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An efficient silver-catalyzed δ-regioselective C(sp3)–H heteroarylation of free alcohols has been developed. Various alcohols reacted with quinolines, isoquinoline, pyridines, pyrimidine, phthalazine, 4-hydroxyquinazoline, acridine, quinoxaline and pyrazine to give the corresponding C(sp2)–H alkylation products in 31–89% yields. Notably, all types (1°, 2°, and 3°) of δ-C(sp3)–H bonds in the alcohols could be regioselectively activated. This protocol provides a platform to access divergent functionalizations of alcohols and heteroaryls by forming the challenging δ-selective C(sp3)–C(sp2) bond.

Online mass spectrometry has proven to be a useful tool for characterizing many aspects of chemical reactions. However, to the best of the authors’ knowledge, no reference standard (RS) quantitatio...

A continuous-flow process for the bromination of conjugated allylic compounds with N-bromosuccinimide (NBS) is developed. The reaction was optimized in a self-made continuous-flow photoreactor based on a commercially available household lamp. The productivity of this continuous step attains 70.5 g/h under the optimal conditions. Compared to batch-mode synthesis, the conversion rate and selectivity of this flow-mode was significantly improved. In addition, the reaction time could be significantly reduced from a few hours to a few minutes.

An efficient visible-light-induced para-selective C(sp2)-H difluoroalkylation of diverse electron-deficient (hetero)aromatic carbonyls (aldehydes and ketones) at ambient temperature has been developed by employing Ir(ppy)3 as the catalyst and 1,10-phenanthroline as the additive. This protocol was highlighted by its wide substrate scope, high regioselectivity, low catalyst usage, and operational simplicity.

This article demonstrates 5,7-dimethyl-1,8-naphthyridine-2-amine based organic salts formation of crystalline solids 1 – 9 , in which the acidic units have been integrated via a variety of non-covalent bonds. Addition of equivalents of the acidic units to the solution of 5,7-dimethyl-1,8-naphthyridine-2-amine generates the single protonated species which direct the anions. The nine compounds crystallize as their salts with the acidic H transferred to the aromatic N of the 5,7-dimethyl-1,8-naphthyridine-2-amine. In 2 , 3 , 4 , and 7 the methyl substituted N-rings were protonated, while others were protonated at the NH 2 substituted N-ring. All salts have been characterized via IR, mp, EA and XRD technique. The major driving force for the salt formation is attributed to the classical H-bonds from 5,7-dimethyl-1,8-naphthyridine-2-amine and the acids. Other extensive intermolecular interactions also play great functions in space association of the molecular assemblies in the relevant crystals. The common R 2 2 (8) graph set has been observed in all salts due to the H-bonds and other intermolecular interactions, except 2 , 4 , and 6 . For the synergistic interactions of the various non-covalent bonds, all salts displayed 3D structures.

Cocrystallization of the bis(imidazole)/bis(benzimidazole) with a series of organic acids gave a total of eight molecular adducts with the compositions: (3,6-bis(imidazole-1-yl)pyridazine): (trichloroacetic acid)2 (1) [(H2L1)2+ · (tca−)2, L1 = 3,6-bis(imidazole-1-yl)pyridazine, tca− = trichloroacetate], (bis(N-imidazolyl)methane): (suberic acid) (2) [(L2) · (H2suba), L2 = bis(N-imidazolyl)methane, H2suba = suberic acid], bis(N-imidazolyl)methane: (3-nitrophthalic acid): 3H2O (3) [(H2L2)2+ · (3-Hnpa-)2 · 3H2O, 3-Hnpa- = 3-nitro hydrogenphthalate], (bis(N-imidazolyl)butane)0.5: (4-nitrophthalic acid): H2O (4) [(H2L3)0.5+ · (4-Hnpa-)- · H2O, L3 = bis(N-imidazolyl)butane, 4-Hnpa- = 4-nitro hydrogenphthalate], (1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole): (3,5-dinitrosalicylic acid) (5) [(HL4) · (3,5-dns-), L4 = 1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole, 3,5-dns- = 3,5-dinitrosalicylate], (1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole): (3-nitrophthalic acid) (6) [(H2L4) · (3-npa2-), L4 = 1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole, 3-npa2-=3-nitrogenphthalate], (bis(N-imidazolyl)butane): (pamoic acid) (7) [(H2L3) · (pam), pam = pamoate], and (3,6-bis(imidazole-1-yl)pyridazine): (1,5-naphthalenedisulfonic acid) [(H2L1)2+ · (npda)2- = 1,5-naphthalenedisulfonate] (8). The eight adducts have been characterized by X-ray diffraction technique, infrared spectrum, and elemental analysis, and the melting points of all adducts were also reported. And their structural and supramolecular aspects are fully analyzed. The result reveals that among the eight investigated crystals both the end ring N in the bis(imidazole) moieties are protonated when the organic acids are deprotonated except 2, and 5, and the crystal packing is interpreted in terms of the strong ionic N H⋯O H-bond between the imidazolium and the deprotonated acidic groups. Except the N H⋯O H-bond, the O H⋯O H-bonds were also found at the salts 3, 4, 5, and 7, salt 5 has the additional N H⋯N H-bond, the N H⋯S H-bond was established at 8. Further analysis of the crystal packing of the adducts indicated that a different set of additional CH O/CH2 O, CH Cl, CH-π/CH2-π, Cl C, Cl N, O O, O-π, OH-π, and π-π associations contribute to the stabilization and expansion of the total 3D frameworks. For the coexistence of the various weak interactions these structures had homo or hetero supramolecular synthons or both. Some supramolecular synthons, such as R12(4), R22(7), and R22(8) usually found in crystals of organic acids with imidazole unit, were again shown to be appeared in constructing most of these H-bond networks.

Cocrystallization of the widely available 4-dimethylaminopyridine, with a series of carboxylic acids gave nine molecular adducts 4-dimethylaminopyridinium trifluoroacetate (1), 4-dimethylaminopyridinium glycolate glycolic acid (2), 4-dimethylaminopyridinium 2-furoate dihydrate (3), tri(4-dimethylaminopyridinium) tri(o-chlorobenzoate) tetrahydrate (4), 4-dimethylaminopyridinium 4-bromobenzoate 4-bromobenzoic acid (5), 4-dimethylaminopyridinium 4-formylbenzoate 4-formylbenzoic acid (6), 4-dimethylaminopyridinium 2,4-dichlorobenzoate (7), 4-dimethylaminopyridinium 2-aminobenzoate 2-aminobenzoic acid (8) and bis(4-dimethylaminopyridinium) 5-nitroisophthalate 5-nitroisophthalic acid methanol solvate (9). The nine adducts have been characterised by X-ray diffraction, IR and elemental analysis, the melting points were also reported. Their structural and supramolecular aspects are fully analyzed. The result reveals that among the nine investigated crystals only the ring Ns in the 4-dimethylaminopyridine moieties are protonated when the carboxylic acids are deprotonated. The crystal packing is interpreted by the strong charge-assisted N-H⋯O hydrogen bond between the NH+ and the deprotonated acidic groups. Except the N-H⋯O hydrogen bonds, the charge assisted or neutral O-H···O hydrogen bonds were also found at 2-6, 8 and 9. The COOH···COO−synthon has been at 2, 5-6 and 8-9. Further analysis of the crystal packing indicated that a different family of additional CH-O/CH2-O/CH3-O, F-F, Br-Br, CH-Cl, CH3-Cl, CH-π/CH3-π, C-H···Cπ, C-π, Cl-O, O-C, O-π and π-π contacts contribute to the stabilization and expansion of the total high-dimensional (2D-3D) framework structures. For the synergism of the various nonbonding contacts there created homo/hetero supramolecular synthons or both.

Cocrystallization of the commonly available organic amine, diisopropylamine, with a series of carboxylic acids gave a total of sixteen molecular salts with the compositions: diisopropylaminium 2-methyl-2-phenoxypropanate [(Hdpa)+ · (mpa−), mpa− = 2-methyl-2-phenoxypropanoate] (1), diisopropylaminium 2-methyl-2-(naphthalen-2-yloxy)-propionate [(Hdpa)+ · (npa−), npa− = 2-methyl-2-(naphthalen-2-yloxy)-propionate] (2), diisopropylaminium indole-3-acetate [(Hdpa)+ · (iaa−), iaa− = indole-3-acetate] (3), diisopropylaminium 4-chlorophenoxyacetate [(Hdpa)+ · (cpa−), cpa− = 4-chlorophenoxyacetate] (4), diisopropylaminium 2,4-dichlorophenoxyacetate [(Hdpa)+ · (dcpa−), dcpa− = 2,4-dichlorophenoxyacetate] (5), diisopropylaminium 4-hydroxybenzoate [(Hdpa)+ · (hba−), hba− = 4-hydroxybenzoate] (6), diisopropylaminium 4-aminobenzoate [(Hdpa)+ · (aba−), aba− = 4-aminobenzoate] (7), tetra(diisopropylaminium) tetra(1-hydroxy-2-naphthoate) trihydrate [(Hdpa)44+ · (2-hnpa)44− · 3H2O, 2-hnpa = 1-hydroxy-2-naphthoate] (8), diisopropylaminium 2-hydroxy-3-naphthoate [(Hdpa)+ · (3-hnpa-), 3-hnpa- = 2-hydroxy-3-naphthoate] (9), diisopropylaminium 5-bromosalicylate [(Hdpa)+ · (bsa−), bsa− = 5-bromosalicylate] (10), diisopropylaminium 3,5-dinitrobenzoate [(Hdpa)+ · (dna−), dna− = 3,5-dinitrobenzoate] (11), diisopropylaminium 3,5-dinitrosalicylate [(Hdpa)+ · (3,5-dns-), 3,5-dns- = 3,5-dinitrosalicylate] (12), tetra(diisopropylaminium) bis(m-phthalate) monohydrate [(Hdpa+)4 · (mpta2−)2 · H2O, mpta2− = m-phthalate] (13), bis(diisopropylaminium) dihydrogen 1,2,3,4-butane tetracarboxylate [(Hdpa+)2 · (H2Bta2−), H2Bta2− = dihydrogen 1,2,3,4-butane tetracarboxylate] (14), bis(diisopropylaminium) mucate [(Hdpa+)2 · (muc2−), muc2− = mucate] (15), and diisopropylaminium hydrogen 1,2-phenylenediacetate [(Hdpa) · (Hpda−), Hpda− = hydrogen 1,2-phenylenediacetate] (16). The sixteen salts have been characterised by XRD technique, IR, and elemental analysis, and the melting points of all the salts were also reported. And their structural and supramolecular aspects are fully analyzed. The result reveals that among the sixteen investigated crystals the NH groups in the diisopropylamine are protonated when the carboxylic acids are deprotonated, and the crystal packing is interpreted in terms of the strong charge-assisted N H⋯O hydrogen bond formation between the ammonium and the deprotonated COOH groups. Except the N H⋯O hydrogen bond, the O H⋯O hydrogen bonds (charge assisted or neutral) were also found at the salts 6, 8, 9, 10, 12, 13, 14, 15, and 16. Further analysis of the crystal packing of the salts indicated that a different family of additional CH O/CH2 O/CH3 O, CH-π/CH3-π, CH3-Cπ, N-π, and π-π associations contribute to the stabilization and expansion of the total structures. For the coexistence of the various weak interactions these structures adopted homo or hetero supramolecular synthons or both.

Cocrystallization of the aromatic bronsted bases with a series of mineral acids gave a total of ten hybrid salts with the compositions: (2-methylquinoline)2: (hydrochloride acid): 3H2O [(HL1)+. (L1)·· (Cl-) · (H2O)3] (1), (6-bromobenzo[d]thiazol-2-amine): (hydrochloride acid) [(HL2)+. (Cl-)] (2), (6-bromobenzo[d]thiazol-2-amine): (nitric acid) [(HL2)+. (NO3-)] (3), (6-bromobenzo[d]thiazol-2-amine): (sulfuric acid) [(HL2)+ · (HSO4)-] (4), (6-bromobenzo[d]thiazol-2-amine): (phosphoric acid) [(HL2)+ · (H2PO4)-] (5), (5,7-dimethyl-1,8-naphthyridine-2-amine): (hydrochloride acid): 3H2O [(HL3)+ · (Cl-) (H2O)3] (6), (5,7-dimethyl-1,8-naphthyridine-2-amine): (hydrobromic acid): CH3OH [(HL3)+ · (Br)- · CH3OH] (7), (5,7-dimethyl-1,8-naphthyridine-2-amine): (sulfuric acid): H2O [(HL3)+ · (HSO4)- · H2O] (8), (2-aminophenol): (phosphoric acid) [(HL4)+ · (H2PO4)-] (9), and (2-amino-4-chlorophenol): (phosphoric acid) [(HL5)+ · (H2PO4)-] (10). The ten salts have been characterized by X-ray diffraction analysis, IR, and elemental analysis, and the melting points of all the salts were also reported. And their structural and supramolecular aspects are fully analyzed. The result reveals that among the ten investigated crystals the ring N of the heterocycle or the NH2 in the aminophenol are protonated when the acids are deprotonated, and the crystal packing is interpreted in terms of the strong charge-assisted classical hydrogen bonds between the NH+/NH3+ and deprotonated acidic groups. Further analysis of the crystal packing of the salts indicated that a different family of additional CH O, CH Cl, CH3 N, CH3 O, CH Br, CH3 Br, Br Cl, Cl S, O S, O O, Br S, H H, and π-π associations contribute to the stabilization and expansion of the total high-dimensional frameworks. For the coexistence of the various weak nonbonding interactions these structures adopted homo or hetero supramolecular synthons or both. Some classical supramolecular synthons, such as R22(8), R42(8), R43(10) and R44(12), usually observed in the organic solids, were again shown to be involved in constructing most of these H-bonding networks.

Cocrystallization of the commonly available organic primary amine, 4-chlorobenzylamine, with a series of organic acids gave a total of nine molecular salts with the compositions: (4-chlorobenzylamine): (p-toluenesulfonic acid) (1) [(HL+) · (ptsa−)], (4-chlorobenzylamine): (m-chlorobenzoic acid) (2) [(HL+) · (mcba−)], (4-chlorobenzylamine): (m-nitrobenzoic acid) (3) [(HL+) · (mba−)], (4-chlorobenzylamine)2: (3-nitrophthalic acid): H2O (4) [(HL+)2 · (3-npa2-) · H2O], (4-chlorobenzylamine)2: (1,5-naphthalenedisulfonic acid) (5) [(HL+)2 · (nds2−)], (4-chlorobenzylamine): (dichloroethanoic acid) (6) [(HL+) · (dca−)], (4-chlorobenzylamine)2: (oxalic acid)2: H2O (7) [(HL+)2 · (Hoxa−)2 · H2O], (4-chlorobenzylamine): (fumaric acid): H2O (8) [(HL+) · (Hfum−) · H2O] and (4-chlorobenzylamine)2: (1,2,3,4-butane tetracarboxylic acid) (9) [(HL+)2 · (H2bta2−)]. The nine salts have been characterized by single crystal X-ray diffraction (SCRD) technique, IR and elemental analysis (EA), the melting points of all salts were also reported, and their structural and supramolecular aspects are analyzed in some detail. The result tells that among the nine investigated crystals the NH2 units in the 4-chlorobenzylamine moieties are protonated when the organic acids are deprotonated, and the crystal packing is interpreted in terms of the strong charge-assisted N-H⋯O H-bond formation from the NH3+ and the deprotonated acidic groups. Except the N-H⋯O H-bond, the O-H⋯O H-bonds were also existed at the salts 4 and 7–9. Further analysis of the crystal packing of the salts unveiled that a distinct set of additional CH-C, CH-O/CH2-O, CH-Cl, CH2-Cl, CH-π/CH2-π, O-O, C-C, O-Cπ and Cl-Cl associations also contribute to the stabilization and extension of the total 2D-3D frameworks. For the concurrence of the manifold weak nonbonding interactions these structures adopted the homo or hetero supramolecular synthons or both. Some classical supramolecular synthons, such as R21(7), R42(8) and R44(12), usually appeared in organic solids of organic acids with amine, were again shown to be involved in constructing some of these H-bonding networks.

The use of online FT-IR is described for investigating the degradation kinetics of the solid amorphous pharmaceutical compound, fosaprepitant dimeglumine (FD), under stress storage conditions (i.e., high temperature, T, and humidity, % RH). It is found that under conditions of elevated T and % RH, the kinetics are denucleation rate limited for the deliquescence of the amorphous FD solid, based on the high quality fits obtained to the authors' dispersive kinetic model for that mechanism. At elevated T and low % RH, it is found that a classical, first-order hydrolysis mechanism for the degradation of FD (which forms crystalline aprepitant, AP) significantly contributes to the overall conversion rate. That mechanism is similar to the one observed previously for the solution-phase hydrolysis of FD. Appropriate kinetic models are proposed for the FD-to-AP conversion under all of the experimental conditions investigated in this work. © 2009 Wiley Periodicals, Inc. Int J Chem Kinet 42: 25–36, 2010

Optical pure (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid, a chiral crown ether, was successfully used as a chiral selector for the stereoisomeric separation of numerous real pharmaceutical compounds. Both practical and mechanistic aspects were described. Effects of chiral selector concentration under different pH values of BGE were discussed. Chiral recognition for the enantiomeric compounds with (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was investigated through model compounds using CE and infrared spectroscopic techniques. Relations between the enantioselectivity of the chiral crown ether and the structural features of the studied compounds were also investigated. Unusual resolutions of compound-p and its enantiomer as well as compound-o and its 2b epimer were described. These compounds contained only tertiary amine, believed to be nonbinding with crown ethers in general. The possible mechanisms for the interaction between compound-o and the chiral crown ether were investigated using CE, electrospray MS (ESI-MS), and proton ((1)H) NMR spectroscopy. All experiments provided clear evidence that binding between compound-o and the chiral crown ether had occurred. ESI-MS spectra indicated that the complexes had a 1:1 stoichiometric ratio. The advantages and disadvantages of using chiral crown ether for stereoisomeric separations were compared with those using sulfated CDs.

A novel approach for the potential on-line determination of the enantiomeric excess (ee) of an M3 antagonist drug substance combining attenuated total reflectance infrared (ATR-IR) spectroscopy, guest-host complexes, and chemometric data analysis is described. Chiral recognition through a formation of diastereomeric complexes was measured by ATR-IR. Small changes on the IR spectra reflect the interaction between the guest (M3) and host (chiral selector). These changes are measured as a function of M3 enantiomer excess. The standard error of prediction is 1.3 ee%. The prediction results based on the IR method were in good agreement with the gravimetric method. The robustness of the calibration model was evaluated by varying the concentration of the chiral selector, the pH of the solution, and the organic solvents. The stability of the calibration model was also demonstrated through measuring different sets of samples on different days. Chirality, 2006. © 2006 Wiley-Liss, Inc.

2-Chloro-N,N-dimethylamino trimethinium chloride salt (CDT-chloride) is a key intermediate in the synthesis of Etoricoxib, a selective COX-2 inhibitor developed by Merck & Co., Inc. The formation of CDT-chloride from a mixture of chloroacetic acid and POCl3 in DMF was monitored by in situ IR and in situ NIR. The buildup of transient intermediates, starting material disappearance, and product/byproduct formation were effectively followed during the course of the reaction using both techniques. The observations confirmed the intermediacy of both chloroacetyl chloride and a Vilsmeier type reagent as well as document the evolution of carbon dioxide.

Thermodynamic analysis of the reversed-phase retention behavior of a doxorubicin–peptide conjugate demonstrated that the degree of non-linearity observed in Van’t Hoff plots was impacted by mobile phase acetonitrile content over the 25–38% acetonitrile (v/v) range tested. Small decreases in the non-polar surface area of the doxorubicin–peptide conjugate as a function of temperature were estimated from these data using linear solvent strength relationships, suggesting that the retention behavior may be the result of minor analyte conformational changes during the chromatographic experiment. This hypothesis was supported via circular dichroism (CD), Raman and 1 H NMR spectroscopic studies of the doxorubicin–peptide conjugate in selected chromatographic mobile phase compositions. The CD and Raman data indicated small changes to the apparent analyte microenvironment as a function of temperature and bulk solvent environment, while 1 H NMR studies specifically demonstrated the environmental sensitivity of protons on three non-polar peptide residues and the proximal aromatic region of the analyte. Together, these data suggest that minor changes to the conformational order of the essentially random structure of the doxorubicin–peptide conjugate are sufficient to impact chromatographic performance.