Sarcosine Anhydride Research Articles

The Solvation Effect of C=O Group of Cyclic Anhydrides in Solution.

The paper reports the results of investigation intermolecular interactions between alanine and sarcosine anhydride in organic solvents. The absorption frequencies of cyclic dipeptide in solvents were measured by IR spectroscopy. The effect of Van der Waals interactions and the hydrogen bonding of solvents on absorption frequencies of the C=O group of anhydrides was discussed. The spectroscopic parameters for C=O∙∙∙H-O hydrogen bonding complexes of anhydride with methanol in aprotic and proton donor solvent are obtained. In multi-particle complexes of dipeptides with aliphatic alcohols, the hydrogen bond enhancement was between 10 and 16%, which is significantly lower than it is for amide complexes.

A General Synthesis of Bis-indolylpiperazine-2,5-diones

The one-pot synthesis of three dragmacidin derivatives is reported. Sarcosine anhydride (4) is brominated and immediately reacted with the corresponding indole to produce the products, namely 3,6-bis(5′-methoxy-3′-indolyl)-1,4-dimethylpiperazine-2,5-dione (1), 3,6-bis(7′-methyl-3′-indolyl)-1,4-dimethylpiperazine-2,5-dione (2) and 3,6-bis-(6′-chloro-3′-indolyl)-1,4-dimethylpiperazine-2,5-dione (3), which are characterized by 1H-NMR.

Thermochemistry of sarcosine and sarcosine anhydride: Theoretical and experimental studies

The standard molar enthalpies of formation, in the gaseous phase, at T=298.15K, of sarcosine, −(388.0±1.0)kJ·mol−1, and sarcosine anhydride, −(334.5±1.6)kJ·mol−1, were calculated by combining, for each compound, the standard molar enthalpy of formation, in the crystalline phase, and the standard molar enthalpy of sublimation, derived from measurements of the standard massic energies of combustion by static bomb combustion calorimetry, and from measurements of vapour pressures by the Knudsen mass-loss effusion method, respectively. The standard (po=0.1MPa) molar enthalpies, entropies and Gibbs functions of sublimation, at T=298.15K, were also calculated. A theoretical study at the G3 and G4 levels has been carried out, and the calculated enthalpies of formation have been compared with the experimental ones.

3,6-Bis(5’-bromo-3’-indolyl)-1,4-dimethypiperazine-2,5-dione

The one-pot synthesis of 3,6-bis(5’-bromo-3’-indolyl)-1,4-dimethylpiperazine- 2,5-dione is reported. Sarcosine anhydride is brominated and immediately reacted with 5-bromoindole to produce the product, which is characterized by 1H NMR, MS and microanalysis.

Oxidation of Cyclic Dipeptides by Photoinduced H-Atom Abstraction. A Laser Flash FT EPR and Optical Spectroscopy Study

Laser flash photolysis with the Fourier transform electron paramagnetic resonance (FT EPR) and optical spectroscopy detection methods on the nanosecond time scale have been employed in order to investigate the oxidation mechanism of cyclic dipeptides glycine, alanine, and sarcosine anhydrides initiated by SO4*- or 9,10-anthraquinone-2,6-disulfonate (2,6-AQDS) triplet in oxygen free aqueous solutions. A direct hydrogen abstraction from the ring C-H position of an anhydride by both oxidants is proposed as the primary reaction, rather then an electron transfer from nitrogen followed by (alpha)C-H deprotonation. The overall second-order rate constants for the reaction with SO4*- were determined to be 7.2 x 10(7) M(-1) s(-1), 1.2 x 10(8) M(-1) s(-1), and 5.2 x 10(8) M(-1) s(-1) for glycine anhydride, alanine anhydride, and sarcosine anhydride, respectively. The rate constants for 2,6-AQDS triplet as oxidizing species are about two times lower. The radical intermediate products derived from cyclic dipeptides observed on the microsecond time scale were assigned to the general structure of piperazine-2,5-dione-3-yl radical. These are spin polarized by the mechanisms of chemically induced dynamic electron polarization (CIDEP). For SO4*- as the oxidant the spectra are exhibiting an E/A* polarization pattern originating partially from F-pairs of two piperazine-2,5-dione-3-yl radicals.

Thiyl Radicals Abstract Hydrogen Atoms from the αC−H Bonds in Model Peptides: Absolute Rate Constants and Effect of Amino Acid Structure

Thiyl radicals are important intermediates in biological oxidative stress and enzymatic reactions, for example, the ribonucleotide reductases. On the basis of the homolytic bond dissociation energies (BDEs) only, the (alpha)C-H bonds of peptides and proteins would present suitable targets for hydrogen abstraction by thiyl radicals. However, additional parameters such as polar and conformational effects may control such hydrogen-transfer processes. To evaluate the potential of thiyl radicals for hydrogen abstraction from (alpha)C-H bonds, we provide the first absolute rate constants for these reactions with model peptides. Thiyl radicals react with (alpha)C-H bonds with rate constants between 1.7 x 10(3) M(-1) s(-1) (N-acetylproline amide) and 4 x 10(5) M(-1) s(-1) (sarcosine anhydride). However, the correlation of rate constants with BDEs is poor. Rather, these reactions may be controlled by conformation and dynamic flexibility around the (alpha)C-H bonds.

H-Atom abstraction by C-centered radicals from cyclic and acyclic dipeptides. A theoretical and experimental study of reaction rates

Using the pulse radiolysis and other radiation chemical techniques, the reaction kinetics of ˙CH3 and ˙CH2OH radicals with alanine anhydride, glycine anhydride and sarcosine anhydride were examined in aqueous solution. The second order rate constant of reaction of ˙CH3 with alanine anhydride has been determined at 2 × 105 dm3 mol−1 s−1. A very similar value (8 × 104 dm3 mol−1 s−1) has been obtained by measuring the methane and ethane yields as a function of the alanine anhydride concentration at different dose rates and evaluation of these data by computer analysis. Similar experiments carried out with glycine anhydride and sarcosine anhydride yielded identical rate constants of 4 × 104 dm3 mol−1 s−1 for these compounds. It was found that ˙CH2OH radical does not react with alanine anhydride at an appreciable rate (k < 2 × 102 dm3 mol−1 s−1). The reactions of ˙CH3, ˙CH2OH, and ˙C(CH3)2OH with both cyclic anhydrides and acyclic glycine and alanine peptides were studied by means of theoretical calculations at the B3LYP/6-311+G(d,p) level of theory. Free energies in the gaseous phase were determined in the classical harmonic oscillator–rigid rotator model, and used to estimate rates of H-transfer reactions at the αC-site of the peptides. The effects of aqueous solution on the activation enthalpies were estimated by the SCIPCM procedure. Using the experimental A-factor for the methyl radical + D,L-alanine anhydride reaction, modified experimental Arrhenius A-factors were obtained for the reactions of the other species, and used to calculate solution-phase rate constants. The reactions are discussed in terms of the charge and spin polarisation in the transition state, as determined by AIM analysis, and in terms of orbital interaction theory. Rate constants, calculated by transition state theory are in good agreement with the available experimental data.

Are α-centered peptide radicals stabilized by a capto-dative effect?

The kinetics of the thermal C-C-cleavage reaction of the dimer of sarcosine anhydride 5 has been investigated between 295 and 333 °C in mesitylene. From the temperature dependence and from the release of strain on dissociation the cyclic α-peptide radical 6 was calculated to have a radical stabilization enthalpy (RSE) of −6.3 ± 1.3 kcal/mol thus indicating the absence of a synergistic capto-dative effect.

Synthèse d'analogues structuraux de thaxtomines, phytotoxines responsables de la gale de la pomme de terre

Cross coupling reactions of lithiated 2,5-piperazinedione anions with gramine methosulfate and alkylhalides were shown to be catalyzed by copper reagents, e.g. dilithium tetrachlorocuprate and copper (I) iodide. Based on this findings, the results of the first method for preparation of racemic thaxtomins are reported. Compound 1c, chosen as a synthetic model, was prepared in five steps in 19% overall yield. The key step was reaction of the lithiated anion of sarcosine anhydride with gramine methosulfate in the presence of a catalytic amount of dilithium tetrachlorocuprate in THF. The remainder of the sequence involved protection of the indole NH, aldol condensation with 3-benzyloxybenzaldehyde, bromohydrin formation and catalytic hydrogenation.

Peptide peroxyl radicals: base-induced superoxide radical ion elimination versus bimolecular decay. A pulse radiolysis and product study

Radiolytically generated OH radicals react with the cyclic dipeptides glycine anhydride (1) and alanine anhydride (2), forming a single type of peptide radical in each case by abstracting a carbon-bound H atom at the ring. In the case of sarcosine anhydride (3), besides the C(3) or C(6) H atoms (78%), the H atoms at the N-methyl groups are also targets of the OH radical attack (22%). In N 2 O/O 2 (4:1 v/v) saturated solutions these peptide radicals add oxygen (k≃2×10 9 dm 3 mol -1 s -1 ) to form the corresponding peroxyl radicals 6 (from 1), 7 (from 2), and 12 and 13 (from 3)

Peptide Free-Radicals: The Reactions of OH Radicals with Glycine Anhydride and its Methyl Derivatives Sarcosine and Alanine Anhydride. A Pulse Radiolysis and Product Study

The reactions of radiolytically generated OH radicals and H atoms with the cyclic dipeptides of glycine, alanine and sarcosine in deoxygenated aqueous solutions and the subsequent reactions of the transient peptide radicals were studied in the absence and presence of K3Fe(CN)6 as oxidant by pulse radiolysis and product analysis. Hydroxyl radicals and H atoms react with glycine anhydride and alanine anhydride by abstracting an H atom bound at C-3; there is no evidence for any other site of attack at these two peptides. The resulting radicals have pKa values of 9.8 and 10.6, respectively. In the absence of an oxidant the radicals decay by second order (2k = 7.0×108 dm3 mol-1 s-1 and 2k = 4.4×108 dm3 mol-1 s-1, resp.), the main fraction (94% of the glycine anhydride-derived radicals, 90% of the alanine anhydride-derived radicals) yielding dehydrodimers (G = 0.58 μmol J-1 and 0.56 µmol J-1 (in monomer units), resp.). A small portion however disproportionates via abstraction of a C-6-bound Η atom followed by isomerization to 2,5-dihydroxypyrazines (pKa values of the parent 2,5-dihydroxypyrazine at about 7.9 and 10.1) and subsequent addition of water to 2,5-diketo-3-hydroxypiperazines, thus indicating that the transfer of a carbon-bound hydrogen atom is prefered to the transfer of a nitrogen-bound hydrogen atom. No disproportionation products but three different dehydrodimers (G = 0.36, 0.18 and 0.04 µmol J-1 (in monomer units)) were found after irradiation of sarcosine anhydride. In this case a dose rate and solute concentration dependence of dehydrodimer formation indicates a radical-solute reaction converting part of the N-methyl radicals (21% of ‘initial’ attack) into the C-3-yl radicals. A rate constant of k = 600 ± 50 dm3 mol-1 s-1 was obtained for this reaction by measuring and computing the dehydrodimer yields as a function of dose rate and solute concentration. Thus the observed transient spectrum accounts only for about 79% of the radicals from the ‘initial’ attack at C-3. The rate of oxidation of the glycine anhydride-derived radicals by Fe(CN)6 3- reflects the pKa of the transient radical. The rate constant for oxidation of the (protonated) radical derived from glycine anhydride is: k = 1.0x 108 dm3 mol-1, the corresponding radical anion is oxidized with k = 3.1 × 108 dm3 mol-1 s-1. No change with pH was observed in the case of the alanine anhydridederived radicals (k = 7.9x 108 dm3 mol-1 s-1). In contrast to the disproportionation, oxidation by Fe(CN)6 3- leads to the removal of a proton from the heteroatom, a carbocation being the intermediate. The resulting dehydropiperazines rapidly add water to yield the corresponding 2,5-diketo-3-hydroxypiperazines (G = 0.61 μmol J-1 after oxidation of the glycine anhydride-derived radicals, G = 0.58 µmol J-1 after oxidation of the alanine anhydride-derived radicals). The radicals derived from sarcosine anhydride are readily oxidized with k = 4.0×108 dm3 mol-1 s-1, independent of pH. 1H and 13C{1H} NMR-spectroscopic and mass-spectroscopic data of the products are given.

Oxidation of cyclic dipeptide radicals in aqueous solution: the rapid hydration of the intermediate 1,6-dihydropyrazine-2,5-diones (cyclic dehydrodipeptides). A pulse-radiolysis study

The lifetimes of radiolytically generated 1,6-dihydropyrazine-2,5-diones (cyclic dehydrodipeptides) in aqueous solution have been studied by pulse radiolysis.Hydroxyl radicals were allowed to react with the 2,5-dioxopiperazines glycine anhyride (1) and alanine anhydride (2). The resulting 3-yl radicals (4) and (5) have been oxidized by IrCl62– in a diffusioncontrolled reaction [k(4)= 3.1 × 109; k(5)= 3.0 × 109 dm3 mol–1 s–1], which yielded the corresponding carbocations which rapidly deprotonate at N-4 (pKa < 2) to form the short-lived 1,6-dihydropyrazine-2,5-diones (6) and (7).At neutrality, spontanous addition of water to the –CN– bond [k(6)= 640; k(7)= 5 ± 2 s–1] prevents the isomerisation of (6) and (7) into their tautomeric 2,5-dihydroxypyrazines. In acidic and basic solutions a proton-catalysed [k(6)= 6.3 × 106; k(7)= 3.7 × 106 dm3 mol–1 s–1] and a basecatalysed [k(6)= 1.4 × 107; k(7)= 2.0 × 105 dm3 mol–1 s–1] addition of water is observed.The 3-yl (8)(79%) and N-methyl (9)(21%) radicals resulting from H abstraction from sarcosine anhydride are also readily oxidized by IrCl62–(k= 3.6 × 109 dm3 mol–1 s–1). Blocking of N-1 and N-4 by methyl groups prevents deprotonation of the resulting carbocations (12) and (14) and their reaction with water can be monitored directly by pulsed-conductivity measurements. The positive charge on the exocyclic carbocation (14) is effectively stabilized by nitrogen and thus addition of water proceeds only slowly [k(14)= 150 s–1]. However, in the case of the endocyclic carbocation (12), which is destabilized by the carbonyl group next to C-3, the reaction with water is fast [k(12)= 2.3 × 106 s–1].The instability of (6) towards attack by water (possibly attended by a general sensitivity towards nucleophiles), may be the reason why no successful synthesis of the tautomeric parent 2,5-dihydroxypyrazine has been reported so far.

ChemInform Abstract: SYNTHESIS OF 3,6‐DIETHOXYCARBONYL‐3,6‐EPIDITHIA‐1,4‐DIMETHYL‐2,5‐PIPERAZINEDIONE AND RELATED COMPOUNDS, FORMATION OF C‐S BOND BY THE REACTION OF CARBANION AND SULFUR MONOCHLORIDE

AbstractDas aus dem Aminomalonsäureester (I) durch Erhitzen auf 160‐180°C unter Stickstoff erhaltene Pyridazindion (II) gibt in Dioxan beim Behandeln mit Natriumhydrid und anschließend mit frisch destilliertem Dischwefeldichlorid das Gemisch aus den Epithia‐Verbindungen (IIIa) (17 %), (IIIb) (9 %) und geringen Mengen von (IIIc) und (IIId).

Synthesis of 3,6-diethoxycarbonyl-3,6-epidithia-1,4-dimethyl-2,5-piperazinedione and related compounds. Formation of C-S bond by the reaction of carbanion and sulfur monochloride.

Reaction of 3, 6-diethoxycarbonyl-1, 4-dimethyl-2, 5-piperazinedione (15), prepared by heating of diethyl methylaminomalonate (14), with NaH in dioxane and followed treatment with S2Cl2 gave 3, 6-epidithio- and 3, 6-epitetrathio-3, 6-diethoxycarbonyl-1, 4-dimethyl-2, 5-piperazinediones (16b and 16d), which have the skeletone (1) observed in fungal metabolites such as sporidesmin. The reduction of 16 with NaBH4 in methanol gave the dethio derivative (15) in good yield. The reaction of 16d with triphenylphosphine in tetrahydrofurane gave 16c and 16b. The reaction of diethyl malonate derivatives (23a, b, and c) with NaH and S2Cl2 in dioxane gave the corresponding disulfides or trisulfides (24a, b, and c). Some reactions of proline anhydride (5) and sarcosine anhydride (7) with S2Cl2 or sulfur were examined.

On some physico-chemical properties of diketopiperazines in water.

Data useful for a characterization of the thermodynamic behaviour of a few nonionic aminoacid anhydrides (diketopiperazines) in water are reported.In particular, results of heat of dilution, heat of solution and osmotic coefficient measurements (the latter two only for sarcosine anhydride) are illustrated.As an interesting extension of our study, the likelihood that the compounds considered might exhibit a denaturant action on globular proteins has been tested using ribonuclease. Our results clearly point out that the diketopiperazines are strong denaturants indeed.A few results of spectral measurements of the monomer‐dimer equilibrium of acridine orange in aqueous diketopiperazines solutions are also reported, as they appear to pertain to the mechanism of ribonuclease unfolding promoted by the diketopiperazines.

Determination of Molecular Binding in Aqueous Solution from Optical Activity Measurements

Although the feasibility of using ORD for determining stability constants of molecular complexes in organic solvent has already been shown, the present investigation appears to be the first attempt to apply it to an aqueous system. Measurements at 330 mμ show distinct changes in the apparent optical activity of the zwitter ionic form of the amino acid when alkylxanthines were added to its solutions. These readings when analyzed by the iterative procedure previously developed for PMR data have yielded self-consistent stability constant values. Results are given for interaction with caffeine, theophylline, 8-methoxycaffeine, 1,3-dimethyluracil, and sarcosine anhydride. From measurements at several temperatures the heat of binding of tryptophan with caffeine was shown to be −4.0 kcal./mole and that with theophylline to be −4.2 kcal./mole. These results appear to be consistent with results obtained previously on related systems.

The chain effect. Part III. Induction of secondary structure in copolymerizations

AbstractStudies of the properties of copolymers of N‐carboxy sarcosine anhydride with other N‐carboxy α‐amino acid anhydrides have shown that the secondary structure may be a function of the type of initiator used. In particular, when polysarcosine is the initiator, and the “chain effect” becomes possible, blocklike character appears in the copolymer. This is the result of selective and rapid polymerization of N‐unsubstituted N‐carboxy α‐amino acid anhydrides by the chain‐effect mechanism. In suitable circumstances, therefore, the latter may be used to induce order into copolymerizations of this type.

Complexes Formed in Aqueous Solutions By Sarcosine Anhydride; Interactions With Organic Acids, Phenols, and Aromatic Alcohols

It has been shown that the interactions between sarcosine anhydride, a cyclic dieptide, and forty-six organic proton donor compounds result in the formation of both soluble and insoluble molecular complexes. The studies illustrate the importance of the aromatic and hydrophobic character of the molecule, as well as the nature of the polar groups and their positions, on complexin activity. The stoichiometry of a large number of insoluble complex species found were determined from analysis of phase diagrams and chemical analysis of the solid materials. Apparent stability constants were determined for the soluble complexes formed in the investigation. It is suggested that many biochemical and drug actions are mediated through formation of complexes of this type.

SPECTROSCOPICAL STUDY OF AMINO-ACID ANHYDRIDES. II. LIGHT ABSORPTIONS OF SOME AMINO-ACIDS, THEIR ESTERS, PEPTIDES AND ANHYDRIDES

Abstract (1) Glycocoll, alanine, leucine, phenylalanine, tyrosine, glycocoll ester, tyrosine esters, glycylleueine, glycyl-l-phenylalanine, glycyl-d,l-phenyl alanine, glycyl-l-tyrosine anhydride, tyrosine anhydride, glycyl-l-leucine anhydride, leucine anhydride, glycyl-l-phenylalanine anhydride and phenylalanine anhydride were spectrochemically studied in aqueous, alcoholic or glacial acetic acid solutions. (2) Among these compounds only those which contain phenyl and oxy-phenyl groups in their molecules show selective light absorptions ; i.e., tyrosine, phenylalanine and their derivatives, except phenylalanine, anhydride absorb selectively. (3) Although two phenyl groups exist in its molecule, phenylalanine anhydrid show only end absorption, perhaps due to the mutual effect of these two chromophores symmetrically situated to each other. (4) Derivatives of either tyrosine or phenylalanine absorb identically with their mother substances. (5) Other amino-acids, their esters, pepetides and anhydrides show no selective absorptions, as in the cases of glycocoll anhydride, alanine anhydride and sarcosine anhydride which were described in our previous paper. (6) As for the constitution of amino-acid anhydrides, the same conclusion as was previously mentioned, may be applied again to the substances now studied, that is to say, all these anhydrides are in keto-form.