定及分子力学计算的方法而完成的。     

Versatile 2‐aminothiazoles,building blocks for highly functionalised heterocycles

The reactions of quantitatively available 4‐phenyl‐ and 4‐(4‐antipyrinyl)‐2‐aminothiazole [“4‐antipyrinyl‐” is used as a short‐term for “4‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1‐H‐pyrazol‐4yl)‐”] with chloroacetyl chloride, acetic anhydride, ethyl cyanoacetate and carbon disulphide are reported. The products are transformed further by Knoevenagel condensations and coupling reactions with aromatic diazonium salts. The latter occur both at the thiazole ring and at the active methylene sites. The tautomerism of these products is studied on the basis of density functional theory calculations at the B3LYP/6‐31G* level.     

Unimolecular dissociation of aniline molecular ion: A theoretical study

The potential energy surface (PES) for dissociation of aniline ion was determined using density functional theory molecular orbital calculations at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G(d) level. On the basis of the PES obtained, kinetic analysis was performed by Rice–Ramsperger–Kassel–Marcus (RRKM) calculations. The RRKM dissociation rate constants agreed well with previous experimental data. The most favorable channel was formation of the cyclopentadiene ion by loss of HNC, occurring through consecutive ring opening and re-closure to a five-membered ring. Loss of H could compete with the HNC loss at high energy, which occurred by direct cleavage of an N–H bond or through ring expansion.     

金属串配合物[Ni3(L)4(NCS)2](L = dpa-, mpta-, mdpa-, mppa-)结构和磁性的理论研究

应用密度泛函理论BP86方法结合自然键轨道分析方法对具有分子导线潜在应用前景的金属串配合物[Ni₃(L)₄(NCS)₂](L = dpa^- (1), mpta^- (2), mdpa^- (3), mppa^- (4))进行研究,分析了桥联配体L对Ni―Ni相互作用和磁耦合性质的影响.结果得到: (1)配合物的基态均是对应于五重态(HS)的反铁磁(AF)单重态, HS的能量和结构与AF态相近, Ni₃⁶⁺链形成了三中心四电子σ键(σ₂σ_nb¹σ^*1). (2) dpa^-引入甲基成为mdpa^-,对Ni―Ni、Ni―N距离影响不大; 3H-吡咯环和噻唑环取代吡啶环后, N1―N2、Ni―Ni距离增大, Ni2―N2键长缩短,但噻唑环的影响较小;故Ni―Ni相互作用强度为1 ≈ 3 > 2 > 4. (3)预测了3和4的J_ab值为-103和-88 cm^-1,随Ni―Ni相互作用增强磁耦合效应增大. Ni―Ni相互作用越大,通过Ni₃⁶⁺链σ型轨道的直接磁耦合越强; Ni2―N2键越强,通过涉及桥联配体的间接磁耦合越强,直接磁耦合比间接磁耦合更强.     

尿嘧啶和5-氯尿嘧啶1S0→1S2跃迁动态结构的共振拉曼光谱

采用含时量子波包理论的简单模型对5-氯尿嘧啶和尿嘧啶的共振拉曼光谱开展了强度分析拟合, 获得了1(π, π*)激发态的几何结构变化动态特征. 结果表明, 尿嘧啶1S0→1S2跃迁的动态结构特征因5-位氯原子取代而改变. 5-氯尿嘧啶的动态结构特征主要沿C5=C6伸缩振动+C6H12 弯曲振动和N3H9/N1H7弯曲振动+N1C6伸缩振动反应坐标展开, 而尿嘧啶的动态结构特征主要沿嘧啶环的伸缩振动+C5H11/C6H12/N1H7弯曲振动和C4=O10伸缩振动反应坐标展开. π和π*轨道中氯原子的pz电子参与嘧啶环的p-π共轭作用导致了在1(π, π*)激发态上5-氯尿嘧啶的振动重组能更多地配分给嘧啶环的弯曲振动模式和C5=C6伸缩振动模式. 尿嘧啶在甲醇中的激发态动态结构特征与在水中的基本一致, 但波包沿C5H11/C6H12/N1H7弯曲振动+N1C6伸缩振动(υ12)和环呼吸振动(υ17)反应坐标的运动明显增强.     

Electronic and chelation effects on the unusual C2-methylation of N-(para-substituted)phenylaziridines with lithium organocuprates

Density functional theory calculations with the B3LYP functional were performed for the title ring‐opening reaction to understand the intrinsic activating and directing effects of the N‐substituents, as well as the electron donating effect of the para‐substituted (Y = Cl, H, Me) phenyl group at the more hindered benzylic C2 atom. The N‐tosyl group (i.e., N‐Tos) or the N‐(2‐pyridyl)sulfonyl group (i.e., N‐Py) was introduced to activate the ring nitrogen atom (N1) and the para‐substituted (Y = Cl, H, Me) phenyl group for the activation of the C2 atom. Conformational searches and geometry optimizations were performed for the N‐(para‐substituted)phenylaziridines ( 1 ～ 6 ). Calculations indicate that the aziridine 6 (i.e., Py/Me) has the most elongated C2? N1 bond intrinsically due to the electronic activating effects, implying the aziridine 6 to be the most potent candidate for the more‐hindered C2 opening. Transition states (TSs) were investigated for the prospective ring‐opening paths (I～IV), considering the types of intermolecular push–pull interactions between the N‐activated phenylaziridines and the cuprate. The N‐Py group provides an unique C2‐favored TS along the path IV, which the N‐Tos group cannot afford, due to the less charge transfer from the nucleophilic CH of the cuprate into the electrophilic C2 atom. Furthermore, the e‐donating effect of the para‐substituents (Y = Cl, H, Me) enhances the C2 opening for the path IV. This study enables us to understand the unusual ring‐opening phenomena in terms of electronic and directing effects and hence may serve as a tool to design substrates for highly regioselective ring openings. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

N8H8链状异构体结构与稳定性的理论研究

采用密度泛函理论(DFT), 在B3LYP/6-311＋＋G(d,p)基组上计算得到了21种N₈H₈链状异构体, 并研究了这些异构体间可能的互变异构情况. 为了得到更为精确的能量信息, 计算了QCISD(T)/6-311G(d,p)基组水平上各物质的能量. 所得的21种异构体分为4类(4种类型链状化合物): A为直链, B有一个支链, C有2个支链, D有3个支链; D类只有一种, A类稳定构型2种, B类稳定构型12种, C类稳定构型6种; 相对稳定的分别为: B2-1构型, B2-3构型和C23-2构型. 我们研究发现N₈H₈链状异构体中含有明显N＝N双键特征有利于化合物稳定性的提高.     

新型含噻唑和三唑环的亚胺类化合物的合成及生物活性研究

设计合成了一系列新型含有噻唑和三唑环的亚胺类化合物, 其结构经元素分析、1H NMR和X射线晶体衍射确证. 生物活性测试结果表明, 部分化合物在50 μg/L浓度下对苹果轮纹菌具有一定的杀菌活性.     

Aromaticity in cyclic alkali clusters

Density functional calculations on a hexagonal 1D sodium cluster and a 2D potassium cluster show that the M6 (M = Na, K) rings in the chain present in 3D [Na2MoO3L(H2O)2]n (1) and 2D [K2MoO3L(H2O)3]n (2) are aromatic in character according to the nucleus independent chemical shift (NICS) and multicenter bond indices (MCI) values. The NICS values at the center of the Na6 rings and at the cage center of the K6 rings are comparable to the corresponding values of their polyacene analogues in most cases. The stability and reactivity patterns of the M6 rings also follow a similar trend as their organic analogues.     

Bifurcated hydrogen-bonding effect on the shielding and coupling constants in trifluoroacetyl pyrroles as studied by 1H, 13C and 15N NMR spectroscopy and DFT calculations

According to the (1)H, (13)C and (15)N NMR spectroscopic data and DFT calculations, bifurcated N--H...N and N--H...O intramolecular hydrogen bond is shown to be present in 2-trifluoroacetyl-5-(2'-pyridyl)-pyrrole. This bifurcated hydrogen bond causes an increase in the absolute size of the (1)J(N,H) coupling constant by about 6 Hz, and the deshielding of the bridge proton by 2 ppm. DFT calculations show that the influence of the N--H...N and N--H...O intramolecular hydrogen bonds on the (1)J(N,H) coupling and proton shielding is almost additive, although the components of the bifurcated hydrogen bond slightly weaken each other. In 2-trifluoroacetyl-5-(2'-pyridyl)-pyrrole, the coupling constants involving the fluorine and the N--H covalent bond nuclei depend dramatically on the spatial position of the pyridine ring. The pyridine ring rotation operates as a quantum switch controlling the spin information transfer between the (19)F and (15)N nuclei, as well as the proton.     

Copper(II) coordination chemistry of westiellamide and its imidazole, oxazole, and thiazole analogues

The copper(II) coordination chemistry of westiellamide (H(3)L(wa)), as well as of three synthetic analogues with an [18]azacrown-6 macrocyclic structure but with three imidazole (H(3)L(1)), oxazole (H(3)L(2)), and thiazole (H(3)L(3)) rings instead of oxazoline, is reported. As in the larger patellamide rings, the N(heterocycle)-N(peptide)-N(heterocycle) binding site is highly preorganized for copper(II) coordination. In contrast to earlier reports, the macrocyclic peptides have been found to form stable mono- and dinuclear copper(II) complexes. The coordination of copper(II) has been monitored by high-resolution electrospray mass spectrometry (ESI-MS), spectrophotometric and polarimetric titrations, and EPR and IR spectroscopies, and the structural assignments have been supported by time-dependent studies (UV/Vis/NIR, ESI-MS, and EPR) of the complexation reaction of copper(II) with H(3)L(1). Density functional theory (DFT) calculations have been used to model the structures of the copper(II) complexes on the basis of their spectroscopic data. The copper(II) ion has a distorted square-pyramidal geometry with one or two coordinated solvent molecules (CH(3)OH) in the mononuclear copper(II) cyclic peptide complexes, but the coordination sphere in [Cu(H(2)L(wa))(OHCH(3))](+) differs from those in the synthetic analogues, [Cu(H(2)L)(OHCH(3))(2)](+) (L = L(1), L(2), L(3)). Dinuclear copper(II) complexes ([Cu(II) (2)(HL)(mu-X)](+); X = OCH(3), OH; L = L(1), L(2), L(3), L(wa)) are observed in the mass spectra. While a dipole-dipole coupled EPR spectrum is observed for the dinuclear copper(II) complex of H(3)L(3), the corresponding complexes with H(3)L (L = L(1), L(2), L(wa)) are EPR-silent. This may be explained in terms of strong antiferromagnetic coupling (H(3)L(1)) and/or a low concentration of the dicopper(II) complexes (H(3)L(wa), H(3)L(2)), in agreement with the mass spectrometric observations.     

Dimers of boroglycine and methylamine boronic acid: a computational comparison of the relative importance of dative versus hydrogen bonding

Boronic acids are widely used in materials science, pharmacology, and the synthesis of biologically active compounds. In this Article, geometrical structures and relative energies of dimers of boroglycine, H2N-CH2-B(OH)2, and its constitutional isomer H3C-NH-B(OH)2, were computed using second-order M?ller-Plesset perturbation theory and density functional theory; Dunning-Woon correlation-consistent cc-pVDZ, aug-cc-pVDZ, cc-pVTZ, and aug-cc-pVTZ basis sets were employed for the MP2 calculations, and the Pople 6-311++G(d,p) basis set was employed for a majority of the DFT calculations. Effects of an aqueous environment were incorporated into the results using PCM and COSMO-RS methodology. The lowest-energy conformer of the H2N-CH2-B(OH)2 dimer was a six-membered ring structure (chair conformation; Ci symmetry) with two intermolecular B:N dative-bonds; it was 14.0 kcal/mol lower in energy at the MP2/aug-cc-pVDZ computational level than a conformer with the classic eight-centered ring structure (Ci symmetry) in which the boroglycine monomers are linked by a pair of H-O...H bonds. Compared to the results of MP2 calculations with correlation-consistent basis sets, DFT calculations using the PBE1PBE and TPSS functionals with the 6-311++G(d,p) basis set were significantly better at predicting relative conformational energies of the H2N-CH2-B(OH)2 and H3C-NH-B(OH)2 dimers than corresponding calculations using the BLYP, B3LYP, OLYP, and O3LYP functionals, particularly with respect to dative-bonded structures.     

Preparation of halogenated derivatives of thiazolo[5,4‐d]thiazole via direct electrophilic aromatic substitution

Chlorination and bromination reactions of thiazolo[5,4‐d]thiazole led to the generation of its mono‐ and dihalogenated derivatives. These are the first instances of successful direct electrophilic aromatic substitution in the thiazolo[5,4‐d]thiazole ring system. X‐ray analysis demonstrates that both 2‐bromothiazolo[5,4‐d]‐thiazole and 2,5‐dibromothiazolo[5,4‐d]thiazole are planar structures, with strongly manifested π‐stacking in the solid state. Theoretical analysis of the pyridine‐catalyzed halogenation (MP2/6‐31+G(d) and B3LYP/6‐31+G(d) calculations) reveals that introduction of one halogen actually leads to a slightly enhanced reactivity towards further halogenation. Several halogenation mechanisms have been investigated: 1) The direct C‐halogenation with N‐halopyridine as electrophile; 2) C‐halogenation via intermediate N‐halogenation, and 3) C‐halogenation following an addition ‐ elimination pathway, with intermediate formation of a cyclic halonium ion. The theoretical studies suggest that the direct C‐halogenation is the favored mechanism.     

天冬酰胺的环化缩合反应及其在合成拮抗剂与吗啡肽中的应用

天冬酰胺的环化缩合反应及其在合成拮抗剂与吗啡肽中的应用;四氢嘧啶酮;构象;内源性吗啡肽     

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole,pyrazole and/or pyridine ring systems

A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4-aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-thiazole analogues involves cyclization of the precursor N-phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2-((4-(pyrazole-1-carbonyl)phenyl)amino)-nicotinonitrile derivatives 9–10 . The 2-((4-(4-thiazolylidene-pyrazole-1-carbonyl)-phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6-amino-4-aryl-3,5-dicyano-2-oxo-1-(4-substitutedbenzamido)-pyridines 19 were synthesized by Knoevenagel condensation N′-(2-cyanoacetyl)-benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile-thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.