Cyclic Diamide Research Articles

Synthesis of Stereochemically Flexible Cyclic Biphenylbisphosphinite Ligands: Control of the Dynamics and Selectivity

AbstractNovel l‐tartaric acid based stereodynamic biphenylbisphosphinite ligands with anilino linkers were prepared as cyclic diamide compounds. The influence of the constitutional substitution pattern of the amino group at the aniline moiety on the diastereoselective formation of the ligand was investigated. While the meta‐anilino bridged ligands showed a highly dynamic behavior and no discrimination between (Rax) and (Sax) configuration, l‐tartaric acid substitution on ortho‐anilino bridged ligands leads to diastereoselective self‐alignment of the central biphenol axis, which controls the stereoselectivity of the ligand and catalyst. The experimental findings were corroborated by theoretical calculations. In the rhodium‐catalyzed enantioselective hydrogenation of methyl 2‐acetamidoacrylate (MAA), an enantiomeric ratio of 75 : 25 (R/S) was obtained for the ortho‐substituted ligand.

Redox-Dependent Binding to an Electroactive Urea: Comparison of Ferrocene and Phenylenediamine Redox Couples with Two Different Guests

In previous work in our lab, the redox-dependent binding behavior of a phenylenediamine urea, UHH, was investigated in the presence of different guests in CH2Cl2. The urea functionality contains two good H-donors in the two urea NH bonds (a DD motif) that are capable of H-bonding with two appropriately spaced H-acceptors (AA motif). Examples are the cyclic diamide PZD (see Figure) and 1,8-naphthyridine, naph. 1H NMR studies indicated a modest Kbinding of 100 M-1 with PZD and 30 M-1 with naph in CH2Cl2. The expectation was that oxidation of the phenylenediamine couple in UHH to the radical cation would increase the acidity of one of the NH’s leading to stronger H-bonding with the guests and a negative shift in the observed redox potential upon addition of these guests. A small negative shift was observed with PZD, but further research indicated that the actual overall reaction occurring upon oxidation of UHH was not the simple 1 electron oxidation to the radical cation expected, but rather 2 electron oxidation of one UHH accompanied by proton transfer to a reduced UHH to give UH+ and HUHH+ as shown in the Figure. Addition of PZD does not change this overall reaction. An alternative explanation of the potential shift is that PZD is actually H-bonding to the protonated HUHH+, which would also be a stronger H-donor. Interestingly, similar magnitude shifts are observed upon oxidation of the ferrocene-containing urea, FcUHH. Since Fc is only capable of being oxidized by 1 electron, oxidation of the Fc also makes a +1 charge, which appears to have a similar effect on the H-bonding ability of the urea as does protonation. In contrast to the PZD, addition of naph causes the current for the oxidation of UHH to increase with little change in peak potential. This can be explained by proton transfer from the UHH radical cation to the naphthyridine. The resulting neutral radical will be immediately oxidized by a second electron leading to the increase in current. The proton transfer will change the H-bonding motif from AA-DD to AD-DA, which is inherently weaker because of unfavorable secondary interactions. In addition, because of the two electron oxidation, both binding partners in the resulting complex, (naphH+)(UH+), will be positively charged. Therefore it is not surprising that the H-bonding does not strengthen upon oxidation. It will be of interest to compare this behavior to that of FcUHH and naph. Cyclic voltammetry experiments will be run with FcUHH and naphthyridine to see if eliminating the possibility of the second electron transfer prevents proton transfer and results in the expected stronger H-bonding to the oxidized form. Figure 1

ChemInform Abstract: 1,6‐Enyne Cyclizations Catalyzed by N‐Heterocyclic Carbene Supported Gold Complexes: Deconvoluting Sterics and Electronics.

AbstractNovel NHC‐gold complexes having cyclic diamide type structures are developed.

Effect of H-Bonding on the Electrochemistry of a p-Phenylenediamine-Based Urea. Competition Between Another Urea and a Cyclic Diamide Guest

In previous work done by our group, we reported the observation of strong oxidation-based redox dependent hydrogen bonding between an electroactive urea 1-phenyl-3-(p-N,N-dimethylaminophenyl)urea U(H)H and a cyclic diamide 1,4-dimethylpiperizine-2,3-dione (PZD) in methylene chloride.1Large negative shifts in the apparent, reversible one electron oxidation of U(H)H are observed upon addition of PZD, consistent with strong H-bonding of PZD to the radical cation of U(H)H.However, with further study of U(H)H and similar molecules, it is clear that the electrochemistry and the mechanism is not as straightforward as once believed. Instead of undergoing a simple one electron oxidation, a variety of data now suggests that U(H)H actually undergoes a two electron oxidation to the quinoidal form with transfer of a proton to another U(H)H, which deactivates the second U(H)H. Thus the overall process corresponds to one electron per urea. Because acetonitrile is more polar than methylene chloride, it can better solvate the quinoidal urea and the protonated, unoxidized urea to prevent them from hydrogen bonding to each other. In contrast, stronger H-bonding between the quinoidal urea and the protonated, unoxidized urea is expected in the less polar solvent, methylene chloride and we believe this is what facilitates the observed reversible electrochemistry.In the current study we are re-investigating the addition of PZD to U(H)H in light of our better understanding of the electrochemistry of U(H)H by itself. According to our new NMR titration data, PZD is H-bonded to U(H)H even without oxidation, which is consistent with our previous study. The binding constants, K, measured in different electrolyte solutions between PZD and U(H)H show that there is an electrolyte effect. In the NMR titration experiment without electrolyte, due to the solvent effect, PZD is more strongly H-bonded to U(H)H in the less polar solvent CH2Cl2 than in CH3CN (K in CH2Cl2 = 60.4 M− 1and K in CH3CN = 17.8 M− 1). With a large anion electrolyte, NBu4B(C6F5)4 in CH2Cl2 , the binding constant is greater (K = 95.9 M− 1) than with a small anion electrolyte, NBu4PF6 in CH2Cl2 (K = 48.6 M− 1). This is consistent with the larger potential shift observed with the addition of PZD in NBu4B(C6F5)4 in CH2Cl2 solution relative to NBu4PF6 in CH2Cl2. This suggests that the smaller PF6−ion may be competing with PZD for the binding site.Re-examination of the cyclic voltammetry of U(H)H suggests the same overall reaction, 2e− oxidation of half the urea with proton transfer to the other half, is occurring with or without PZD present. However, the peak potentials are affected by the presence of PZD indicating the overall reaction is facilitated by PZD.1. Jessica E. Woods, Yu Ge, and Diane K. Smith, Journal of the American Chemical Society 2008 130 (31), 10070-10071.

Preparation, characterization and copolymerization of the 12‐membered cyclic diamide 1,6‐diazacyclododecane‐2,5‐dione

ABSTRACTA 12‐membered cyclic diamide monomer for nylon 64 was successfully synthesized in fairly high yield (∼45%). The synthesis conditions were varied to see the effect of the diamine and succinyl chloride reactants on yield. Threefold excess of 1,6‐hexamethylenediamine (HDA) gave the highest yield, while further increasing the amount of HDA decreased the yield. Using N,N‐diisopropylethylamine as acid scavenger resulted in the formation of two different cyclic amides, which were fully analyzed by 1H and 13C solution nuclear magnetic resonance spectrometry and mass spectrometry. Copolymerization of cyclic amides with ε‐caprolactam via an anionic route gave a block copolyamide with a two distinct endotherms in the differential scanning calorimetry analysis. However, copolymerization by the hydrolytic route gave only nylon 6 with terminal 64 units. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 96–103

Successive Formation of Two Amide Linkages between Two Benzene Rings

Abstract To successively construct two amide bonds between two benzene rings, the reaction of methyl N-alkylanthranilate and N-alkylisatoic anhydride in the presence of a base was studied. When the reaction was carried out with lithium hexamethyldisilazide and N,N,N′,N′-tetramethylethylenediamine in THF at 70 °C under reduced pressure, a cyclic diamide was obtained in high yield.

Modeling the Infrared and Circular Dichroism Spectroscopy of a Bridged Cyclic Diamide

Density functional theory based molecular dynamics simulations are used to study the structure, infrared (IR) spectroscopy, circular dichroism (CD) spectroscopy, and coupling between the amide I vibrations of a bridged cyclic diamide in the gas phase and in aqueous solution. IR spectra computed via the dipole moment time correlation function show a large red-shift of 30 cm(-1) in the amide I vibration in solution compared to the gas phase, and are in good agreement with experiment. Conformationally averaged CD spectra computed using the CIS(D) method are highly sensitive to the structures used, and structures sampled in the aqueous phase simulation are required to obtain qualitatively correct CD spectra. Analysis of the coupling between the amide I modes shows that in the aqueous phase there is an increased localization of the vibrations on the individual peptide groups and a reduction in the mode coupling parameter compared to the gas phase. Overall, the results illustrate the significance of incorporating molecular dynamics in the simulation of IR and CD spectra.

Very Strong Redox-Dependent Hydrogen Bonding between a bis-Dimethylaminophenylurea and a Cyclic Diamide

not Available.

Cyclic oxaalkyl diamide of o-phthalic acid as a new macrocyclic ligand for complexation of Li + cation

Cyclic diamide of o-phthalic acid (CPhDA) was synthesised in the reaction between phtalic anhydride and 1,2-bis(2-aminoethoxy)ethane in high dilution conditions and its ability to form the 1:1 and 2:1 complexes with Li + cations was detected by ESI mass spectrometry. The 1:1 complex was obtained in the solid state and studied by X-ray diffraction, FT-IR, NMR and PM5 semiempirical methods. The structure of 1:1 complex was also studied in acetonitrile. It was found that the structures of 1:1 complex are different in the solid and in solution.

Very Strong Redox-Dependent Hydrogen Bonding between a bis-Dimethylaminophenylurea and a Cyclic Diamide

not Available.

Spectroscopic, semiempirical and X-ray structural study of the 2:1 complex of a cyclic diamide of o-phthalic acid with water molecule

Cyclic diamide of o-phthalic acid with 3,6-dioxa-octyl-1,8-diamine (CPhDA) was synthesised by a new method and its hydrate structure has been studied by X-ray diffraction, FT-IR, NMR and PM5 semiempirical methods. The crystal of this compound is orthorhombic, space group Pbcn, with a = 16.7033(11), b = 8.8823(5), c = 19.6182(12) and Z = 8. The IR spectrum of the crystal is consistent with the results obtained by the X-ray study and provides spectroscopic evidence for the formation of the H-bonded complex with water molecules. The calculated structure of the complex and the structural parameters are comparable with those determined by the X-ray method.

Selective Protection of 1,4,8,11-Tetraazacyclotetradecane (Cyclam) in Position 1,4 with the Phosphonothioyl Group and Synthesis of a Cyclam-1,4-bis(methylphosphonic Acid). Crystal Structures of Several Cyclic Phosphonothioamides

A new cyclam-based ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-bis(methylphosphonic acid) (1,4-H4te2p), was synthesized. Cyclam was protected by the reaction with PhP(S)Cl2 to form exclusively five-membered cyclic phenylphosphonothioic diamide 2 in a moderate yield. The solid-state structures of 2 and several by-products were determined. Compound 2 was isolated as two stable conformers differing in a mutual position of benzene ring and sulfur atom with respect to the cyclam ring. Compound 2 was used for the synthesis of 1,4-dibenzylcyclam. However, the deprotection of the thiophosphoryl-protected bis(methylphosphonate diester) with aqueous HCl under non-optimized conditions led to a mixture of cyclam derivatives differently substituted with methylphosphonic acid groups. The crystal structures of the target product, 1,4-H4te2p, and also 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrakis(methylphosphonic acid) (H8tetp) were determined. A similar reaction with cyclen (1,4,7,10-tetraazacyclododecane) led only to hardly purifiable mixtures.

Synthesis, characterization and X-ray crystal structures of cyclam derivatives. Part VI. Proton binding studies of a pyridine-strapped 5,12-dioxocyclam based macrobicycle

The 14-membered cyclic diamide 1,4,8,11-tetraazacyclotetradecane-5,12-dione (5,12-dioxocyclam) can be considered as a trans-autodiprotected tetraazamacrocycle and provides a convenient starting material for the preparation of macrobicyclic receptors. As an example, the secondary amine nitrogen atoms located at the 1 and 8 positions were cross-bridged with a 1,3-pyridyl strap, affording the constrained ansa-dioxocyclam ligand 1,9,12,18,22-pentaazatricyclo[7.6.6.13,7]docosa-3,5,7(22)-triene-13,19-dione (L1). The proton binding properties of this cage-type compound, which possesses a hemispherical cavity, were fully investigated by spectroscopic (IR, NMR, UV, MALDI-TOF MS), quantum chemical, and potentiometric methods. While both bridgehead tertiary amines have their free lone pairs oriented inside the cavity, intramolecular hydrogen bonding was found to play a key role in determining the structural features of the free base and its protonated forms. L1 behaves as a diprotic base in water with log K011 = 8.94(1) and log K012 = 2.32(9), but most interestingly shows slow proton-transfer rates on the NMR timescale.

Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries

The distribution of neuropeptide Y (NPY)-immunorective nerves and the receptors involved in the effects of NPY upon electrical field stimulation (EFS)- and noradrenaline (NA)-elicited contractions were investigated in horse penile small arteries. NPY-immunoreactive nerves were widely distributed in the erectile tissues with a particularly high density around penile intracavernous small arteries. In small arteries isolated from the proximal part of the corpora cavernosa, NPY (30 nM) produced a variable modest enhancement of the contractions elicited by both EFS and NA. At the same concentration, the NPY Y(1) receptor agonist, [Leu(31), Pro(34)]NPY, markedly potentiated responses to EFS and NA, whereas the NPY Y(2) receptor agonist, NPY(13-36), enhanced exogenous NA-induced contractions. In arteries precontracted with NA, NPY, peptide YY (PYY), [Leu(31), Pro(34)]NPY and the NPY Y(2) receptor agonists, N-acetyl[Leu(28,31)]NPY (24-36) and NPY(13-36), elicited concentration-dependent contractile responses. Human pancreatic polypeptide (hPP) evoked a biphasic response consisting of a relaxation followed by contraction. NPY(3-36), the compound 1229U91 (Ile-Glu-Pro-Dapa-Tyr-Arg-Leu-Arg-Tyr-NH2, cyclic(2,4')diamide) and eventually NPY(13-36) relaxed penile small arteries. The selective NPY Y(1) receptor antagonist BIBP3226 ((R)-N(2)-(diphenacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginineamide) (0.3 microM) shifted to the right the concentration-response curves to both NPY and [Leu(31), Pro(34)]NPY and inhibited the contractions induced by the highest concentrations of hPP but not the relaxations observed at lower doses. In the presence of the selective NPY Y(2) receptor antagonist BIIE0246 ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-y1]-1-piperazinyl]-2-oxoethyl]cyclo-pentyl-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2, 4-triazol-4-yl]ethyl]-argininamide) (0.3 microM), the Y(2) receptor agonists NPY(13-36) and N-acetyl[Leu(28,31)]NPY (24-36) evoked potent slow relaxations in NA-precontracted arteries, under conditions of nitric oxide (NO) synthase blockade. Mechanical removal of the endothelium markedly enhanced contractions of NPY on NA-precontracted arteries, whereas blockade of the neuronal voltage-dependent Ca(2+) channels did not alter NPY responses. These results demonstrate that NPY can elicit dual contractile/relaxing responses in penile small arteries through a heterogeneous population of postjunctional NPY receptors. Potentiation of the contractions evoked by NA involve both NPY Y(1) and NPY Y(2) receptors. An NO-independent relaxation probably mediated by an atypical endothelial NPY receptor is also shown and unmasked in the presence of selective antagonists of the NPY contractile receptors.

Synthesis of a tetrabenzyl-substituted 10-membered cyclic diamide

A conformationally constrained 10-membered cyclic diamide was designed and synthesized. Conformational analysis suggested that the 9-membered ring formation was preferred to the direct formation of 10-membered ring. On the basis of the prediction, lactonization of 9-membered lactone, followed by intramolecular ester–amide transformation afforded the desired 10-membered cyclic diamide.

Experimental intrinsic barriers to amide–amide interaction. Transannular cyclolization in a cyclic diamide

N-(2-Aminoacetyl)-ε-caprolactam (1) was synthesized. When 1 is dissolved in aprotic solvents such as chloroform or dichloromethane and water (D2O), a ca. 1 ∶ 1 equilibrium is established between two isomeric forms: cyclol1c and macrocyclic diamide1d. The methylene protons –NHCH2CON– for both forms become diastereotopic. Therefore, the diastereotopic interconversion of 1c and 1d can be followed by dynamic 1H-NMR. In D2O, specific base catalysis is observed for both interconversions. Since the equilibrium K = kobs.f/kobs.r for the 1c = 1d transformation remains the same over the wide pD range studied (2 < pD < 11), a mechanism is proposed whereby the exchange occurs through the cyclol1c conjugate base. According to this mechanism, kobs.f and kobs.r can be measured by the diastereotopic interconversions of 1c and 1d respectively. Therefore, K = kobs.f/kobs.r = k2[H2O]Ka/k−2Kw, where k2 is the rate of cleavage of the cyclol 1c (of acidity constant Ka) conjugate base toward the macrocyclic diamide, and k−2 represents the reverse amino amide-to-carbonyl amide attack (transannular cyclolization). Values for k2 of 1.8 × 102 M−1 s−1 (ΔG‡ = 59.8 kJ mol−1 at 25 °C), and k−2 of 1 × 105 M−1 s−1 (ΔG‡ = 44.3 kJ mol−1 at 25 °C) were obtained. The uncatalyzed rates of kobs.f = ko1c and kobs.r = ko1d were also measured. These values are 2 s−1 (ΔG‡ = 71.1 kJ mol−1 at 25 °C) and 4 s−1 (ΔG‡ = 69.4 kJ mol−1 at 25 °C), respectively.

Electronic Structure of a Rigid Cyclic Diamide

Interest in the electronic structure of amides and polypeptides arises in part because optical spectroscopy such as electronic circular dichroism (CD) may be readily used to monitor conformational changes of peptides and proteins in solution. Our current, albeit somewhat incomplete, understanding of the relationship between polypeptide conformation and CD spectra has come in part from experimental and theoretical studies of model systems such as cyclic diamides. In this paper, we study the interactions between amide groups in a bridged cyclic diamide, diazabicyclo[2.2.2]octane-3,6-dione, through the measurement of its infrared (IR) and ultra-violet (UV) absorption and electronic CD spectra and through ab initio calculations of its electronic structure. The particular rigidity of the bridged cyclic diamide removes ambiguity regarding the conformation of the molecule in solution, which must remain close to the structure determined by X-ray crystallography. The theoretical study has been performed using the ...

Synthesis, high-field NMR, X-ray structure, and conformational analysis of a 10-membered diamide disulfide ring

N,N′-[Dimethyl-(2,2′-dithiobisacetyl)]ethylenediamine (1) has been synthesized in 30% overall yield from N,N′-dimethylethylenediamine and thioacetic acid by an improved procedure involving simultaneous deprotection and oxidative cyclization with iodine. This cyclic diamide disulfide exists in solution as a mixture of two Z,Z and one Z,E disulfide, and amide ring conformers and has been characterized by nuclear Overhauser effect (NOE), 1H–1H, 1H–13C shift-correlated 2D-NMR and molecular modelling studies. Among the Z,Z ring conformers Z,Z1 and Z,Z2, the former predominates and interconverts with the latter isomer by rotation about the S—S bond with an activation energy of 14.5 ± 1.3 kcal/mol. Coalescence of N-CH3 signals occurred at ca. 127 °C (500 MHz), which corresponded to an approximate barrier to amide rotation of 19.3 kcal/mol. Aromatic solvent-induced shifts in C6D6 corroborated molecular mechanics and NOE predictions of amide stereochemistry. The structure of the Z,E stereoisomer of 1 has been determined by single-crystal X-ray diffraction at 296 K. A large geminal N-CH2 inequivalence (&gt;2 ppm in CDCl3) was observed for the Z,Z conformers. Proton chemical shifts have been calculated for the conformers of 1 and related molecular fragments with DFT/GIAO theory. Absolute chemical shifts are modelled within 0.2 ppm of experiment. The unusual nonequivalence of geminal N-CH2 and S-CH2 protons can be understood as a combination of shielding mechanisms derived from short N-methyl contacts, amide group orientation, and sulfur lone-pair disposition. An implication of these results is the possibility of using α-CH (and eventually α-CH) shifts to probe the local conformational space in cyclic peptides and other conformationally constrained rings. Keywords: amide/disulfide rotamers, conformational analysis, density functional theory, DFT/GIAO NMR shift calculations, methylene nonequivalence, molecular modelling.

Lithiumsalze des Tris(trimethylsilylamino)silans ‐ Zur Struktur in Lösung und im Festkörper

Lithium Salts of Tris(trimethylsilylamino)silane - Their Structures in Solution and in the Solid State* Amides, which result from the reaction of tris(trimethylsilylamino)silane (Me3SiNH)3SiH (1) with n-butyllithium in the molar ratio 1:1 and 1:2 in nonpolar solvents, form a system in which the aminosilane 1, the monoamide (Me3SiNLi)(Me3SiNH)2SiH (2a), the diamide (Me3SiNLi)2(Me3SiNH)SiH (3), and the triamide (Me3SiNLi)3SiH (4) are in equilibrium. When the monoamide 2a is dissolved in THF only the dimeric monolithiated THF adduct 2b is obtained. An X-ray structure analysis of the lithium silylamide 2b reveals that in the dimeric unit one of the lithium atoms is coordinated by THF, the two lithium atoms thus differing in coordination number (3 versus 4). An X-ray study of the triamide 4 reveals a centrosymmetric polycycle. Multipole interactions are formed between the lithium and the nitrogen atoms. The reaction of the diamide 3 with chlorotrimethylsilane in boiling THF yields the cis isomer of the cyclic diamide [(Me3SiNLi)(Me3SiNH)SiN(SiMe3)]2· 2 THF (5) as a byproduct. According to an X-ray structure analysis of 5 the lithium centers are coordinated by one oxygen and three nitrogen atoms, which form a strongly distorted tetrahedron. The interactions between lithium and nitrogen atoms N(1) and N(2), which are part of the four-membered Si2N2 cycle, have to be considered as weak on the basis of the remarkably long Li-N distances (233 and 243 pm).

Base-catalysed rearrangement of temazepam

Temazepam undergoes a rearrangement reaction in strongly alkaline media to form a cyclic diamide, 7-chloro-1-methyl-5-phenyl-4,5-dihydro-2 H-benzodiazepin-2,3(1 H)-dione. Thermodynamic parameters ( E act , ΔH‡, ΔS‡, ΔG‡ ) involved in the rearrangement reaction, studied using either CH 3CN-0.2 N NaOH in H 2O (1:1, v/v) or CH 3CN-0.2 N NaPD in D 2O (l:l, v/v) as the solvent, were similar with an isotope effect ( k H k D ) of 0.77 ± 0.03. Kinetics of the rearrangement reaction were studied as a function of NaOH concentration, temperature and ionic strength. Results indicated that the rate-determining step did not involve proton exchange with solvent. Mass spectral analysis of the cyclic diamides derived by using either D 2O or H 2 18O in the solvent mixtures suggested that the formation of the cyclic diamide involved a nucleophilic addition of a hydroxide ion at the C2 carbonyl carbon of temazepam.