Direct Alkyl Research Articles

Carbonylation of Boranes – A Computational Study

AbstractThe classical simple picture of stepwise B‐to‐C migratory insertion of all three alkyl groups in the carbonylation reaction of trialkyl boranes with CO was shown not to be correct, except for the first alkyl group shift affording an acyl borane. The second and third direct alkyl shifts turned out to be kinetically hampered due to the non‐activated character of the B−C bond in electron‐poor B atoms. The latter can only be achieved by either the autocatalytic action of the final alkyl boron oxide or by formation of dimeric species with weakened B‐alkyl bonds at borate centres. Both thermodynamic and several NICS‐related parameters pointed to scarce, even “negative”, aromatic character for boroxines, the final cyclotrimerization products of alkyl‐boron oxides.

On the Role of N-Heterocyclic Carbene Salts in Alkyl Radical Generation from Alkyl Alcohols: A Computational Study.

Formation of carbon-carbon bonds through cross-coupling reactions using readily available substrates, like alcohols, is crucial for modern organic chemistry. Recently, direct alkyl alcohol functionalization has been achieved by the use of N-Heterocyclic Carbene (NHC) salts via in situ formation of an alcohol-NHC adduct and its activation by a photoredox catalyst to generate carbon-centered alkyl radicals. Experimentally, only electron deficient NHC activators work but the reasons of this behavior remain underexplored. Herein, a DFT computational study of the mechanism of alcohol activation using up to seven NHC salts is performed to shed light into the influence of their electronic properties in the alkyl radical formation. This study demonstrates that four reaction steps are involved in the transformation and characterizes how the electronic properties of the NHC salt affect each step. A fine balance of the NHC electron-richness is proved to be determinant for this transformation.

Undirected, Asymmetric Alkyl Group Functionalizations through Alkane Dehydrogenation.

Direct asymmetric alkyl group functionalizations can potentially convert abundant and inexpensive hydrocarbon feedstocks into value-added chiral fine chemicals. Here, we report a one-pot, dehydrogenation-based strategy for enantioselective formal benzylic C(sp3)-H bond borylation. Dehydrogenation of alkylarenes by a pincer-Ir complex produces aryl alkenes via a tandem dehydrogenation/alkene-isomerization catalysis. The subsequent Cu-catalyzed asymmetric alkene hydroboration affords benzylic boronate esters with excellent site- and enantioselectivity. The generality of this strategy has been further demonstrated by asymmetric alkyl group amination.

Ti-Catalyzed Diastereoselective Cyclopropanation of Carboxylic Derivatives with Terminal Olefins.

Cyclopropanols and cyclopropylamines not only serve as important structural motifs in medicinal chemistry but also show diverse reactivities in organic synthesis. Owing to the high ring strain energy, the development of a general protocol from stable and readily available starting materials to afford these cyclopropyl derivatives remains a compelling challenge. Herein, we describe that a Ti-based catalyst can effectively promote the diastereoselective syntheses of cyclopropanols and cyclopropylamines from widely accessible carboxylic derivatives (acids, esters, amides) with terminal olefins. To the best of our knowledge, this method represents the first example of direct converting alkyl carboxylic acids into cyclopropanols. Distinct from conventional studies in Ti-mediated cyclopropanations with reactive alkyl Grignard reagents as nucleophiles or reductants, this protocol utilizes Mg and Me2SiCl2 to turn over the Ti catalyst. Our method exhibits broad substrate scope with good functional group compatibility and is amenable to late-stage synthetic manipulations of natural products and biologically active molecules.

Rare-Earth-Metal Complexes Bearing an Iminodibenzyl-PNP Pincer Ligand: Synthesis and Reactivity toward 3,4-Selective Polymerization of 1,3-Dienes.

A PNP-pincer ligand provides a versatile ligation framework, which is highly useful in organometallic chemistry and catalytic chemistry. In this work, by a de novo strategy, a simple and efficient synthetic pathway, has been developed to prepare the new iminodibenzyl-based PNP pincer proligand imin-RPNP(Li or H) (R = isopropyl, phenyl). By employing salt metathesis or direct alkyl elimination, we successfully synthesized a series of iminodibenzyl-PNP rare-earth-metal (Ln = Sc, Y, Dy, Ho, Er, Tm, Lu) complexes and characterized them by NMR and X-ray diffraction analyses. Upon addition of a borate and triisobutylaluminum (TIBA), the rare-earth-metal complexes 2-Y, 2-Dy, 2-Ho, 2-Er, and 2-Tm bearing the imin-PhPNP ligand exhibited unexpectedly high 3,4-selectivity (up to 95%) for the polymerization of 1,3-dienes (isoprene and myrcene); in particular, the chosen yttrium complex 2-Y promoted the 1,3-diene polymerization in a living manner. A computational study suggested that the sterically congested configuration around the metal center imposed by the imin-RPNP ligand might be the main reason for this unusual selectivity.

On the origin of the difference between type A and type B skeletal isomerization of alkenes catalyzed by zeolites: The crucial input of ab initio molecular dynamics

Alkene skeletal isomerization elementary steps catalyzed by acid zeolites are key reactions in refining, petrochemistry and biomass conversion. We unravel the atomic-scale origin of the higher rate constant of type A isomerization (involving a direct alkyl transfer, without any change in the branching degree) than the one of type B isomerization (involving non-classical carbonium ions such as protonated cyclopropane (PCP), inducing a change in the branching degree) of C7 carbenium ions in chabazite. Accurate free energy barriers are calculated at 300 and 500 K for both reactions by means of molecular dynamics in combination with blue moon ensemble approach, whereas the static approach is shown to fail to describe these reactions. The slow transformation between individual rotational isomers, causing non-ergodic sampling of reactant state, largely overlooked in literature, is carefully addressed in the present work. At 500 K (representative of experimental conditions), free energy barriers of 83.4 kJ/mol and 15.0 kJ/mol are determined for type B and type A isomerization respectively. The much lower barrier for type A is thus recovered, and assigned to a loose transition state, with free rotation of the migrating alkyl group, while the transition state of type B isomerization is tighter, with such a rotation blocked, due to the simultaneous hydride shift taking place on the edge of the PCP.

Visible‐Light‐Driven Direct Oxidative Coupling Reaction Leading to Alkyl Aryl Ketones, Catalyzed by Nano Pd/ZnO

Direct alkyl sp3 C–H activation to form new C–C bonds is one of the major challenges in synthetic chemistry. Herein, for the first time, we represent a new method, using nano Pd/ZnO which plays both as photoredox and transition‐metal catalyst, for C–C bond formations. By using this catalyst, we have accomplished an oxidative coupling reaction between aryl halides and tertiary amines to yield the corresponding naturally occurring alkyl aryl ketones by using visible light irradiation. Furthermore, the carbonylation process was carried out on a 10 gram scale, with visible light and thermal condition, and it was proved to be scalable, efficient, and economical.

Cu(II)-Mediated N-H and N-Alkyl Aryl Amination and Olefin Aziridination.

Cu(II)-mediated direct NH2 and NH alkyl aryl aminations and olefin aziridinations are described. These room-temperature, one-pot, environmentally friendly procedures replace costly Rh2 catalysts and, in some instances, display important differences with comparable Rh2- and Fe-supported reactions.

Direct dehydrogenative alkyl Heck-couplings of vinylarenes with umpolung aldehydes catalyzed by nickel

Alkenes are fundamental functionalities in nature and highly useful intermediates in organic synthesis, medicinal chemistry and material sciences. Transition-metal-catalyzed Heck couplings with organic halides as electrophiles have been established as a powerful protocol for the synthesis of this valuable building block. However, the requirement of organic halides and the generation of stoichiometric hazardous halide wastes may cause significant sustainable concerns. The halide-free oxidative Heck alkenylations involving organometallics or arenes as the coupling partners provide a facile and alternative pathway. Nonetheless, stoichiometric amounts of extra oxidant are essential in most cases. Herein, we present a direct dehydrogenative alkyl Heck-coupling reaction under oxidant-free conditions, liberating hydrogen, nitrogen and water as the side products. Excellent regioselectivity is achieved via neighboring oxygen atom coordination. Broad substrate scope, great functional group (ketone, ester, phenol, free amine, amide etc) tolerance and modification of pharmaceutical candidates and biological molecules exemplified its generality and practicability.

Iodine-promoted radical alkyl sulfuration of imidazopyridines with dialkyl azo compounds and elemental sulfur.

Dialkyl azo compounds were found to be effective alkyl radical sources for direct alkyl sulfuration with imidazopyridines using elemental sulfur under metal-free conditions. Iodine, an inexpensive and mild reagent, could promote alkyl sulfuration. A variety of quaternary cyanoalkyl radicals were successfully coupled with elemental sulfur. A subsequent C-H sulfuration of imidazopyridines afforded a diverse array of imidazopyridine derivatives bearing cyanoalkylthio groups. The cyano group could be modified and further underwent condensation with 2-aminothiazole to afford an interesting heterocyclic amide. Control experiments showed that iodine could greatly suppress the self-coupling of cyanoalkyl radicals, thus making the sulfuration proceed smoothly.

Radical Chemistry of Iminepyridine Ligands

AbstractThe reactivity of metal fragments MeLi(THF), Me2Mg, Me2Zn and Me3Al with a variety of imine/pyridine ligands was studied by DFT methods. Ligands having at least two such groups in conjugation very effectively accept an electron from a metal–carbon bonding orbital and thus assist alkyl dissociation: the M–Me dissociation free energy ΔGd decreases by about 45 kcal/mol for the Li, Mg and Zn fragments, and by 60–70 kcal/mol for Me3Al. Paths for transfer of an alkyl group to the ligands were also explored. Paths for transfer to ligand carbon atoms were found to have high barriers, and such transfers are instead proposed to proceed via initial M–Me dissociation. Direct alkyl transfer to ligand nitrogen atoms is somewhat easier, and for the most electropositive metal Li such a transfer might compete with radical chemistry. For Dimpy, the most stable products are the C3 and C4 alkylation ones. However, the observed regioselectivity of alkyl transfer (often to Npy or C2) does not correlate with product stability and is likely to be a complicated function of radical stability, steric factors and unpaired electron density distribution. The results illustrate that Dimpy and related ligands should be considered strong, reversible oxidants.

Direct intramolecular gas‐phase transfer reactions during fragmentation of sildenafil and thiosildenafil analogs in electrospray ionization mass spectrometry

A study is made of the mass spectral fragmentation pathways of sildenafil, thiosildenafil, and analogous compounds. A prominent gas-phase reaction that occurs during collision-induced dissociation (CID) of thiosildenafil compounds is the transfer of an alkyl group from the piperazine nitrogen atom to the sulfur atom of the thiocarbonyl group. This phenomenon is clearly demonstrated through a comparison of electrospray ionization mass spectral fragmentation patterns of four sildenafil-type compounds and three related thiosildenafil derivatives. Molecular modeling and fragmentation patterns support a direct intramolecular alkyl transfer mechanism rather than an ion-neutral complex mechanism. CID of thiohydroxyhomosildenafil results in a facile hydroxyethyl migration to the sulfur atom followed by a second intramolecular reaction to form a spiro-1,3-oxathiolane ring, which fragments in two directions to generate both carbonyl and thiocarbonyl product ions from this thiocarbonyl compound. While methyl migration to the thiocarbonyl sulfur atom of thiosildenafil is dominant, methyl migration to the carbonyl oxygen atom of sildenafil may occur to a small extent.

On the Kinetic and Thermodynamic Reactivity of Lithium Di(alkyl)amidozincate Bases in Directed Ortho Metalation

Sequential reaction of HTMP (= 2,2,6,6-tetramethylpiperidine) with nBuLi and Et2Zn affords unsolvated polymer chains of EtZn(micro-Et)(micro-TMP)Li 6. The scope of this reagent in directed ortho metalation (DoM) chemistry has been tested by its reaction with N,N-diisopropylnaphthamide in THF to give EtZn(micro-C10H6C(O)NiPr2-2)2Li.2THF 7. Data reveal that 6 has undergone reaction with 2 equiv of aromatic tertiary amide and imply that it exhibits dual alkyl/amido basicity. DFT calculations reveal that direct alkyl basicity is kinetically disfavored and instead point to a stepwise mechanism whereby 6 acts as an amido base, liberating HTMP during the first DoM event. Re-coordination of the amine at lithium then incurs the elimination of EtH. Reaction of the resulting alkyl(amido)(arylamido)zincate with a second equivalent of N,N-diisopropylnaphthamide eliminates HTMP and affords 7. Both DoM steps involve the exhibition of amido basicity and each reveals a low kinetic barrier to reaction. Understanding of this reaction sequence is tested by treating 6 with N,N-diisopropylbenzamide in THF. On the basis of theory and experiment, the presence of THF solvent (in place of stronger Lewis bases) combined with the use of a sterically less congested aromatic amide is expected to encourage threefold, stepwise reaction. Isolation and characterization of the resulting tripodal zincate Zn(micro-C6H4C(O)NiPr2-2)3Li.THF 8 bears this out and suggests a significant new level of control in zincate-induced DoM chemistry through the combination of experiment and DFT studies.

Reaction of the Diimine Pyridine Ligand with Aluminum Alkyls: An Unexpectedly Complex Reaction

The diimine pyridine ligand 2,6-{2,6-iPr2C6H3NCMe}2C5H3N (1) was reacted with a series of aluminum alkyls (Me3Al, Et3Al, iBu3Al, iBu2AlH, Et2AlCl). Depending on the choice of alkyl, addition to the imine carbon and the pyridine C2 and C4 positions was observed. Addition to C2 usually dominates but is reversible; the C4 alkylation product eventually dimerizes via double C−C coupling. Reaction of 1 with AlCl3 gave the ionic complex [1·AlCl2]+[AlCl4]-. DFT calculations were used to support NMR assignments of the various addition products and also to study alkyl transfer from Et2AlCl to simplified model ligand 1‘. Direct alkyl transfer from coordinated Et2AlCl to the ligand C4 position is not possible. Introduction of a second molecule of Et2AlCl results in formation of the ion pair [1‘·AlEtCl]+[Et3AlCl]-, from which alkyl transfer to any position of the ligand is relatively easy. The dimerization of the C4-alkylated product is symmetry-forbidden and was calculated to follow a stepwise biradical path with an unusually low barrier.

Direct α-Iodinationof Aryl Alkyl Ketones by Elemental Iodine Activated by1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneBis(tetrafluoroborate)

Selective introduction of an iodine atom at the α-carbon-yl position in various aryl alkyl ketones was effectively achieved by reaction of target molecules with elemental iodine in the presence of N-F reagents. The best results were obtained by using 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectfluorF-TEDA-BF 4 ) as the iodination mediator and methanol as the solvent. Despite a strongly activated aromatic ring, iodomethyl derivatives were thus exclusively obtained from the corresponding hydroxy and methoxy substituted acetophenone derivatives, 3-acetylindole and 2-acetylbenzofuran, while the α-iodo derivative was the main product in the case of iodination of 1,5,6,7-tetrahydro-4H-indol-4-one and 6,7-dihydro-1-benzothiophene-4(5H)-one.

Polymorphisms in DNA repair and environmental interactions

The repair of damage to DNA is critical to the survival of a cell. However, not all organisms nor all individuals express a similar response to challenges to their genetic material. Numerous polymorphisms in genes involved in DNA repair have been found in individuals with DNA repair-related disease as well as in the general population. Studies of these variants are critical in understanding the response of the cell to DNA damage. In some cases, these changes predispose the carrier to a greatly increased risk of cancer. In other cases, the effects are subtler and depend on interactions between the alleles of several genes, or with environmental factors. Consequently, the health effects of exposure to genotoxic or carcinogenic compounds or agents can depend on the variations in these genes. This review will highlight some of the effects that variants, found in many of the genes involved in human DNA repair pathways, have on the response to damage, and their role in susceptibility of the cell and organism to environmental genotoxins. This review will concentrate on the mismatch repair, nucleotide repair, base excision repair, strand break repair, and direct alkyl repair pathways.

Determination of the fragmentation mechanisms of organophosphorus ions by H2O and D2O atmospheric‐pressure ionization tandem mass spectrometry II—dialkyl alkylphosphonate ions

AbstractDiethyl methylphosphonate (DEMP), diisopropyl methylpbosphonate (DIMP), diethyl isopropylphosphonate (DEIP) and diethyl ethylphosphonate (DEEP) were characterized by H2O and D2O atmospheric pressure ionization tandem mass Spectrometry (API‐MS/MS). Collision‐induced dissociation (CID)/fragmentation pathways included alkyl ions by direct cleavage, alkyl radical and water loss processes and McLafferty and McLafferty‐type rearrangements by six‐ and five‐membered ring transition states, respectively. D2O API proved particularly useful in that certain decomposition pathways (i.e. water and methanol neutral losses) had a statistical distribution as to the loss of an acid deuteron and proton(s). This phenomenon was manifested by two pairs of ions in the D2O API daughter‐ion mass spectrum for each phosphonate compound (e.g. both m/z 79/80 and 65/66 for DEMP and DIMP). The observed ion intensity ratios for these pairs of ions served as guides in the determination of their predicted ion relative abundance ratios and CID decomposition pathways.Water neutral losses as opposed to ether and alcohol neutral losses were favored for most of the protonated organophosphonate molecular ion decomposition schemes.

Dienone–phenol rearrangements of bicyclic cyclohexa-2,5-dienones; confirmation of a multistage mechanism

Two mechanisms are well established for the dienone–phenol rearrangements of bicyclic cyclohexadienones of the 4a-alkyl-5,6,7,8-tetrahydronaphthalen-2(4aH)-one type, of which the 4a-methyl compound (1) and the steroidal 1,4-dien-3-ones are examples. They involve, for (1), either a direct alkyl shift from C-4a to C-4 and deprotonation to give a 4-alkyl-5,6,7,8-tetrahydro-2-naphthol or a shift of the 4a,5-bond from C-4a to C-8a with formation of a spiran intermediate and further ring migration from C-8a to C-1 to from a 4-alkyl-5,6,7,8-tetrahydro-1-naphthol. A further mechanism, for which there was little strong evidence, involves an alkyl shift from one angular position, C-4a, to the other, C-8a, followed by further ring migrations via a spiran intermediate to give an additional route to the 4-alkyltetrahydro-2-naphthol product. The products of rearrangement of 3,4a-and 1,4a-dimethyl-5,6,7,8-tetrahydronaphthalen-2(4aH)-ones in aqueous sulphuric acid, and in acetic anhydride with sulphuric acid catalysis, have been studied critically. The use of quantitative 13C n.m.r. spectroscopy confirms the identity and ratios of products deduced using 1H n.m.r. spectroscopy and other techniques. The results show that the third, suspect, mechanism does indeed operate, and that it contributes significantly to the formation of 4-alkyltetrahydro-2-naphthol products from both dienones.

Direct alkyl chain cleavage after C-hydroxylation of dialkylnitrosamines in rats. A new pathway of the oxidative biotransformation.

Comparative in vivo investigations on the biotransformation of di-n-butylnitrosamine (DBNA) and (2-hydroxybutyl)-n-butylnitrosamine (HBBNA) showed the known omega-oxidation. However, a new metabolic mechanism of direct oxidative alkyl chain cleavage in the vicinity of the hydroxy group of HBBNA could be demonstrated.

Beam studies of the energy dependence of the reactions of tritium atoms with n-hexane, cyclopentane, n-butane, and 1-chlorobutane

The reactions of monoenergetic tritium atoms with simple alkanes and halocarbons have been studied in the 1–200 eV range by a molecular beam technique. Excitation functions σi (E) for the different reaction channels are derived from the product yields by a Kinetic Theory Analysis. It is found that: (1) T for H substitution cross sections (to form labeled parent alkanes) are similar for all alkanes studied (n-butane, n-hexane, cyclopentane, and cyclohexane): threshold at 1.5± 0.5 eV, a rapid rise to a maximum at 9–12 eV and 1–3 Å2 and a slow decline at higher energies. The asymptotic high energy parent yields correlate well with the degeneracy of the reaction path, a fact that further demonstrates the independence from structural details of T for H substitution for a single reaction path. (2) In the formation of degraded alkanes by C–C bond breakage, drastic structural dependence of the reaction cross section is found. (a) When the hydrogen atoms along a C–C bond are staggered, as in the thermodynamically stable conformation of most alkanes, the C–C bond is effectively shielded from direct attack by the hydrogen envelope, and the dominant mode of reaction consists of the sequence: H displacement followed by decomposition of energetic primary reaction products and stabilization of the fragment species. (b) When the hydrogens are eclipsed (as exemplified to a good approximation by cyclopentane in its thermodynamically stable half chair form), the C–C bond is exposed to direct attack by incoming T atoms, and direct alkyl displacement is facilitated. Direct alkyl displacement is a low energy process on our scale, with a threshold E0<1.2 eV, and with most of the reaction occurring below a few electron volts. At higher energies (E>4 eV), mechanism (a) takes over, since the products from (b) decompose. (3) T for Cl displacement in 1-chlorobutane occurs at higher average energies than H substitution. The cross section for the former process has an onset in the 1 eV region and goes through a maximum at ∼15 eV. The probability of displacing a Cl atom exceeds that for displacement of a given H atom by a factor of 2–3.