Tertiary Alkylamines Research Articles

Supported Gold Nanoparticles for Efficient α‐Oxygenation of Secondary and Tertiary Amines into Amides

AbstractAlthough the α‐oxygenation of amines is a highly attractive method for the synthesis of amides, efficient catalysts suited to a wide range of secondary and tertiary alkyl amines using O2 as the terminal oxidant have no precedent. This report describes a novel, green α‐oxygenation of a wide range of linear and cyclic secondary and tertiary amines mediated by gold nanoparticles supported on alumina (Au/Al2O3). The observed catalysis was truly heterogeneous, and the catalyst could be reused. The present α‐oxygenation utilizes O2 as the terminal oxidant and water as the oxygen atom source of amides. The method generates water as the only theoretical by‐product, which highlights the environmentally benign nature of the present reaction. Additionally, the present α‐oxygenation provides a convenient method for the synthesis of 18O‐labeled amides using H218O as the oxygen source.

ChemInform Abstract: Tuning Reactivity and Selectivity in Hydrogen Atom Transfer from Aliphatic C—H Bonds to Alkoxyl Radicals: Role of Structural and Medium Effects

AbstractReview: 50 refs.

Tuning reactivity and selectivity in hydrogen atom transfer from aliphatic C-H bonds to alkoxyl radicals: role of structural and medium effects.

Hydrogen atom transfer (HAT) is a fundamental reaction that takes part in a wide variety of chemical and biological processes, with relevant examples that include the action of antioxidants, damage to biomolecules and polymers, and enzymatic and biomimetic reactions. Moreover, great attention is currently devoted to the selective functionalization of unactivated aliphatic C-H bonds, where HAT based procedures have been shown to play an important role. In this Account, we describe the results of our recent studies on the role of structural and medium effects on HAT from aliphatic C-H bonds to the cumyloxyl radical (CumO(•)). Quantitative information on the reactivity and selectivity patterns observed in these reactions has been obtained by time-resolved kinetic studies, providing a deeper understanding of the factors that govern HAT from carbon and leading to the definition of useful guidelines for the activation or deactivation of aliphatic C-H bonds toward HAT. In keeping with the electrophilic character of alkoxyl radicals, polar effects can play an important role in the reactions of CumO(•). Electron-rich C-H bonds are activated whereas those that are α to electron withdrawing groups are deactivated toward HAT, with these effects being able to override the thermodynamic preference for HAT from the weakest C-H bond. Stereoelectronic effects can also influence the reactivity of the C-H bonds of ethers, amines, and amides. HAT is most rapid when these bonds can be eclipsed with a lone pair on an adjacent heteroatom or with the π-system of an amide functionality, thus allowing for optimal orbital overlap. In HAT from cyclohexane derivatives, tertiary axial C-H bond deactivation and tertiary equatorial C-H bond activation have been observed. These effects have been explained on the basis of an increase in torsional strain or a release in 1,3-diaxial strain in the HAT transition states, with kH(eq)/kH(ax) ratios that have been shown to exceed one order of magnitude. Medium effects on HAT from aliphatic C-H bonds to CumO(•) have been also investigated. With basic substrates, from large to very large decreases in kH have been measured with increasing solvent hydrogen bond donor (HBD) ability or after addition of protic acids or alkali and alkaline earth metal ions, with kinetic effects that exceed 2 orders of magnitude in the reactions of tertiary alkylamines and alkanamides. Solvent hydrogen bonding, protonation, and metal ion binding increase the electron deficiency and the strength of the C-H bonds of these substrates deactivating these bonds toward HAT, with the extent of this deactivation being modulated by varying the nature of the substrate, solvent, protic acid, and metal ion. These results indicate that through these interactions careful control over the HAT reactivity of basic substrates toward CumO(•) and other electrophilic radicals can be achieved, suggesting moreover that these effects can be exploited in an orthogonal fashion for selective C-H bond functionalization of substrates bearing different basic functionalities.

Iron-Catalyzed Cα-H Oxidation of Tertiary, Aliphatic Amines to Amides under Mild Conditions.

De novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe-catalyzed Cα-H functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild Cα-H cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis.

Iron‐Catalyzed CαH Oxidation of Tertiary, Aliphatic Amines to Amides under Mild Conditions

AbstractDe novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe‐catalyzed CαH functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild CαH cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis.

High-Density Noncovalent Functionalization of DNA by Electrostatic Interactions

Preserving DNA hybridization in organic solvents could someday serve to significantly extend the applicability of DNA-based technologies. Here, we present a method that can be used to solubilize double-stranded DNA at high concentrations in organic media. This method requires first precipitating a DNA molecule from the aqueous environment with an anilinium derivative and subsequently exchanging this moiety with an amine-containing surfactant in organic solvent. We demonstrate that this method yields complete exchange of the surfactant and allows for the modification of DNA with hydrophobic primary, secondary, and tertiary alkylamines and ordered functional π-systems. Using this approach, we fabricate a multichromophoric light harvesting system that would be unattainable by traditional methods. Additionally, this method makes it possible to use small, hydrophilic molecules to solubilize DNA in organic solvents, which reduces the shielding around the DNA and makes the macromolecule more accessible for further chemical modification. We believe that this approach will prove tremendously beneficial in expanding the scope of DNA-based nano- and biotechnologies.

Chemistry of cobalt bis(1,2-dicarbollide) ion; the synthesis of carbon substituted alkylamino derivatives from hydroxyalkyl derivatives via methylsulfonyl or p-toluenesulfonyl esters

In this paper we report the synthetic procedures providing the C-substitution of the cobalt bis(dicarbollide) sandwich anion [(1,2-C2B9H11)-3,3′-Co]− with primary, secondary and tertiary alkylamine groups of different length of the aliphatic spacer attached to the carbon C(1) or C(1) and C(1′) cage positions. Reaction pathways leading to these compounds proceed via synthesis of mono [(1-X-O-(CH2)n-1,2-C2B9H10) (1′,2′-C2B9H11)-3,3′-Co]Me4N (where n = 1–3 and X = –SO2CH3 or –SO2(-C6H4-4-CH3) esters (2a–f) and diesters [(1,1′-X-O-(CH2)n-1,2-C2B9H10)2-3,3′-Co]Me4N (3a-c) (n = 1 and 2). These compounds are readily accessible in good to excellent yields by reactions of trimethylammonium salts of alkylhydroxy derivatives (1a–e) of the parent ion with methylsulfonyl or p-toluenesulfonyl chloride. The esterifications proceeded with lower conversions only for methylene hydroxy derivatives. The series of primary amines of general formulation [(1-1R2RN-(CH2)n-1,2-C2B9H10) (1′,2′-C2B9H11)-3,3′-Co]− (where n = 1–3 and 1R = 2R = H) (4a–c), along with the diamine [(1,1′–NH2–C2H5)2-1,2-C2B9H10)2-3,3′-Co]− (5), and compounds comprising secondary and tertiary amino functions (1R = nBu, 2R = H, 1R = Bn, 2R = H and 1R = 2R = Et) (6a–h) were prepared in generally good yields by reactions of the esters with ammonia and primary or secondary amines. However, the reactions of the bis(methylene methylsulfonyl) diester resulted in almost quantitative in situ dialkylation of the amine group leading to the formation of a triatomic bridge between two carbon atoms of the cage [(1,1′-μ-(-CH2NRCH2-) (1,2-C2B9H10)2-3,3′-Co]− (R = H or Bu) (7a, b). We believe this observation contributes further to rich evidence on the preference of bridge substitutions at the cobalt bis(dicarbollide) cage.

Advanced Synthesis of Dihydrofurans: Effect of Formic Acid on the Mn(III)-Based Oxidation

The Mn(III)-based oxidation of a tertiary alkylamine, such as nitrilotris(ethane-2,1-diyl) tris(3-oxobutanoate) (1) with 1,1-diphenylethene (2a), effectively proceeded in an acetic acid–formic acid mixed solvent to give nitrilotris(ethane-2,1-diyl) tris(2-methyl-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate) (3). Other typical Mn(III)-based reactions of various β-diketo esters 4a–e, 2,4-pentanedione (6a), malonic acid (6b), and diethyl malonate (6c) with 1,1-diarylthenes 2a–d were also investigated in a similar acetic acid–formic acid mixed solvent and the reaction rate was accelerated and the product yield increased.

First rhodium-catalyzed hydroformylation of cyclopentadiene

This paper describes the first rhodium-catalyzed hydroformylation of cyclopentadiene (Cpd) using a homogeneous catalyst system consisting of [Rh(OAc)2]2 and the chelate ligand BISBI. At a reaction temperature of 100°C and a syngas pressure of 30bar the cyclopentane carbaldehyde is formed in 68% yield while 20% of the respective dialdehyde species are obtained within 3hours. An important side reaction in Cpd hydroformylation reaction can be the dimerization of Cpd to its dimer dicyclopentadiene (Dcpd). This unwanted side reaction could be overcome by the use of tertiary alkyl amines as additives. Furthermore, the possibility to steer the reaction via the influence of the bite angle of diphosphine ligands was found.

ChemInform Abstract: A Novel Pd‐Catalyzed N‐Dealkylative Carbonylation of Tertiary Amines for the Preparation of Amides.

AbstractVarious aryl iodides and alkyl tertiary amines are applicable in the title reaction to afford a series of N,N‐disubstituted amides with moderate to excellent yields.

Effect of secondary and tertiary alkylamines for the synthesis of Zeolite L

Zeolite L was synthesized at 180°C/72h under hydrothermal condition in the presence of diethylamine and triethylamine. Effects of alkylamines on crystallization, textural and morphological behaviors of zeolite L were investigated. Alkylamines facilitated in the crystallization of phase pure zeolite L. The triethylamine modified samples exhibited highest surface area (367m2g−1) and microporosity compared to those prepared in the presence of diethylamine. Clam-shaped crystals with nonuniform thickness of the particles were obtained in the presence of diethylamine, while triethylamine yielded cylindrical shaped crystals with hexagonal faced crystal habit. The role of amines having different chemical behaviors toward crystal growth of zeolite L was illustrated with a tentative mechanism.

Synthesis of some acyclic quaternary ammonium compounds. Alkylation of secondary and tertiary amines in a two-phase system

A series of acyclic symmetrical and asymmetrical quaternary ammonium chlorides of the general formula R1R2R3N+AR4Cl– (R1 = Me, Bu; R2 = n-C12H25, PhCH2, C n H2n+1(OCH2CH2) m , n = 9 and 12, m = 1 and 2; R3 = n-C12H25, PhCH2, HOCH2CH2,–OOCCH2; R4 = n-C12H25, PhCH2; A = (CH2CH2O)1,2, CH2C(O)O) was synthesized by the alkylation of tertiary amines in a two-phase system containing water. A convenient method for the synthesis of the initial symmetrical and asymmetrical tertiary amines of the general formula MeNR1R2 (R1 = Me, Bu; R2 = n-C12H25, PhCH2, CnH2n+1(OCH2CH2) m , n = 9 and 12, m = 1 and 2) in an organic phase-aqueous phase heterogeneous system, which allows the use of aqueous solutions of alkali and amines, was developed. The improved method for the preparation of intermediate ethylene glycol and diethylene glycol monoethers is monoalkylation of glycols in dioxane using solid KOH in a two-phase system.

A novel Pd-catalyzed N-dealkylative carbonylation of tertiary amines for the preparation of amides.

A novel and convenient protocol for the formation of amides via palladium-catalyzed N-dealkylative carbonylation of alkyl tertiary amines has been developed. In the presence of PdCl2(PhCN)2, CuO, PhCN and CO, a range of substituents on both aryl iodides and alkyl tertiary amines were compatible with the reaction to afford a series of N,N-disubstituted amides in moderate to excellent yields.

Iridium–CNP complex catalyzed cross-coupling of primary alcohols and secondary alcohols by a borrowing hydrogen strategy

A highly efficient C–C bond formation has been developed through the cross-coupling of primary and secondary alcohols. The corresponding functionalized ketones were obtained with an iridium–CNP complex as a catalyst through the borrowing hydrogen strategy. The present methodology provides an easy alternative method to aldol reaction derivatives. More importantly, the complexes were also effective catalysts for the alkylation of an aromatic amine with a tertiary alkyl amine.

Preparation of 2-azabicyclo[3.3.1]nonan-3-ones by a Radical C-Carbonylation of Methylcyclo-Hexylamines

The search for a rational method for the synthesis of 2-azabicyclo[3.3.1]nonane, needed for pharmaceutical studies, has led us to the idea that the -C-carbonylation of tertiary alkylamines and the synthesis of lactams can be effected similarly to the radical C-carboxylation of branched alkanes [1, 2]. Remote -carbonylation of alkanols is associated with a 1,5-H transfer on a generated alkoxyl radical [3-6]. As a result, a -hydroxylalkyl radical is formed which reacts with carbon monoxide to give the corresponding acyl radical. This stage is reversible hence a high pressure of the carbon monoxide is needed to ensure the cyclization. The only limitation of such -CH-functionalization reactions of alkanols in a singleelectron oxidation process (e.g., by the action of Pb(OAc)4) is that tertiary alcohols can not be used [7]. Under the conditions given above a -CH-functionalization of the tert-alkylamines can be accomplished, however further oxidation of the substrate occurs [8]. In a modified method for generating -aminoand -amidoalkyl radicals it was necessary to use not only an oxidant but also iodine [4]. However, this variation is inapplicable to amines 1a,b since it can lead to -C-iodination and the subsequent formation of a pyrrolidine ring [4]. Azacyclization using NBS also proceeds via formation of an aminoalkyl bromide intermediate [9] and is not applicable to carbonylation. Hence, despite the expected oxidative side reactions, we had to use Pb(OAc)4 in the presence of K2CO3 by analogy with the study [1]. The amine 1b has a fixed axial amino group and presumably can ensure the 1,5-H transfer on an aminyl radical. Analysis of the reaction mixture of amines 1a,b has shown that, in fact, the corresponding 2-azabicyclo[3.3.1]nonanes 4a,b are formed, but in the case of amine 1a the yield of bicycle 4a relative to the other reaction products is 19% (68% conversion) while the yield of bicycle 4b in the reaction of amine 1b is only 6% (52% conversion). Such result can only be explained by a more rapid azacyclization of radical B due to stabilized conformation that is optimal for formation of bicycle 2b. This is confirmed by the domination of the products of in situ oxidation of amine 2b (imine 3b in 11% and lactam 7b in 22% yields) when an excess of

Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols

New quaternary alkylammonium conjugates of steroids were obtained by two step reaction of sterols (ergosterol, cholesterol, dihydrocholesterol) with bromoacetic acid bromide, followed by bimolecular nucleophilic substitution with a long chain tertiary alkylamine. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry and PM5 semiempirical methods. The pharmacotherapeutic potential of synthesized compounds has been estimated on the basis of Prediction of Activity Spectra for Substances (PASS).

Chemical Derivatization of Peptide Carboxyl Groups for Highly Efficient Electron Transfer Dissociation

The carboxyl groups of tryptic peptides were derivatized with a tertiary or quaternary amine labeling reagent to generate more highly charged peptide ions that fragment efficiently by electron transfer dissociation (ETD). All peptide carboxyl groups-aspartic and glutamic acid side-chains as well as C-termini-were derivatized with an average reaction efficiency of 99%. This nearly complete labeling avoids making complex peptide mixtures even more complex because of partially-labeled products, and it allows the use of static modifications during database searching. Alkyl tertiary amines were found to be the optimal labeling reagent among the four types tested. Charge states are substantially higher for derivatized peptides: a modified tryptic digest of bovine serum albumin (BSA) generates ~90% of its precursor ions with z > 2, compared with less than 40% for the unmodified sample. The increased charge density of modified peptide ions yields highly efficient ETD fragmentation, leading to many additional peptide identifications and higher sequence coverage (e.g., 70% for modified versus only 43% for unmodified BSA). The utility of this labeling strategy was demonstrated on a tryptic digest of ribosomal proteins isolated from yeast cells. Peptide derivatization of this sample produced an increase in the number of identified proteins, a >50% increase in the sequence coverage of these proteins, and a doubling of the number of peptide spectral matches. This carboxyl derivatization strategy greatly improves proteome coverage obtained from ETD-MS/MS of tryptic digests, and we anticipate that it will also enhance identification and localization of post-translational modifications.

Thermodynamics of ketone + amine mixtures. Part X. Excess molar enthalpies at 298.15 K for N,N,N-triethylamine + 2-alkanone systems. Characterization of tertiary amine + 2-alkanone, and of amino-ketone + n-alkane mixtures in terms of DISQUAC

Molar excess enthalpies, HmE, at 298.15K and 0.1MPa have been measured using a Tian–Calvet microcalorimeter for N,N,N-triethylamine (TEA)+2-alkanone mixtures. These data have been used to determine ΔHN-CO, the enthalpy of the amine-ketone interaction, which is practically independent of the ketone size. This allows explain the observed HmE decrease when the ketone size is increased in terms of a lower positive contribution to HmE from the breaking of the alkanone-alkanone interactions. Inspection of molar excess volumes and of molar excess internal energies at constant volume (determined in this work) reveals the existence of structural effects, which are more important for mixtures with 2-heptanone. Tertiary alkyl amine+2-alkanone, and amino-ketone+n-alkane mixtures have been treated in terms of DISQUAC. The interaction parameters for the carbonyl/amine contacts are reported. It is shown that such contacts are essentially dispersive. Proximity effects in amino-ketone mixtures lead to increased dispersive parameters in comparison to those of amine+ketone solutions. Steric effects related to the length of the alkyl chains attached to the N atom lead to decreased dispersive parameters. DISQUAC describes accurately vapour–liquid equilibria (VLE) and HmE of the investigated mixtures, which have been also treated using UNIFAC (Dortmund version). UNIFAC predictions compare well with DISQUAC results for TEA mixtures. For amino-ketone systems, UNIFAC calculations largely differ from the experimental results. This reveals that interactions parameters must be modified to take into account proximity effects.

ChemInform Abstract: Copper‐Catalyzed Electrophilic Amination of Organoboron Compounds

AbstractReview: ca. 100 refs.

Wormlike Micelle Formation by Acylglutamic Acid with Alkylamines

Rheological properties of alkyl dicarboxylic acid-alkylamine complex systems have been characterized. The complex materials employed in this study consist of an amino acid-based surfactant (dodecanoylglutamic acid, C12Glu) and a tertiary alkylamine (dodecyldimethylamine, C12DMA) or a secondary alkylamine (dodecylmethylamine, C12MA). (1)H NMR and mass spectroscopic data have suggested that C12Glu forms a stoichiometric 1:1 complex with C12DMA and C12MA. Rheological measurements have suggested that the complex systems yield viscoelastic wormlike micellar solutions and the rheological behavior is strongly dependent on the aqueous solution pH. This pH-dependent behavior results from the structural transformation of the wormlike micelles to occur in the narrow pH range 5.5-6.2 (in the case of C12Glu-C12DMA system); i.e., positive curved aggregates such as spherical or rodlike micelles tend to be formed at high pH values. Our current study offers a unique way to obtain viscoelastic wormlike micellar solutions by means of alkyl dicarboxylic acid-alkylamine complex as gemini-like amphiphiles.