Substituent

About: Substituent is a research topic. Over the lifetime, 42877 publications have been published within this topic receiving 516716 citations. The topic is also known as: side chain & side group.

Intramolecular “Hydroiminiumation” of Alkenes: Application to the Synthesis of Conjugate Acids of Cyclic Alkyl Amino Carbenes (CAACs)

Abstract: Nitrogen-containing heterocyclic systems have attracted considerable interest over the years because they form the core structures, and are key intermediates, of natural products.[1] One of the most appealing synthetic approaches for their preparation is the intramolecular hydroamination of alkenes, in which the nitrogen–carbon bond is formed by addition of an amine to an olefin.[2] Various catalysts have been used to effect this transformation, which include alkali metals,[3] early[4] and late transition metals,[5] and f-block elements.[6] Interestingly, despite the buffering effect of amines, intramolecular[7] and even intermolecular[8] acid-catalyzed hydroaminations have recently been developed. Schlummer and Hartwig[7a] reported the cyclization of amino alkenes bearing an electron-withdrawing group on the nitrogen atom by catalysis with triflic or sulfuric acid (20 mol %; Scheme 1). A mechanistic study of this process suggested that in contrast to similar transformations using various electrophiles as promoters (for example, iodine-,[9] bromine-,[10] and selenium-based electrophiles[11]), the first step was protonation of the amine, followed by intramolecular transfer of the proton to the double bond in the rate-determining step, and lastly trapping of the generated cation by the amino group. Accordingly, in the absence of electron-withdrawing groups on the nitrogen atom, the cyclization does not occur because of the excessive basicity of the amino group, which prevents the transfer of the proton to the olefin. Scheme 1 a) Schematic representation of acid-catalyzed intramolecular hydroamination; EWC = electron-withdrawing group, n = l,2. b) The hydroiminiumation reaction as a potential synthetic route to cyclic iminium salts A. c) CAAC/H+ salts A′, the precursors ... Imines are certainly less basic than amines, and therefore it was decided to investigate the feasibility of “hydroiminiumation” reactions, which would be an atom-economical route to cyclic iminum salts A (Scheme 1). Providing there is a bulky aryl substituent on the nitrogen atom and that there is a quaternary carbon atom in the position α to the aldiminium carbon atom, salts A′ are the direct precursors of stable cyclic alkyl amino carbenes (CAACs) B.[12] We have shown that CAACs can compete with N-heterocyclic carbenes (NHCs)[13] as ligands for transition-metal-based catalysts,[12a] and also allow the preparation of very low coordinate transition-metal centers.[12b] We report herein our preliminary results on the scope of the thermally induced hydroiminiumation reaction and its application to the synthesis of a variety of CAAC precursors. To establish the viability of this hydroiminiumation methodology, the synthesis of the previously reported CAAC/H+ compound 4a[12a] was chosen as an initial test. Deprotonation of aldimine 1a, derived from 2,6-diisopropyl-aniline (DippNH2) and cyclohexane carboxaldehyde, with lithium diisopropylamide (LDA) leads to the corresponding 1-aza-allyl anion, which readily reacts at room temperature with 3-bromo-2-methylpropene (or 3-chloro-2-methylpropene) to afford the alkenyl aldimine 2a in 94% yield (Scheme 2). Addition of a stoichiometric amount of a 2M solution of HCl/Et2O to a toluene solution of 2a at −78 °C resulted in the immediate formation of a white precipitate. After 15 minutes at −78 °C, the mixture was allowed to warm to room temperature and stirring was continued for an additional 15 minutes. After filtration and recrystallization from chloroform, a new compound 3a was isolated as white crystals in 92% yield. The ionic character of 3a was apparent from its low solubility in toluene, while its acyclic nature was revealed by the presence of a 13C NMR signal at δ = 117.0 ppm from an ethylenic CH2 fragment. The protonation of the nitrogen atom was indicated by a 1H NMR signal at δ = 15.5 ppm, and by the deshielding of the N=CH 13C and 1H NMR signals (2a: (δ = 173.6 and 7.6 ppm; 3a: (δ = 189.8 and 8.0 ppm). A single-crystal X-ray diffraction study unambiguously proved the alkenyl aldiminium structure of 3a (Figure 1). [14] Pleasingly, it was noted that heating an aceto-nitrile solution of 3a in a tube sealed by a teflon stopcock at 50 °C for 18 h afforded the desired cyclic iminium salt 4a in 88% yield. Obviously, the last two steps of the synthesis (2a→4a) can be performed in situ, and the best results (88% yield of isolated product) were obtained when a twofold excess of HCl was used. The overall transformation (1a→4a) can thus be done in 83% yield, which compares extremely favorably with the previously reported method (48 % yield); moreover, the new route uses the same precursor 1a, but avoids the use of the costly reagents 1,2-epoxy-2-methylpropane and trifluoromethane sulfonic anhydride. Figure 1 Molecular structure of 3a in the solid state. Scheme 2 Influence of the nature of the R and R1 substituents on the rate of the hydroiminiumation reaction; Dipp = 2,6-iPr2C6H3; Mes = 2,4,6-Me3C6H2. [a] Time and temperature required for complete conversion of 3. [b] Yield of isolated product, without isolation ... To study the influence of various steric and electronic factors on the hydroiminiumation reaction, several different alkenyl aldimines 2b–h were prepared (Schemes 2, ​,3,3, and ​and4).4). Without exception, the protonation occurred smoothly at the nitrogen atom, and the ensuing alkenyl aldiminium salts 3b–h were obtained in good to excellent yields. The cyclization process occurs slightly more easily when bulky substituents are used on both sides of the NCC fragment (Scheme 2). Indeed, when two methyl groups were used in place of the cyclohexyl group of 3a, the formation of 4b required 24 h at 50 °C, whereas for derivative 3c (Ar = Mes, CR1R1 = CMe2) 24 h at 70 °C are necessary to achieve complete conversion. Not surprisingly, a limitation to the methodology was found when an electron-donating tert-butyl group was placed on the nitrogen atom. Here, because of the high basicity of the nitrogen center, no trace of the cyclic iminium salt 4d was detected when a toluene solution of 3d was heated at 110°C for 24 h. Scheme 3 Influence of the nature of the alkene substituents R1 and R2 on the rate and regioselectivity of the hydroiminiumation reaction. Tos=toluene-4-sulfonyl. [a] Time and temperature required for complete conversion of 3. [b] Yield of isolated product, without ... Scheme 4 Synthesis of six-membered heterocyclic aldiminium salt 4h. Use of alkenyl aldiminium salts 3a and 3e–g allowed study of the influence of the substitution pattern of the carbon–carbon double bond on the fate of the hydroiminiumation reaction, especially with regard to its regioselectivity (Scheme 3). The temperature required for cyclization was found to increase along the series 3a<3e<3f<3g. More importantly, in all cases five-membered heterocycles 4 resulting from exo cyclization were obtained, with no trace of the six-membered-ring isomers being detected. Strikingly, the cyclization of 3g affords exclusively five-membered heterocycle 4g (Figure 2), despite the presence of a phenyl group at the terminal carbon atom of the olefin, which would be expected to stabilize a benzylic carbocation intermediate. Together these observations favor a mechanism in which the proton would be transferred intramolecularly to the double bond in the rate-determining step, similarly to the mechanism proposed by Schlummer and Hartwig for the acid-catalyzed hydroamination reaction.[7a] When compared to the latter reaction involving alkenyl amine I, for which the formation of the six-membered ring II was observed, our result suggests that the addition of N—H across the double bond has a greater “concerted” character[15] in the hydroiminiumation than in the hydroamination reaction.[7a] Figure 2 Molecular structures of 3g (left) and 4g (right) in the solid state. Six-membered heterocyclic aldiminium salts can also be accessed as shown by the preparation of 4h (Scheme 4). However, as observed in the hydroamination reaction,[7a] the cyclization to 4h is more difficult than for the homologous five-membered ring 4e. Besides the easy preparation of a wide variety of CAAC/H+ compounds, the intramolecular hydroiminiumation reported here features some distinct advantages when compared to the intramolecular hydroamination reaction. The resulting iminium ions are very reactive, potentially allowing for the subsequent addition of a large range of nucleophiles, and since they are often prochiral, this chemistry offers the possibility of facile construction of a new stereogenic center a to the nitrogen atom. The extension of this work to other protonated sp2-nitrogen-containing species is under active investigation.

Inductive Effects on the Energetics of Prolyl Peptide Bond Isomerization: Implications for Collagen Folding and Stability.

Abstract: The hydroxylation of proline residues in collagen increases the stability of the collagen triple helix. Previous X-ray diffraction analyses had demonstrated that the presence of an electron-withdrawing substituent on the pyrrolidine ring of proline residues has significant structural consequences [Panasik, N., Jr.; Eberhardt, E. S.; Edison, A. S.; Powell, D. R.; Raines, R. T. Int. J. Pept. Protein Res. 1994 , 44, 262−269]. Here, NMR and FTIR spectroscopy were used to ascertain kinetic and thermodynamic properties of N-acetyl-[β,γ-13C]d,l-proline methyl ester (1); N-acetyl-4(R)-hydroxy-l-proline [13C]methyl ester (2); and N-acetyl-4(R)-fluoro-l-proline methyl ester (3). The pKa's of the nitrogen atom in the parent amino acids decrease in the following order: proline (10.8) > 4(R)-hydroxy-l-proline (9.68) > 4(R)-fluoro-l-proline (9.23). In water or dioxane, amide I vibrational modes decrease in the following order: 1 > 2 > 3. At 37 °C in dioxane, the rate constants for amide bond isomerization are greater...

Substituent Effect on the Oxidation of Phenols and Aromatic Amines by Horseradish Peroxidase Compound I

Abstract: A stopped-flow kinetic study shows that the reduction rate of horseradish peroxidase compound I by phenols and aromatic amines is greatly dependent upon the substituent effect on the benzene ring. Moreover it has been possible to relate the reduction rate constants with the ionization constants of monosubstitutcd substrates by a linear free-energy relationship (Hammett equation). The correlation of log (rate constants) with σ values (Hammett equation) and the absence of correlation with σ+ values (Okatnoto-Brown equation) can be explained by a mechanism of aromatic substrate oxidations, in which the substrate gives an electron to the enzyme compound I and simultaneously loses a proton. The analogy which has been made with oxidation potentials of phenols or anilines strengthens the view that the reaction is only dependent on the relative ease of oxidation of the substrate. The rate constant obtained for p-aminophenol indicates that a value of 2.3 × 108 M−1 s−1probably approaches the diffusion-controlled limit for a bimolecular reaction involving compound I and an aromatic substrate.

Free radical macrophotoinitiators: an overview on recent advances

Abstract: This paper provides an overview of the recent advances on polymeric photoinitiators for UV curing. During the last decade, significant developments have been achieved in the synthesis of macrophotoinitiators, due to the advantages derived of their macromolecular nature, in comparison with their corresponding low molecular weight analogues. In particular, a variety of macromolecules containing the two main types of free radical photoinitiators: hydrogen-abstracting (thioxanthone, benzil, anthraquinone, camphorquinone) and photofragmenting chromophores (benzoin ether, acylphosphine oxides) are described. For hydrogen-abstracting photoinitiator, the photoinitiation activity have been examined in terms of volume and nature of substituent in the polymeric coil, and their influence to prevent the recombination of radicals favouring their reaction with the monomer. Also, copolymers bearing chromophore and amine groups with potential synergistic effects of activity are reported. It has been found that the approach of the tertiary amine to the chromophore to produce the corresponding exciplexes is dependent on both the monomeric or polymeric nature of chromophore and the tertiary amine. Type II polymeric photoinitiators, such as benzoin ether derivatives having the benzoin methyl ether moieties connected to the main chain through the benzyl aromatic are reported. And a fragmentation mechanism involving the formation of an stable quinoid structure and aliphatic acyl radical is proposed for the above copolymers, which would justified their lower initiating efficiency than the corresponding low molecular weight model. In addition, polymers bearing phosphine oxide moieties are described. The efficiency in the polymerisation of all photoinitiators was found to be similar and irrespective of the presence of flexible spacer in their structure. However, it was found that the flexible oligomethylene spacer enhanced the compatibility of the new polymeric photoinitiators in acrylic adhesive formulations. Finally, polysilanes as photoinitiators are reported. Under UV irradiation, polysilanes undergo main-chain scission leading to free silyl radicals capable of reacting with olefinic monomers. The silyl radicals generated by photolysis can be oxidised by appropriate onium salts to yield cationic initiating species (photoinitiated radical promoted cationic polymerisation). The photoinitiation efficiency of polysilanes having different aliphatic and aromatic side groups has been investigated and compared with commercial low molecular weight photoinitiators as benzoin.