Cyclic polypeptides by thermal polymerization of α‐amino acid N‐carboxyanhydrides

The NCAs of the following five amino acids were polymerized in bulk at 120 °C without addition of a catalyst or initiator: sarcosine (Sar), L ‐alanine (L ‐Ala), D ,L ‐phenylalanine (D ,L ‐Phe), D ,L ‐leucine (D ,L ‐Leu) and D ,L ‐valine (D,L ‐Val). The virgin reaction products were characterized by viscosity measurements ¹³C NMR spectroscopy and MALDI‐TOF mass spectrometry. In addition to numerous low molar mass byproducts cyclic polypeptides were formed as the main reaction products in the mass range above 800 Da. Two types of cyclic oligo‐ and polypeptides were detected in all cases with exception of sarcosine NCA, which only yielded one class of cyclic polypeptides. The efficient formation of cyclic oligo‐ and polypeptides explains why high molar mass polymers cannot be obtained by thermal polymerizations of α‐amino acid NCAs. Various polymerization mechanisms were discussed. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4012–4020, 2008     

Attempted polymerization of substituted pipecolic acid NCA's: Dimerization and mechanism

Racemic and optically active N-carboxyanhydrides (NCA)s of 2-methyl- and cis-6-methylpipecolic acid, when subjected to polymerization conditions in solution or in bulk whether with “weak” or “strong” base initiators, resisted polymerization under all conditions tried. Instead, the NCA of 2-methylpipecolic acid gave the corresponding cyclic dipeptide and the NCA of cis-6-methylpipecolic acid formed the cyclic dipeptide derived from trans-6-methylpipecolic acid. The mechanism of dimerization of these NCA's was investigated. Evidence was provided for the proposed mechanism in which the active moiety is not a carbamate ion but an amino group. Methyl 2-methylpipecolate underwent an intermolecular S_N2-type reaction upon heating, yielding equimolar quantities of methyl N-methyl-2-methylpipecolate and 2-methylpipecolic acid.     

Peptide synthesis in aqueous environments: the role of extreme conditions on amino acid activation

The free energy surfaces and reaction mechanisms underlying the activation of amino acids by COS in bulk water at ambient conditions as well as extreme temperature-pressure thermodynamic conditions were studied using accelerated ab initio molecular dynamics. The results for the reaction sequence leading from glycine to its activated form, a so-called Leuchs anhydride or alpha-amino acid N-carboxyanhydride (NCA), suggest that extreme conditions not far from the critical point of water may favor the formation of this activated species. This is traced back to appropriately affecting relative stabilities of neutral versus charged or zwitterionic molecular species which shifts equilibria, affects relative barriers, and thus modifies reaction rates. Furthermore, it is shown that the N-carboxyanhydride of glycine is not formed from N-thiocarboxyl glycine by its direct cyclization, but instead an indirect mechanism, the so-called isocyanate route, is clearly preferred at both conditions. The work quantitatively underpins the impact of extreme solvent conditions on the investigated organic reactions in aqueous media which implies that the presented results are of relevance to fields such as prebiotic chemistry and green chemistry.     

The peptide formation mediated by cyanate revisited. N-carboxyanhydrides as accessible intermediates in the decomposition of N-carbamoylamino acids

Similar to many ureas, N-carbamoylamino acids were shown to be hydrolyzed in aqueous solution through elimination mechanisms at close to neutral pH, the nucleophilic attack of water being a minor process. Two competing elimination mechanisms can take place involving either cyanate or isocyanate transient intermediates. Peptide formation was observed and attributed to the latter pathway through the intermediacy of amino acid N-carboxyanhydride (NCA). Eventually, cyanate and its precursors (including urea) unexpectedly behave as amino acid activating agents because of their ability in amino acid carbamoylation. Owing to its ability to generate a background prebiotic production of NCAs on the primitive Earth, this reaction is suggested to have contributed to the origin of life process.     

13C-NMR Sequence Analysis. XVIII. Tacticity of Poly(D,L-β-amino Acids)

D, L-Cis-2-aminocyclobutane-1-carboxylic acid NCA, D, L-cis-and trans-2-aminocyclohexane-1-carboxylic acid N-carboxyanhydride (NCA) and D, L-cis-2-aminocyclohexane-1-carboxylic acid NCA were polymerized under various conditions. The ¹³C-NMR spectra of the resulting β-polyamides measured in trifluoro-acetic acid show splittings of all signals reflecting diads and triads. Poly-D, L-3-aminobutyric acid obtained by anionic polymerization of D, L-4-methyl acetidinone does not display tacticity effects in its ¹³C-NMR spectrum. Hence it is concluded that tacticity effects are observable only if both α- and β-carbons have a substituent. Furthermore, it was found that the reaction conditions do not have a strong influence on the stereospecificity of the NCA-polymerization. In all cases nearly random sequences of D and L-units were obtained.     

Polymerization of N-carboxy anhydrides by organotin catalysts

Organotin compounds were found to lead to polymerization of N-carboxy anhydrides. The polymerization was studied in detail using γ-benzyl N-carboxyl-t-glutamate anhydride (BGA). Compounds such as tributyltin methoxide, bis(tributyltin)oxide, and N-tributyltin imidazole polymerized BGA while others like dibutyltin dichloride, which are Lewis acids, failed. Polymerization of BGA in dioxane at various monomer to dibutyltin dimethoxide ratios showed a first order reaction to monomer. The plot of In M₀/M₁ vs time showed two stage kinetics, the second one being faster. The pseudo first order rate constants were smaller than those for primary amine initiated polymerizations and much smaller than that for polymerization initiated by sodium methoxide. The molecular weights were independent of the monomer to initiator ratio both in dioxane and in DMF. In the reaction of an equimolar amount of tributyltin methoxide with NCA, the methyl ester of the amino acid was formed.The mechanism suggested is that of addition of the organotin compound to the NCA forming an organotin carbamate which decarboxylates, leaving an active -N-Sn-group which adds to another NCA molecule. This process is repeated in every step of the propagation.     

DFT study on reaction mechanisms of cyclic dipeptide generation

In this work, three possible reaction pathways (Path 1, Path 2 and Path 3) for the generation process of cyclic dipeptide from amino acid have been investigated in detail using density functional theory. Path 1 and Path 2 are the intramolecular reaction processes, while Path 3 involves the intermolecular reaction process that assisted with water molecule. Our calculated results indicate that Path 3 is more energy favorable than Path 1 and Path 2. There are four steps in Path 3 proceed from the amino acid to cyclic dipeptide. The first step is two adjacent amino acids to form precursor of dipeptide, the second step is the removal of water molecule of precursor of dipeptide for the formation of the linear dipeptide, the third step is generation of precursor of cyclic dipeptide associated with other hydrogen atom transfer, and the last step is another dehydration process to generate the final product of cyclic dipeptide. Moreover, the obtained results indicate that the generation mechanisms of different cyclic dipeptides are similar, and the energy barrier of the rate-determined step influenced somewhat by the hydrophilic or hydrophobic group linked to the C_α atom. Additionally, the potential energy profiles suggest that the generation reactions of the studied nine cyclic dipeptides are exothermic processes. The detailed mechanisms should be helpful for people to understanding the title reaction at the molecular level, and the proposed novel intermolecular process might provide valuable insights on rational improve reaction condition for this type of reaction.     

Stereoselective and Asymmetric-Selective Polymerization of α-Amino Acid N-Carboxyanhydride

The enantiomer selectivity in the propagation reaction of NCA was investigated by using suitable model reactions. Contrary to the assumption usually made, the enantiomer selectivity in the nucleophilic addition of chiral amines to NCA depended strongly on the structure of amine or NCA and the solvent. In the polymerization by an activated-NCA mechanism, the addition of activated NCA to NCA was found for the first time to be enantiomer-selective. In addition to this, the chiral penultimate unit was found to participate in the enantiomer selection. Structures of the transition states leading to the different types of enantiomer selection were proposed.     

Polymerization of α-amino acid N-carboxy anhydrides initiated by histamine in N,N-dimethylformamide

The polymerization of α-amino acid N-carboxy anhydrides (NCAs) initiated by 4-aminoethylimidazole (histamine) was studied in order to synthesize poly(amino acids) containing an imidazole nucleus at the end of polymer chain. On the basis of the kinetical measurements, it was found that the rate of polymerization is proportional to the first order in both NCA and initiator concentrations and that the initiation reaction is predominantly caused by the primary amine with the highest basicity in a histamine molecule. Binding of the histamine fragment to the end of polymer chain was confirmed by elementary analysis, nuclear magnetic resonance spectroscopy, and measuring the number-average molecular weight of the resulting polymers. It was thus possible to prepare poly(amino acids) with a pendant histamine. In addition, the lowering of the number-average degree of polymerization of the polymers prepared was observed under the condition that the initial molar ratio of NCA to histamine was larger. It was caused by the reinitiation of polymerization by the imidazole nucleus at the chain end.     

Multiple Mechanism of NCA Polymerization: Effect of N-Acetylglycine NCA and Related Additives

Polymerization of α-aminoisobutyric acid NCA by alkaline salts of various basicity as well as amines has been investigated. The study was focused on the effect on the initial polymerization rate of additives such as N-acetylglycine NCA and some other less electrophilic additives (l-acetyl-2-pyrrolidone, 3-acetyl-2-oxazolidone, 1-acetyl-3-methylhydantoin) which are all models of the growing chain end produced by the NCA anion pathway. The acetyl endgroup was detected by 250 MHz ¹H-NMR in all the polymers of α-aminoisobutyric acid NCA obtained in the presence of l-acetyl-3-methylhydantoin and triethyl amine or sodium methoxide initiators, whereas the additives influenced variously the kinetics of polymerization according to the nature of the initiator used. The results were interpreted in the light of a multiple mechanism supposing the simultaneous presence of the initiator anion, its conjugate acid, and NCA anion for basic salt initiation. Thus, the observed effect has to be considered as the sum of an elementary acceleration due to NCA anion and of an elementary deceleration due to the initiator anion. Predominance of the pathways involving NCA anion could be shown this way. This conclusion could be extended to γ-benxyl-L-glutamate NCA which is a more reactive NCA. However, the deceleration observed with some additives led us to believe that a nonnegligible participation of initiator anion during initiation cannot be excluded.     

Polymerization of α-amino acid N-carboxy anhydrides. III. Mechanism of polymerization of L- and DL-alanine NCA in acetonitrile

The polymerization of L - and DL -alanine NCA initiated with n-butylamine was carried out in acetonitrile which is a nonsolvent for polypeptide. The initiation reaction was completed within 60 min.; there was about 10% of conversion of monomer. The number-average degree of polymerization of the polymer obtained increased with the reaction period, and it was found to agree with value of W/I, where W is the weight of the monomer consumed by the polymerization and I is the weight of the initiator used. The initiation reaction of the polymerization was concluded as an attack of n-butylamine on the C₅ carbonyl carbon of NCA. The initiation, was followed by a propagation reaction, in which there was attack by an amino endgroup of the polymer on the C₅ carbonyl carbon of NCA. The rate of polymerization was observed by measuring the CO₂ evolved, and the activation energy was estimated as follows: 6.66 kcal./mole above 30°C. and 1.83 kcal./mole below 30°C. for L -alanine NCA; 15.43 kcal./mole above 30°C., 2.77 kcal./mole below 30°C. for DL -alanine NCA. The activation entropy was about ?43 cal./mole-°K. above 30°C. and ?59 cal./mole-°K. below 30°C. for L -alanine NCA; it was about ?14 cal./mole-°K. above 30°C. and ?56 cal./mole-°K. below 30°C. for DL -alanine NCA. From the polymerization parameters, x-ray diffraction diagrams, infrared spectra, and solubility in water of the polymer, the poly-DL -alanine obtained here at a low temperature was assumed to have a block copolymer structure rather than being a random copolymer of D - and L -alanine.     

Enhancement of Homochirality in Oligopeptides by Quartz

The onset of homochirality in oligopeptide chains is spontaneous. We show that the oligomerization of dilute racemic NCA (N‐carboxyanhydride=cyclic anhydride) leucine in the presence of quartz in aqueous solution yields oligopeptides that are characterized by a high degree of homochiral (L _n and D _n) sequences on the quartz surface. A similar effect is also observed, although to a lesser extent, for hydrophilic chains, namely in the oligomerization of racemic NCA glutamic acid in presence of hydroxylapatite. We argue that these findings may be relevant for the chemical evolution of homochirality.     

Polymerization in the crystalline state. VIII. Polymerization in N-carboxy anhydrides of γ-benzyl glutamate, γ-methyl glutamate,and ϵ-carbobenzoxylysine

The kinetics of the solid-state polymerization of the N-carboxy anhydrides (NCA) of the L - and racemic forms of γ-benzyl glutamate (BG), γ-methyl glutamate (MG), and ?-carbobenzoxylysine (CL) were studied as a function of temperature and aqueous vapor pressure. The reaction of the L -forms of BG and MG was characterized by an induction period, while the CL derivative reached its maximum polymerization rate at the outset of the reaction. Water vapor had only a minor effect in accelerating the reaction and reducing the chain length of the polypeptides formed. The racemic monomers were found to have different crystal structures from those of the L -isomers and the racemic MG and CL derivatives polymerized much more slowly than the corresponding optically active crystals. All polymers gave diffuse x-ray diffraction patterns. Infrared spectra of the L -polypeptides showed that they were largely in the α-helical form. The polymer derived from the racemic BG–NCA had a content of α-helical material which suggested that it consisted of polypeptides with long blocks of D and L residues.     

Hydrogen-bonding interactions in acetic acid monohydrates and dihydrates by density-functional theory calculations

Equilibrium structures and the respective binding energies of acetic acid monohydrates and dihydrates have been determined by density-functional theory calculations with different basis sets, including 6-31+G(3d,p), 6-311++G(d,p), and 6-311++G(3df,3pd). Given that the C=O and OH groups in acetic acid provide the predominant hydrogen-bonding interactions with water, six stable conformer structures have been found each for the monohydrate and syn-dihydrate. Of the three syn- and three anti-conformers of acetic acid with water, the most stable monohydrate structure is found to be that of the syn-conformer bonding with water in a cyclic double H-bonded geometry. Similarly, the syn-conformer bonding with two water molecules in a cyclic double H-bonded geometry has also been determined to be the most stable among the six plausible structures for the syn-dihydrate. Frequency analysis of the stable conformers has been performed and the vibrational spectra of the most stable monohydrate and dihydrate structures are compared with the experimental gas-phase and matrix data. Furthermore, the calculated binding energies between an acetic acid and a water molecule for both monohydrate and dihydrate are larger than that between two water molecules, which supports our recent experimental observation of coevaporation of acetic acid with water upon annealing acetic acid on ice.     

Analysis of aromatic amines in water samples by liquid-liquid-liquid microextraction with hollow fibers and high-performance liquid chromatography

N-Carboxyanhydrides of amino acids (NCAs) are very reactive monomers able to polymerize into oligopeptides. They are assumed to be prebiotic precursors of the first polypeptides. Few reports have been published on the study of NCA polymerization in aqueous solution. In this work, a kinetic study focused on the hydrolysis of NCA and its coupling with amino acids and homopeptides (up to tripeptide) was carried out, taking L-valine derivatives as model compounds. For that purpose, capillary electrophoresis appeared to be an effective and reliable technique for the measurement of the kinetic constants. The electrophoretic separation conditions, the procedure for stopping NCA reactivity, as well as the conditions of reaction are discussed in detail. We report the variation of the kinetic constant of the coupling reaction of the NCA of valine with an oligovaline as a function of its degree of polymerization. Finally, a temperature study also allowed us to estimate the activation energies associated with the NCA of valine hydrolysis and its coupling reaction with valine.     

Mechanistic insights into the hydrolysis of a nucleoside triphosphate model in neutral and acidic solution

Nucleoside triphosphate hydrolysis is an essential component of all living systems. Despite extensive research, the exact modus and mechanism of this ubiquitous reaction still remain elusive. In this work, we examined the detailed hydrolysis mechanisms of a model nucleoside triphosphate in acidic and neutral solution by means of ab initio simulations. The timescale of the reaction was accessed through use of an accelerated sampling method, metadynamics. Both hydrolyses were found to proceed via different mechanisms; the acidic system reacted by means of concerted general acid catalysis (found to be a so-called D(N)A(N)A(H)D(xh) mechanism), whereas the neutral system reacted by way of a different mechanism (namely, D(N)*A(N)D(xh)A(H)). A neighboring water molecule took on the role of a general base in both systems, which has not been seen before but is a highly plausible reaction path, meaning that substrate-assisted catalysis was not observed in the bulk water environment.     

CO2 in 1-butyl-3-methylimidazolium acetate. 2. NMR investigation of chemical reactions

The solvation of CO(2) in 1-butyl-3-methylimidazolium acetate (Bmim Ac) has been investigated by (1)H, (13)C, and (15)N NMR spectroscopy at low CO(2) molar fraction (mf) (x(CO(2)) ca. 0.27) corresponding to the reactive regime described in part 1 of this study. It is shown that a carboxylation reaction occurs between CO(2) and Bmim Ac, leading to the formation of a non-negligible amount (~16%) of 1-butyl-3-methylimidazolium-2-carboxylate. It is also found that acetic acid molecules are produced during this reaction and tend to form with elapsed time stable cyclic dimers existing in pure acid. A further series of experiments has been dedicated to characterize the influence of water traces on the carboxylation reaction. It is found that water, even at high ratio (0.15 mf), does not hamper the formation of the carboxylate species but lead to the formation of byproduct involving CO(2). The evolution with temperature of the resonance lines associated with the products of the reactions confirms that they have a different origin. The main byproduct has been assigned to bicarbonate. All these results confirm the existence of a reactive regime in the CO(2)-Bmim Ac system but different from that reported in the literature on the formation of a reversible molecular complex possibly accompanied by a minor chemical reaction. Finally, the reactive scheme interpreting the carboxylation reaction and the formation of acetic acid proposed in the literature is discussed. We found that the triggering of the carboxylation reaction is necessarily connected with the introduction of carbon dioxide in the IL. We argue that a more refined scheme is still needed to understand in details the different steps of the chemical reaction in the dense phase.     

Improving the stability of LiNi_(0.80)Co_(0.15)Al_(0.05)O_2 by AlPO_4 nanocoating for lithium-ion batteries

Nickel-rich layered materials,such as LiNi_(0.8)0Co_(0.15)Al_(0.05)O_2(NCA),have been considered as one alternative cathode materials for lithium-ion batteries(LIBs) due to their high capacity and low cost.However,their poor cycle life and low thermal stability,caused by the electrode/electrolyte side reaction,prohibit their prosperity in practical application.Herein,AlPO4 has been homogeneously coated on the surface of NCA via wet chemical method towards the target of protecting NCA from the attack of electrolyte.Compared with the bare NCA,NCA@AlPO_4 electrode delivers high capacity without sacrificing the discharge capacity and excellent cycling stability.After 150 cycles at 0.5 C between 3.0-4.3 V,the capacity retention of the coated material is 86.9%,much higher than that of bare NCA(66.8%).Furthermore,the thermal stability of cathode is much improved due to the protection of the uniform coating layer on the surface of NCA.These results suggest that AlPO4 coated NCA materials could act as one promising candidate for next-generation LIBs with high energy density in the near future.     

Heterogeneous versus Homogeneous Copper(II) Catalysis in Enantioselective Conjugate‐Addition Reactions of Boron in Water

We have developed Cu^II‐catalyzed enantioselective conjugate‐addition reactions of boron to α,β‐unsaturated carbonyl compounds and α,β,γ,δ‐unsaturated carbonyl compounds in water. In contrast to the previously reported Cu^I catalysis that required organic solvents, chiral Cu^II catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)₂ with chiral ligand L1 ; cat. 2: Cu(OH)₂ and acetic acid with ligand L1 ; and cat. 3: Cu(OAc)₂ with ligand L1 . Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β‐unsaturated carbonyl compounds and an α,β‐unsaturated nitrile compound, including acyclic and cyclic α,β‐unsaturated ketones, acyclic and cyclic β,β‐disubstituted enones, acyclic and cyclic α,β‐unsaturated esters (including their β,β‐disubstituted forms), and acyclic α,β‐unsaturated amides (including their β,β‐disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43 200 h^?1) for an asymmetric conjugate‐addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ‐unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4‐Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ‐unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ‐unsaturated carbonyl compounds with compound 2 , whereas 1,4‐addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6‐addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate‐addition reactions in water were investigated and we propose stereochemical models that are supported by X‐ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.     

Modeling H-bonding and solvent effects in the alkylation of pyrimidine bases by a prototype quinone methide: a DFT study

Nucleophilicity of NH(2), N3, and O(2) centers of cytosine toward a model quinone methide (o-QM) as alkylating agent has been studied using DFT computational analysis [at the B3LYP/6-311+G(d,p) level]. Specific and bulk effects of water (by C-PCM model) on the alkylation pathways have been evaluated by analyzing both unassisted and water-assisted reaction mechanisms. An ancillary water molecule, H-bonded to the alkylating agent, may interact monofunctionally with the o-QM oxygen atom (passive mechanisms) or may participate bifunctionally in cyclic hydrogen-bonded structures as a proton shuttle (active mechanisms). A comparison of the unassisted with the water-assisted reaction mechanisms has been made on the basis of activation Gibbs free energies (DeltaG(++)). The gas-phase alkylation reaction at N3 does proceed through a passive mechanism that is preferred over both the active (by -6.3 kcal mol(-1)) and the unassisted process. In contrast, in the gas phase, the active assisted processes at NH(2) and O(2) centers are both favored over their unassisted counterparts by -4.0 and -2.2 kcal mol(-1), respectively. The catalytic effect of a water molecule, in gas phase, reduces the gap between the TSs of the O(2) and NH(2) reaction pathways, but the former remains more stable. Water bulk effect significantly modifies the relative importance of the unassisted and water-assisted alkylation mechanisms, favoring the former, in comparison to the gas-phase reactions. In particular, the unassisted alkylation becomes the preferred mechanism for the reaction at both the exocyclic (NH(2)) and the heterocyclic (N3) nitrogen atoms. By contrast, alkylation at the cytosine oxygen atom is a water-catalyzed process, since in water the active water-assisted mechanism is still favored. As far as competition, among all the possible mechanisms, our calculations unambiguously suggest that the most nucleophilic site both in gas phase (naked reagents: N3 > O(2) >or= NH(2)) and in water solution (solvated reagents: N3 > NH(2) > O(2)) is the heterocyclic nitrogen atom (N3) (DeltaG(++)(gas) = +7.1 kcal mol(-1), and DeltaG(++)(solv) = +13.7 kcal mol(-1)). Our investigation explains the high reactivity and selectivity of the cytosine moiety toward o-QM-like structures both in deoxymononucleoside and in a single-stranded DNA, on the basis of strong H-bonding interactions between reactants and solvent bulk effect. It also offers two general reactivity models in water, uncatalyzed and active water-catalyzed mechanisms (for nitrogen and oxygen nucleophiles, respectively), which should provide a general tool for the planning of nucleic acid modification.