Diastereotopic Protons Research Articles

Chiral 1,2-Diols: The Assignment of Their Absolute Configuration by NMR Made Easy

The absolute configuration of a 1,2-primary/secondary diol can be easily determined by preparation of its bis-(R)- and bis-(S)-9-AMA ester derivatives, followed by comparison of the NMR chemical shifts of the diastereotopic methylene protons in the two derivatives. Alternatively, the assignment can be carried out using only one derivative if the evolution with temperature of the signals corresponding to the CalphaH protons is analyzed.

Multicomponent, Hydrogen-Bonded Cylindrical Capsules

Self-assembled, hydrogen-bonded capsules emerge from synthetic resorcinarene-derived cavitands and soluble glycolurils when appropriate guest molecules are present. The assembly consists of 2 cavitands, 4 glycolurils and guest(s), and the arrangement of glycolurils leads to a chiral structure. The capsule features a space of approximately 620 A(3) and accommodates narrow guests such as n-alkanes from C(14) to C(19), or other molecules (e.g., capsaicin) and combinations of molecules of up to approximately 22 A in length (e.g., two p-methylstyrene molecules). Positions of encapsulated nuclei can be predicted from NMR chemical shifts, with intense shielding of deltaDelta = -5 ppm near the resorcinarene ends and mild deshielding of +0.5 to 1 ppm near the glycolurils at the capsule's center. Computational methods using nucleus independent chemical shifts (NICS) were used to map the induced magnetic shielding/deshielding for the inner space of the cavity. The asymmetric arrangement of the spacers creates a chiral steric and magnetic environment in the capsule and the geminal hydrogen atoms of encapsulated alkanes show diastereotopic proton signals. The two enantiomers interconvert (racemize) through an achiral intermediate involving a slight rotation of the spacers and lengthening of the cavity. Accordingly, longer, compressed alkanes accelerate the racemization by applying pressure from the inside on the capsule's ends. Guests that place hydrogen bond donors and acceptors near the glycolurils in the middle (e.g., p-isopropylbenzyl alcohol) also accelerate the racemization by facilitating the rotation of the glycolurils. Slow tumbling of guest on the NMR time scale inside the capsule leads to social isomerism of para-disubstituted benzenes such as p-methylstyrene. Flexible guests such as hexane tumble inside the cavity with an activation barrier of DeltaG(++) =16.2 kcal/mol. The middle of the extended capsule is narrow, but still accommodates phenyl groups such as those presented by p-quaterphenyl and alkylated biphenylcarbonitriles. The aromatic units in these guests report their positions by imparting magnetic anisotropy to the capsule components. Gases such as propane, butane, isobutane, propylene, 2-methylpropene, and 1,3-butadiene even xenon are coencapsulated with other guests and their motions inside are examined.

Quantifying End‐to‐End Conformational Communication of Chirality through an Achiral Peptide Chain

Successful communication: Two diastereotopic protons more than 60 bonds from the nearest chiral center appear as an AB system, showing that the intervening structure is a well-ordered helix. Decay of anisochronicity quantifies the linear persistence of a helix of achiral amino acids: as little as 3.5 % of the chiral influence is lost with each additional achiral residue.

Direct Arylation Mediated by Palladium Complexes with Rigid Phosphine-Functionalized N-Heterocyclic Carbenes

New phosphine-functionalized N-heterocyclic carbene ligand precursors (L1H·I and L2H·I) were prepared. The former compound contains a PPh2 moiety, whereas the latter one has a more electron-donating PCy2 group. A reaction of L1H···I with PdCl2 in the presence of base afforded the complex PdL1ClI. An interconversion process between the two structural isomers of PdL1ClI was observed by variable-temperature NMR. The coalescence temperature (Tc) is at 368 K with the free energy of activation (ΔG⧧) found to be 68.9 kJ mol−1. A similar reaction of L2H·I with PdCl2 produced a mixture of PdL2ClI, PdL2Cl2, and PdL2I2. Unlike PdL1ClI, PdL2ClI undergoes a much faster exchange between the two structural isomers. Pure PdLI2 (L = L1 and L2) can be obtained by adding NaI in the reaction mixture to facilitate ligand exchange. [PdL(CH3C≡N)2](BF4)2 were also prepared straightforwardly by salt metathesis reactions. In total, seven new palladium complexes of L were structurally characterized, and in each of these structures an anagostic interaction exists between the palladium center and one of the diastereotopic methylene protons. The interaction also exists in solution, as evidenced by the downfield NMR shift of the proton. The new complexes PdLI2 and [PdL(CH3C≡N)2](BF4)2 show mediocre activities in benchmark Suzuki coupling reactions under conventional and microwave heating. They are, however, highly promising in mediating direct arylation of phenyl halides and diphenylacetylene, affording 9-benzylidene-9H-fluorene in good yields.

Solution structure determination of oligoureas using methylene spin state selective NMR at 13C natural abundance

Ability of N,N'-linked oligoureas containing proteinogenic side chains to adopt a stable helix conformation in solution has been described recently. NMR as well as circular dichroism (CD) spectroscopies were employed to gain insight into their specific fold. It is herein proposed to extend the structural information available on these peptidomimetics by an advantageous use of a methylene spin state selective NMR experiment. Homodecoupling provided by the pulse scheme made it possible to readily measure conformation-dependent (3)J(HH) constants that are difficult if not impossible to obtain with standard NMR experiments. Adding those couplings to the NMR restraints improved the quality of the structure calculations significantly, as judged by a ca 30% decrease of the root mean square deviation (RMSD) obtained over an ensemble of 20 structures. Moreover, accurate determination of individual (1)J(CH) couplings within each methylene group revealed uniform values throughout the oligourea sequence, with (1)J(CH) systematically slightly larger for the pro-S hydrogen than for the pro-R. As shown in this study, the methylene spin state selective NMR experiment displays a good intrinsic sensitivity and could therefore provide valuable structural information at (13)C natural abundance for peptidomimetic molecules and foldamers bearing diastereotopic methylene protons.

1H and 13C NMR assignments for new heterocyclic TAM leuco dyes, (2Z,2′E)‐2,2′‐(2‐phenyl propane‐1,3‐diylidene) bis(1,3,3‐trimethylindoline) derivatives. Part II

The (1)H and (13)C NMR spectra of the novel heterocyclic Leuco-TAM dyes, (2Z, 2'E)-2,2'-(2-phenyl propane-1,3-diylidene) bis(1,3,3-trimethylindoline) derivatives 1-4 as precursors of triarylmethane (TAM)(+) (Malachite Green FB-analog) dyes were completely assigned by 1D and 2D NMR experiments, including DEPT, COSY, HSQC, HMBC, and NOESY. Especially, the diastereotopic gem-dimethyl protons at the C3 and C3' positions of the FB rings were definitively assigned. The (Z,E) isomers adopt the energetically favored three-bladed propeller conformation in solution.

Exploring Helical Folding of Oligoureas During Chain Elongation by High‐Resolution Magic‐Angle‐Spinning (HRMAS) NMR Spectroscopy

The development of novel folding oligomers (foldamers) for biological and biomedical applications requires both precise structural information and appropriate methods to detect folding propensity. However, the synthesis and the systematic conformational investigation of large arrays of oligomers to determine the influence of factors, such as chain length, side chains, and surrounding environment, on secondary structure can be quite tedious. Herein, we show for 2.5-helical N,N'-linked oligoureas (gamma-peptide lineage) that the whole process of foldamer characterization can be accelerated by using high-resolution magic-angle-spinning (HRMAS) NMR spectroscopy. This was achieved by monitoring a simple descriptor of conformational homogeneity (e.g., chemical shift difference between diastereotopic main chain CH2 protons) at different stages of oligourea chain growth on a solid support. HRMAS NMR experiments were conducted on two sets of oligoureas, ranging from dimer to hexamer, immobilized on DEUSS, a perdeuterated poly(oxyethylene)-based solid support swollen in solvents of low to high polarity. One evident advantage of the method is that only minute amount of material is required. In addition, the resonance of the deuterated resin is almost negligeable. On-bead NOESY spectra of high quality and with resolution comparable to that of liquid samples were obtained for longer oligomers, thus allowing detailed structural characterization.

Cesium Selective Calix[6]arene Bisbridged Receptor

Calixcrowns are macromolecular hybrid structures composed of calix[n]arenes and crown ethers which have been demonstrated to be very effective complexing agents for alkali and other metal ions. In particular, calix[4]arene crown-6 hosts have been extensively investigated in the sequestration and removal of radioactive Cs ions from aqueous waste mixtures. Cesium-137 is a relatively abundant nuclear fission product and constitutes a major source of heat in nuclear waters along with strontium-90. Much effort has been made to the development of improved processes for the removal of cesium-137 from nuclear wastes. For the efficient removal of cesium, several crown ethers have been prepared and their binding properties were investigated. Calixcrowns have been constructed from all four conformational isomers of calix[4]arenes (cone, partial cone, 1,2-, and 1,3-alternate) and structure-property correlations have been developed to a level where application of these molecules has become common. Also the bisbridged calix[4]crowns has been developed since the introduction of a second bridging unit generally increases the rigidity of the calix[4]arene framework. For the development of a selective ligand for cesium ion, calix[6]arenes have been utilized as a receptor. But, selectivity over potassium and rubidium is not quite high. The lack of selectivity has been attributed into the flexibility of the parent calix[6]arene moieties. The most effective approach to make them immobile is to build a bridge at the lower. Since Gutsche’s lower rim-bridged calix[6]arene in 1993, several lower rim-multibridged calix[6]arenes and their ion binding properties were reported. For the purpose of developing cesium selective ion receptors, we prepared three new calix[6]arene bisbridged receptor and investigated their structural and alkali metal ion binding properties by UV, H NMR and solvent extraction. The bridging of the calix[6]arene was accomplished by the reaction of 1,4-dialkyl ethers 1 and 1,2-bis(bromomethyl)benzene in the presence of Cs2CO3 in dilute solution as shown in Scheme 1. H NMR spectrum of 2c showed two pairs of doublets at δ 4.4-3.0 for the bridged methylene protons and a pair of doublets of eight diastereotopic bridged methylene protons (ArCH2O-) at δ 5.0-4.4. But, H NMR spectrum of 2a and 2b did not show clear two pairs of doublets for the bridged methylene protons. The 1,2-bridged calix[6]arene ligands 1,2,3 could be defined as cone or 1,2,3alternate conformer based on H NMR. The crystal structure confirms that 2a exists as the 1,2,3alternate conformation as shown in Figure 1. Two methoxymethyl substituents were tilted inward to fill the empty calixarene cavity. Table 1 shows the detail data for X-ray structure refinement for 2a. The alkali metal binding properties were investigated from

Stretched Poly(methyl methacrylate) Gel Aligns Small Organic Molecules in Chloroform. Stereochemical Analysis and Diastereotopic Proton NMR Assignment in Ludartin Using Residual Dipolar Couplings and 3J Coupling Constant Analysis

Poly(methyl methacrylate) (PMMA) gels prepared by copolymerizing methyl methacrylate (MMA) and various amounts of ethylene glycol dimethacrylate (EGDMA) in the presence of the radical initiator V-70 (2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile)) can orient small organic molecules when swollen in NMR tubes with CDCl(3). The aligning properties of the stretched PMMA gels were evaluated by monitoring the quadrupolar splitting of the (2)H NMR signal of CDCl(3), and the aligning degree is proportional to the cross-linking density. Natural abundance one-bond (1)H-(13)C residual dipolar couplings (RDCs) for menthol measured in the gels depended on the cross-link density. The stereochemistry and assignment of the diastereotopic protons of the gastroprotective and nonsteroidal aromatase inhibitor sesquiterpene lactone ludartin, isolated from Stevia yaconensis var. subeglandulosa, were unambiguously determined using a combination of natural abundance one-bond (1)H-(13)C RDCs measured in a PMMA gel and a (3)J coupling constant analysis.

Assigning the NMR Spectrum of Glycidol: An Advanced Organic Chemistry Exercise

This exercise combines conformational analysis and 1-D and 2-D NMR spectroscopy to correctly assign the proton and carbon NMR spectra of 2,3-epoxy-1-propanol (glycidol). In the process, students learn how to read DEPT-135, HETCOR, and COSY spectra. One set of diastereotopic protons is assigned using dihedral angles and the Karplus relationship. The assignment of the other set of diastereotopic protons requires that conformational modeling be done to complete the assignment of protons to signals.

Discrimination of enantiomers of α‐amino acids by chiral derivatizing reagents from trans‐1,2‐diaminocyclohexane

New chiral derivatizing reagents (CDAs) derived from trans-1,2-diaminocyclohexane, having an electron-deficient aromatic substituent (either an aromatic imide or 3,5-dinitrobenzamide) and rigid structure (either an amide or a urea linker), are reported. Significant shift differences of diastereotopic protons in the 1H NMR signals are observed for enantiomers of suitably protected alpha-amino acids, linked to CDA by a covalent bond. A simple, general model rationalizing the observed enantiomer discrimination and based on semiempirical conformational search is presented.

Determination of the stereochemistry of γ‐Butyrolactones by DPFGSE‐NOE experiments

The stereochemistry of gamma-butyrolactons tetrahydro-6a-phenylfuro[3,4-b]furan-2(3H)-one (1), 1,4,5,9b-tetrahydro-3a-methylnaphtho[2,1-b]furan-2(3aH)-one (2), 1,4,5,9 b-tetrahydro-3a-methylfuro[2,3-c]quinolin-2(3aH)-one (3) and hexahydro-furo[3,2-c]benzofuran-2-one (4) was studied using DPFGSE-NOE experiments. Compounds 1-3 contain two stereocenters, while 4 contains three. Both (1)H and (13)C spectra showed a single diastereomer of all the compounds. Routine 2D experiments (DQF)-COSY, HMQC/HSQC, and HMBC were used to assign (1)H and (13)C spectra completely. Diastereotopic methylene protons with resolved (1)H NMR signals as well as protons of cyclohexane served as references for the construction of the spatial arrangement in the molecules. NOE contacts between protons attached to the stereocenter and the diastereotopic protons were thus used to determine the configuration of the molecules. Vicinal coupling constants (3)J assisted the assignment of the conformational arrangement of the cyclohexane ring of 4.

Triazene derivatives of (1,x)-diazacycloalkanes. Part VIII. Synthesis and characterization of a series of 1,4-di[2-aryl-1-diazenyl]-2-methylpiperazines1

A series of 1,4-di-[2-aryl-1-diazenyl]-2-methylpiperazines (4a–n) have been synthesized by the reaction of 2-methylpiperazine with 2 equiv. of the appropriate diazonium salt. The products have been characterized by IR and NMR spectroscopy, and the molecular composition has been verified by HR-EIMS, with accurate mass measurement of the molecular ion. The presence of a chiral centre at C2 of the piperazine ring in the bistriazene 4 creates a multitude of diastereotopic protons in the methylene groups of the piperazine ring, as evidenced by the complexity of the NMR spectra, which nevertheless can be fully assigned in some cases, such as the tolyl- (4h) and phenyl- (4j) derivatives. These two compounds also show a discrimination between the two N-arydiazenyl groups, as evidenced by the doubling of several aromatic-carbon signals in the 13C NMR spectra. The assignment of the proton and carbon signals in 4h and 4j has been aided by the use of 2D NMR spectroscopy. A DEPT spectrum of 4j clearly discriminates the methylene carbons and also indicates the methine carbons of the piperazine ring. COSY spectra provide clear information about the interactions between diastereotopic protons; when these results are combined with the results of HSQC spectroscopy, the proton and carbon signals can be fully correlated, leading to an unequivocal assignment of the proton and carbon atoms of the piperazine ring. The HSQC spectrum of 4j also gives a complete correlation of the aromatic-proton and -carbon signals. These results compare favorably with the previously reported assignments of proton and carbon signals for triazenes of type 1 and bistriazenes of type 3.Key words: triazene, bistriazene, piperazine, 2-methylpiperazine, diastereotopic protons, diazonium coupling, 2D NMR, COSY, DEPT, HSQC.

Use of RDCs in rigid organic compounds and some practical considerations concerning alignment media

AbstractA molecule that is introduced into a liquid crystal or alignment medium forfeits its isotropic tumbling motion. The resulting partial alignment leads to observable anisotropic interactions, dipolar couplings being one. To control the degree of alignment that the molecule experiences is essential to retain the quality of high‐resolution solution‐state spectra. An overview of alignment media is given. The problems associated with very large residual dipolar couplings (RDCs) are pointed out, and means to reduce residual dipolar couplings (RDCs) for strychnine in substituted polyglutamate liquid crystals are described. The use of RDCs for the assignment of diastereotopic protons and for the determination of the relative configuration in rigid compounds is then described in detail, also pointing out some pitfalls. © 2007 Wiley Periodicals, Inc. Concepts Magn Reson Part A 30A: 65–80, 2007.

Anion binding in (arene)ruthenium(ii)-based hosts

Asymmetric ruthenium(II) complexes of a flexible aminomethylpyridine derivative exhibit diastereotopic ligand methylene protons, as measured by NMR spectroscopy; binding of external anions renders these protons equivalent possibly by increasing dynamically averaged symmetry; the amount of anion needed to raise average symmetry correlates to the anion binding constant.

Synthesis and characterization of a series of 3-methyl-3-{3-[1-methyl-3-aryl-2-triazenyl]propyl}-1-aryl-1-triazenes and related compounds

A series of diazonium salts has been coupled to both secondary nitrogen atoms of the bis-secondary amine, N,N′-dimethyl-1,3-propanediamine (MeNHCH2CH2CH2NHMe), to afford the new bistriazene series, the 3-methyl-3-{3-[1-methyl-3-aryl-2-triazenyl]propyl}-1-aryl-1-triazenes (9). These compounds have been fully characterized by IR and NMR spectroscopy, with supporting data from elemental analysis and high-resolution mass spectrometry. A limited number of model compounds in the N,N-dimethyl-N-{3-[1-methyl-3-aryl-2-triazenyl]propyl}amine series (10) have been synthesized to aid in the interpretation of the NMR spectra of the bistriazenes (9). A series of related compounds, the 3-ethyl-3-{(E)-4-[1-ethyl-3-aryl-2-triazenyl]-2-butenyl}-1-aryl-1-triazenes (11), have been synthesized by diazonium coupling with the bis-secondary amine N,N′-diethyl-2-butene-1,4-diamine (15), and the diazonium coupling reaction with trans-N,N′-dimethycyclohexane-1,2-diamine (19) has been used to prepare another related series of bistriazenes, the 3-methyl-3-{2-[1-methyl-3-aryl-2-triazenyl]cyclohexyl}-1-aryl-1-triazenes (12). The 1H NMR spectra of these compounds are complex because of the presence of two chiral centres in the cyclohexanediamine moiety; the diastereotopic protons of the methylene groups in the cyclohexane ring are clearly distinguished in the 500 MHz spectra of these compounds.Key words: triazene, bistriazene, synthesis, nuclear magnetic resonance, propanediamine, 1,4-diamino-2-butene, cyclohexanediamine.

Determining the absolute configuration of secondary alcohols by means of a chiral auxiliary and NOESY

The absolute configuration of secondary alcohols can be determined by NOE between the diastereotopic protons of the lactam and the protons of the alcohol moieties in some 1-(alkoxymethyl)-methyl-2-pyrrolidone-5-carboxylate derivatives. Two simple methods based on conformational analysis and 1H NMR data have been developed. The main conformer, in all cases, was established by means of MM, semi-empirical, and ab initio calculations.

Dicondensed indolinobenzospiropyrans as precursors of thermo‐ and photochromic spiropyrans. Part II: assignment of 1H and 13C NMR spectra

The (1)H and (13)C NMR spectra of dicondensed indolinobenzospiropyrans as precursors of thermo- and photochromic spiropyrans, DC1-DC5, were completely assigned. Especially, the (1)H assignment and coupling characteristics of the diastereotopic protons at the carbon-3 position of the benzopyran rings were achieved by conducting (1)H-(1)H COSY and nOe experiments. The dihedral angles (theta(1), theta(2) and theta(3)) calculated from the experimental values of the vicinal coupling constants ((3)J) of DC5 are in good agreement with the observed values in the solid state. All of the carbons in the DC dye molecules were investigated through a combination of heteronuclear 2D-shift correlation spectroscopy (HETCOR) and DEPT135.

Triazene derivatives of (1,x)-diazacycloalkanes. Part V.1 Synthesis and characterization of 4-ethyl-3-({6-ethyl-3-[2-aryl-1-diazenyl]hexahydro-1-pyrimidinyl}methyl)-1-[2-aryl-1-diazenyl)hexa- hydropyrimidines from the reaction of diazonium salts with mixtures of formaldehyde and 1,3-diaminopentane

A new series of bistriazenes has been synthesized from a general reaction of diazonium salts with a mixture of 1,3-diaminopentane (DYTEK® EP diamine) and formaldehyde, which affords the 4-ethyl-3-({6-ethyl-3-[2-aryl-1-diazenyl]hexahydro-1-pyrimidinyl}methyl)-1-[2-aryl-1-diazenyl]hexahydropyrimidines (1). Each of the molecules of type 1 is built up of two equivalent 3-(aryldiazenyl)-6-ethylhexahydro-1-pyrimidinyl groups attached to a central methylene group. The importance of this study is in part due to the fact that the formaldehyde–1,3-diaminopentane system has not previously been investigated. All new compounds have been characterized by IR and NMR spectroscopy, with elemental analysis for selected compounds; one example from the series has been unequivocally characterized by X-ray crystallography. Although analysis of the NMR spectra is made somewhat difficult because of broadness and coalescence of signals due to the rotational dynamics of the N—N single bonds, it is possible to fully assign the proton spectra of all compounds and to detect 94% of all carbon signals. The fine structure within the proton spectra illustrate the diastereotopic nature of the methylene group protons because of the presence of a stereocenter in each hexahydropyrimidine ring. The general conclusion of this study is that alkanediamines with three carbon atoms in the spacer link between the nitrogen atoms give rise to the linear bicyclic molecules of type 1, 2, and 3, in contrast to the case of ethylenediamine (spacer link has two carbon atoms), which affords molecules of type 7 that exemplify the bridged bicyclic bistriazene structure. The new compounds of series 1 represent an extension of a broad ranging study of the synthesis of new bistriazene derivatives of (1,x)-diazacycloalkanes.Key words: triazene, diazonium coupling, hexahydropyrimidine, diaminopentane, diazacycloalkanes, stereocenter, diastereotopic protons.

Crystallization by Slow Halogen Exchange in Hypercoordinate Silicon Chelates and the first X‐ray Structure of a trans‐Featured Hexacoordinate Difluorosilicon‐bis‐Chelate

AbstractStarting from silicon tetrahalides SiCl4 and SiBr4, respectively, and the bidentate 2‐iminomethylphenol‐type ligand HO‐C6H3‐2‐[C(C6H5)=N(CH2‐C6H5)]‐5‐OCH3, three novel complexes with hypercoordinate silicon atom were synthesized. Their coordination spheres consist of two halogen atoms (F, Cl, Br) and two six membered ring systems created by chelating bidentate ligands of 2‐iminomethylphenolate type. Demonstrated by crystal structure analysis, the dichloro‐ and difluorosilicon complexes {O‐C6H3‐2‐[C(C6H5)=N(CH2‐C6H5)]‐5‐OCH3}SiX2 (X = Cl, F) reveal all‐trans‐configuration in solid state. The difluorosilicon complex {O‐C6H3‐2‐[C(C6H5)=N(CH2‐C6H5)]‐5‐OCH3}SiF2 is the first X‐ray crystallographically proven example of a trans‐featured difluorosilicon‐bis‐chelate. Its all‐trans‐configuration, however, is not retained after dissolution. The formation of an octahedral complex with cis‐arranged fluorine atoms is 1H NMR spectroscopically proven by the coupling pattern of diastereotopic benzyl methylene protons of the chelating ligands.