Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation.

CONTEXT: Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation. METHODS: The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program.

Alkylation converts riboflavin into an efficient photosensitizer of phospholipid membranes.

A new decyl chain [-(CH2)9CH3] riboflavin conjugate has been synthesized and investigated. A nucleophilic substitution (SN2) reaction was used for coupling the alkyl chain to riboflavin (Rf), a model natural photosensitizer. As expected, the alkylated compound (decyl-Rf) is significantly more lipophilic than its precursor and efficiently intercalates within phospholipid bilayers, increasing its fluorescence quantum yield. The oxidative damage to lipid membranes photoinduced by decyl-Rf was investigated in large and giant unilamellar vesicles (LUVs and GUVs, respectively) composed of different phospholipids. Using a fluorogenic probe, fast radical formation and singlet oxygen generation was demonstrated upon UVA irradiation in vesicles containing decyl-Rf. Photosensitized formation of conjugated dienes and hydroperoxides, and membrane leakage in LUVs rich in poly-unsaturated fatty acids were also investigated. The overall assessment of the results shows that decyl-Rf is a significantly more efficient photosensitizer of lipids than its unsubstituted precursor and that the association to lipid membranes is key to trigger phospholipid oxidation. Alkylation of hydrophilic photosensitizers as a simple and general synthetic tool to obtain efficient photosensitizers of biomembranes, with potential applications, is discussed.

Tandem Transesterification-Esterification Reactions Using a Hydrophilic Sulfonated Silica Catalyst for the Synthesis of Wintergreen Oil from Acetylsalicylic Acid Promoted by Microwave Irradiation.

SiO2-SO3H, with a surface area of 115 m2/g and pore volume of 0.38 cm3g-1, and 1.32 mmol H+/g was used as a 20% w/w catalyst for the preparation of methyl salicylate (wintergreen oil or MS) from acetylsalicylic acid (ASA). A 94% conversion was achieved in a microwave reactor over 40 min at 120 °C in MeOH. The resulting crude product was purified by flash chromatography. The catalyst could be reused three times.

Functionalization of Conductive Polymers through Covalent Postmodification.

Organic chemical reactions have been used to functionalize preformed conducting polymers (CPs). The extensive work performed on polyaniline (PANI), polypyrrole (PPy), and polythiophene (PT) is described together with the more limited work on other CPs. Two approaches have been taken for the functionalization: (i) direct reactions on the CP chains and (ii) reaction with substituted CPs bearing reactive groups (e.g., ester). Electrophilic aromatic substitution, SEAr, is directly made on the non-conductive (reduced form) of the CPs. In PANI and PPy, the N-H can be electrophilically substituted. The nitrogen nucleophile could produce nucleophilic substitutions (SN) on alkyl or acyl groups. Another direct reaction is the nucleophilic conjugate addition on the oxidized form of the polymer (PANI, PPy or PT). In the case of PT, the main functionalization method was indirect, and the linking of functional groups via attachment to reactive groups was already present in the monomer. The same is the case for most other conducting polymers, such as poly(fluorene). The target properties which are improved by the functionalization of the different polymers is also discussed.

Effect of the Nucleophile's Nature on Chloroacetanilide Herbicides Cleavage Reaction Mechanism. A DFT Study.

In this study, the degradation mechanism of chloroacetanilide herbicides in the presence of four different nucleophiles, namely: Br-, I-, HS-, and S2O3-2, was theoretically evaluated using the dispersion-corrected hybrid functional wB97XD and the DGDZVP as a basis set. The comparison of computed activation energies with experimental data shows an excellent correlation (R2 = 0.98 for alachlor and 0.97 for propachlor). The results suggest that the best nucleophiles are those where a sulfur atom performs the nucleophilic attack, whereas the other species are less reactive. Furthermore, it was observed that the different R groups of chloroacetanilide herbicides have a negligible effect on the activation energy of the process. Further insights into the mechanism show that geometrical changes and electronic rearrangements contribute 60% and 40% of the activation energy, respectively. A deeper analysis of the reaction coordinate was conducted, employing the evolution chemical potential, hardness, and electrophilicity index, as well as the electronic flux. The charge analysis shows that the electron density of chlorine increases as the nucleophilic attack occurs. Finally, NBO analysis indicates that the nucleophilic substitution in chloroacetanilides is an asynchronous process with a late transition state for all models except for the case of the iodide attack, which occurs through an early transition state in the reaction.

Ultrasound-assisted reaction of 1,4-naphthoquinone with anilines through an EDA complex.

Naphthoquinone amino derivatives exhibit interesting physicochemical properties and a wide range of biological activities with potential medicinal applications. A clean, fast and simple method for the preparation of phenylamino-1,4-naphthoquinones is presented by the reaction of naphthoquinone (NQ) and anilines under ultrasound irradiation (US). Anilino derivatives were synthesized in good yields and shorter reaction times in comparison with the conventional method. This ultrasound procedure can be applied to the preparation of naphthoquinone derivatives with anilines containing electron-donor substituents (2-OMe, 4-OMe, 4-Me and 4-OEt) or halogen or electron-withdrawing substituents (4-F, 4-Cl, 4-Br, 3-F, 3-Cl, 3-Br, 4-Ac). This procedure was also applied to the reaction of anilines with 2,3-dichloro-1,4-naphthoquinone (DCNQ). A reaction mechanism involving an EDA complex is proposed based on NMR experiments and previous studies about solid/solid reactions.

Computational study of vicarious nucleophilic substitution reactions.

Vicarious nucleophilic substitution reactions are a versatile way of introducing substituents into aromatic and heteroaromatic electron-deficient compounds. In this project, a kinetic study of these reactions by applying quantum mechanics concepts, such as reaction force, force constant, and electronic reaction flow was proposed. Furthermore, absolute theoretical scales of electrophilicity by applying density functional theory electronic indices were established to classify a series of five and six-membered nitroheteroarenes, and nitrobenzenes with substituents in ortho, meta and para positions. The theoretical model was validated by comparison with experimental kinetic results. Calculations using B3LYP/6-311G(d,p) level of theory allowed analysis of the reactivity patterns and the mechanisms of these chemical reactions. The theoretical scale properly accounts for the activating/deactivating effects promoted by the substituents and agrees with the ability of these substituents to accept or donate electrons, electron acceptor substituents are those that increase electrophilicity, and electron donors those that reduce it.

Transition-metal-free one-pot synthesis of alkynyl selenides from terminal alkynes under aerobic and sustainable conditions.

Alkynyl selenides were synthesized by a straightforward one-pot and three-step methodology, without the need of diselenides as starting reagents, under an oxygen atmosphere and using PEG 200 as the solvent. This procedure involves the in situ generation of dialkyl diselenides through a K3PO4-assisted reaction of an alkyl selenocyanate obtained by a nucleophilic substitution reaction between KSeCN and alkyl halides. Successive reaction with terminal alkynes in the presence of t-BuOK affords the corresponding alkyl alkynyl selenide in moderate to good yields. Finally, this methodology allowed the synthesis of 2-alkylselanyl-substituted benzofuran and indole derivatives starting from convenient 2-substituted acetylenes.

Crystal structure of 5-butyl-amino-3-methyl-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde obtained from a microwave-assisted reaction using caesium carbonate as catalyst.

The title compound, C14H18N4O, synthesized from an unconventional microwave-assisted method using caesium carbonate as catalyst, has an approximately planar conformation with the pyridyl and pyrazole rings inclined by a dihedral angle of 7.94 (3)°, allowing the formation of an intra-molecular N-H⋯N hydrogen bond. The supra-molecular assembly has a three-dimensional arrangement controlled mainly by weak C-H⋯O and C-H⋯π inter-actions.

Dynamical Bifurcation in Gas-Phase XH- + CH3 Y SN 2 Reactions: The Role of Energy Flow and Redistribution in Avoiding the Minimum Energy Path.

The gas-phase reactions of XH- (X=O, S) + CH3 Y (Y=F, Cl, Br) span nearly the whole range of SN 2 pathways, and show an intrinsic reaction coordinate (IRC) (minimum energy path) with a deep well owing to the CH3 XH⋅⋅⋅Y- (or CH3 S- ⋅⋅⋅HF) hydrogen-bonded postreaction complex. MP2 quasiclassical-type direct dynamics starting at the [HX⋅⋅⋅CH3 ⋅⋅⋅Y]- transition-state (TS) structure reveal distinct mechanistic behaviors. Trajectories that yield the separated CH3 XH+Y- (or CH3 S- +HF) products directly are non-IRC, whereas those that sample the CH3 XH⋅⋅⋅Y- (or CH3 S- ⋅⋅⋅HF) complex are IRC. The IRCIRC/non-IRC ratios of 90:10, 40:60, 25:75, 2:98, 0:100, and 0:100 are obtained for (X, Y)=(S, F), (O, F), (S, Cl), (S, Br), (O, Cl), and (O, Br), respectively. The properties of the energy profiles after the TS cannot provide a rationalization of these results. Analysis of the energy flow in dynamics shows that the trajectories cross a dynamical bifurcation, and that the inability to follow the minimum energy path arises from long vibration periods of the X-C⋅⋅⋅Y bending mode. The partition of the available energy to the products into vibrational, rotational, and translational energies reveals that if the vibrational contribution is more than 80 %, non-IRC behavior dominates, unless the relative fraction of the rotational and translational components is similar, in which case a richer dynamical mechanism is shown, with an IRC/non-IRC ratio that correlates to this relative fraction.

Six polycyclic pyrimidoazepine derivatives: syntheses, molecular structures and supramolecular assembly.

A versatile synthetic method has been developed for the formation of variously substituted polycyclic pyrimidoazepine derivatives, formed by nucleophilic substitution reactions on the corresponding chloro-substituted compounds; the reactions can be promoted either by conventional heating in basic solutions or by microwave heating in solvent-free systems. Thus, (6RS)-6,11-dimethyl-3,5,6,11-tetrahydro-4H-benzo[b]pyrimido[5,4-f]azepin-4-one, C14H15N3O, (I), was isolated from a solution containing (6RS)-4-chloro-8-hydroxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine and benzene-1,2-diamine; (6RS)-4-butoxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-8-ol, C18H23N3O2, (II), was formed by reaction of the corresponding 6-chloro compound with butanol, and (RS)-4-dimethylamino-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-8-ol, C16H20N4O, (III), was formed by reaction of the chloro analogue with alkaline dimethylformamide. (6RS)-N-Benzyl-8-methoxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-4-amine, C22H24N4O, (IV), (6RS)-N-benzyl-6-methyl-1,2,6,7-tetrahydropyrimido[5',4':6,7]azepino[3,2,1-hi]indol-8-amine, C22H22N4, (V), and (7RS)-N-benzyl-7-methyl-2,3,7,8-tetrahydro-1H-pyrimido[5',4':6,7]azepino[3,2,1-ij]quinolin-9-amine, C23H24N4, (VI), were all formed by reaction of the corresponding chloro compounds with benzylamine under microwave irradiation. In each of compounds (I)-(IV) and (VI), the azepine ring adopts a conformation close to the boat form, with the C-methyl group in a quasi-equatorial site, whereas the corresponding ring in (V) adopts a conformation intermediate between the twist-boat and twist-chair forms, with the C-methyl group in a quasi-axial site. No two of the structures of (I)-(VI) exhibit the same range of intermolecular hydrogen bonds: different types of sheet are formed in each of (I), (II), (V) and (VI), and different types of chain in each of (III) and (IV).

Two different products from the reaction of 1-aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde with cyclohexylamine when the aryl substituent is phenyl or pyridin-2-yl: hydrogen-bonded sheets versus dimers.

Cyclohexylamine reacts with 5-chloro-3-methyl-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde to give 5-cyclohexylamino-3-methyl-1-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde, C16H20N4O, (I), formed by nucleophilic substitution, but with 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde the product is (Z)-4-[(cyclohexylamino)methylidene]-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one, C17H21N3O, (II), formed by condensation followed by hydrolysis. Compound (II) crystallizes with Z' = 2, and in one of the two independent molecular types the cyclohexylamine unit is disordered over two sets of atomic sites having occupancies of 0.65 (3) and 0.35 (3). The vinylogous amide portion in each compound shows evidence of electronic polarization, such that in each the O atom carries a partial negative charge and the N atom of the cyclohexylamine portion carries a partial positive charge. The molecules of (I) contain an intramolecular N-H...N hydrogen bond, and they are linked by C-H...O hydrogen bonds to form sheets. Each of the two independent molecules of (II) contains an intramolecular N-H...O hydrogen bond and each molecular type forms a centrosymmetric dimer containing one R2(2)(4) ring and two inversion-related S(6) rings.