Chemical Shift Nonequivalence Research Articles

Synthesis of noval chiral tridentate amino alcohols as chiral solvating agents under ball-milling conditions

A new family of chiral solvating agents based on chiral didentate amino alcohols and chloromethyl pyridine derivatives were synthesized by ball milling in solvent free condition. The new chiral tridentate amino alcohols were tested as chiral NMR solvating agents for the Ts-derivatives of amino acids, other several acids and pyrazole drugs. For the Ts-derivatives of amino acids studied herein, chiral tridentate amino alcohol 3a could be used for the assignment of the absolute configurations of their racemes through the chemical shift non-equivalences of their CH3 (Ts) protons with certain confidence.

Highly effective configurational assignment using bisthioureas as chiral solvating agents in the presence of DABCO.

A highly effective (1)H NMR method for determining the absolute configurations of various chiral α-hydroxyl acids and their derivatives has been developed with the use of bisthioureas (R)-CSA 1 and (S)-CSA 1 as chiral solvating agents in the presence of DABCO, giving distinguishable proton signals with up to 0.66 ppm chemical shift nonequivalence. Computational modeling studies were performed with Gaussian09 to reveal the chiral recognition mechanism.

NMR spectroscopic detection of chirality and enantiopurity in referenced systems without formation of diastereomers.

Enantiomeric excess of chiral compounds is a key parameter that determines their activity or therapeutic action. The current paradigm for rapid measurement of enantiomeric excess using NMR is based on the formation of diastereomeric complexes between the chiral analyte and a chiral resolving agent, leading to (at least) two species with no symmetry relationship. Here we report an effective method of enantiomeric excess determination using a symmetrical achiral molecule as the resolving agent, which is based on the complexation with analyte (in the fast exchange regime) without the formation of diastereomers. The use of N,N′-disubstituted oxoporphyrinogen as the resolving agent makes this novel method extremely versatile, and appropriate for various chiral analytes including carboxylic acids, esters, alcohols and protected amino acids using the same achiral molecule. The model of sensing mechanism exhibits a fundamental linear response between enantiomeric excess and the observed magnitude of induced chemical shift non-equivalence in the 1H NMR spectra.

ChemInform Abstract: Lanthanide Complexes as Paramagnetic Probes for 19F Magnetic Resonance

AbstractReview: 35 refs.

Paramagnetic 19F Chemical Shift Probes that Respond Selectively to Calcium or Citrate Levels and Signal Ester Hydrolysis

Paramagnetic magnetic resonance chemical shift probes containing a proximal CF(3) group have been characterised. Different systems have been created that report reversible changes in calcium ion concentrations in the millimolar regime, signal the presence of citrate selectively in competitive aqueous media and allow the monitoring of remote ester/amide hydrolysis in relayed, irreversible transformations. Chemical shift non-equivalence is amplified by the presence of the proximate lanthanide ion, with a mean separation between the CF(3) group and the metal ion of 6.4 Å found for a thulium complex, in an X-ray structure of the metal complex aqua adduct. The enhanced rate of longitudinal relaxation of the (19)F nucleus allows faster data acquisition.

A Practical Solvating Agent for the Chiral NMR Discrimination of Carboxylic Acids

AbstractA bisimidazoline compound has been prepared as a new chiral solvating agent starting from isophthalaldehyde and (S,S)‐1,2‐diphenylethylenediamine through a single‐step synthesis. In the presence of one equivalent of this reagent, carboxylic acid racemates show 1H NMR chemical shift nonequivalences large enough for the discrimination of the enantiomers. Studies with related compounds showed that the 1,3‐disubstituted structure is crucial for the acid‐solvating ability of the bisimidazoline compound.

Cinchona alkaloids as privileged chiral solvating agents for the enantiodiscrimination of N-protected aminoalkanephosphonates—a comparative NMR study

A series of chiral amines of increasing structural complexity, such as 1-(1-naphthyl)ethylamine, ephedrine, quinine, quinidine, 9- O- tert-butylcarbamoylquinine, and 9- O- tert-butylcarbamoylquinidine were studied as chiral solvating agents for the enantiodifferentiation of N-benzyloxycarbonyl derivatives of 1-aminoalkanephosphonic and phosphinic acids by means of 31P NMR spectroscopy. Among the cinchona alkaloids, that induced the most significant chemical shift non-equivalences, non-substituted quinidine exhibited the best effectiveness, excellent for analytical purposes (for example Δ δ = 0.348 up to 1.008 ppm for phosphinic acid analogs). The signal separation of the diionic phosphonic acid enantiomers could be further optimized by the addition of an excess of the solvating agents. The newly obtained results appeared better when compared to the data set previously reported for the same analytes with the application of cyclodextrins.

Deciphering the NMR Fingerprints of the Disordered System with Quantum Chemical Studies

Recent developments in solid-state NMR techniques helped acquire high-resolution NMR spectra for solid systems with structural disorder. But the structural origin of the observed chemical shift nonequivalence in these systems has not been revealed. We report a quantum chemical investigation of the solid-state NMR spectrum in N,N-bis(diphenylphosphino)-N-((S)-alpha-methylbenzyl)amine, where eight nonequivalent (31)P NMR chemical shifts were resolved with a range of 13.0 ppm. Results from using different quantum chemical methods, computational algorithms, intermolecular effects, and structures indicate that for the disordered system, geometry optimization gives the best accord with experimental NMR chemical shifts, which has a theory-versus-experiment correlation R(2) = 0.949 and SD = 1.1 ppm, or R(2) = 0.994 and SD = 0.4 ppm when the average of two unassigned NMR shifts for each molecule is used. In addition, these calculations indicate that the experimental chemical shift nonequivalence in this system is mainly a consequence of the different geometries around the phosphorus atoms due to disordered environments. The experimental (31)P NMR chemical shifts are well correlated (R(2) = 0.981) with two conformation angles and one bond length, each associated with one of the three bonding interactions around the phosphorus atoms. These results will facilitate the use of quantum chemical techniques in structural characterization of disordered solids and elucidation of NMR properties.

The Preparation of Dimethyl α -Hydroxyphosphonates and the Chemical Shift Non-Equivalence of Their Diastereotopic Methyl Ester Groups

Dimethyl α -hydroxyalkyl-, α -hydroxybenzyl-, α -hydroxyfurfuryl-, and α -hydroxy-α -thienylmethyl-phosphonates have been prepared in good yield by the alumina-catalyzed reaction of dimethyl phosphite with the corresponding alkanals, aryl aldehydes (or aryl methyl ketones), furfuraldehyde, and 2- or 3-thiophenecarboxaldehyde, respectively, thus confirming the general utility of this synthetic procedure. The 1H and 13C nmr spectra of the products exhibit characteristic chemical shift non-equivalence of the diastereotopic methyl ester groups, for which a tentative order of non-equivalence is reported and discussed.

Chiral amino alcohols derived from natural amino acids as chiral solvating agents for carboxylic acids

Several chiral amino alcohols have been synthesized conveniently and effectively. 1H NMR was utilized to investigate their enantiodiscriminating abilities. Chiral amino alcohols 2 and 4 were discovered as efficient CSAs for the determination of the enantiomeric compositions of chiral carboxylic acids. In particular, for the Ts-derivatives of amino acids studied herein, 4 could be used for the assignment of the absolute configurations of the Ts-derivatives of amino acids with a neutral side chain through the chemical shift non-equivalences of their NH (Ts) protons with certain confidence.

An NMR Chiral Solvating Agent for the Chiral Recognition of the Two Enantiomers of N-(3,5-Dinitrobenzoyl)-α-amino Acids

Two enantiomers of chiral drugs often show different pharmaceutical activities. Consequently, the study on the stereochemical dependence of the pharmacokinetics and the pharmaceutical activities of chiral drugs is important. Determination of the enantiomeric composition of chiral drugs is, therefore, essential. Enantiomeric composition of chiral compounds has been determined most widely by highperformance liquid chromatographic chiral separations on chiral stationary phases (CSPs). Another important method of determining the enantiomeric composition of chiral compounds is the NMR techniques utilizing chiral solvating agent (CSA). The two transient diastereomeric adducts formed between a CSA and each of the two enantiomers of chiral analytes might induce anisochronous NMR resonances and consequently the enantiomeric composition of chiral analytes can be easily assessed from the NMR spectrum. Most CSAs, which have been developed and successfully utilized in the determination of the enantiomeric composition of chiral compounds by NMR spectroscopy, contain aromatic functional group(s) to induce magnetic anisotropic influence and to invoke π-π interaction with analytes. Derivatives of optically active trans-1,2-diaminocyclohexane has also been utilized as NMR CSAs and these CSAs have also been designed to contain aromatic functional group(s) in order to induce magnetic anisotropic influence and to invoke π-π interaction with analytes. Consequently, CSAs derived from optically active trans-1,2diaminocyclohexane have been utilized for the determination of enantiomeric composition of chiral compounds containing aromatic functional group(s). For example, CSA 1 and CSA 2 derived from (1R,2R)-1,2-diaminocyclohexane shown in Figure 1 have been successfully applied to the determination of enantiomeric composition of chiral carboxylic acids by NMR spectroscopy. Recently, we found that a liquid chromatographic chiral stationary phase (CSP 3, Figure 1) derived from optically active (1S,2S)-1,2-diaminocyclohexane is quite successful for the resolution of N-(3,5-dinitrobenzoyl)-α-amino acids even though the CSP does not contain any aromatic functional group, but contains only a simple primary amino group and a ureide tethering group. From these results, we inferred that CSA 4, which has the same structure as the chiral selector of CSP 3, might show nonequivalences for the two enantiomers of N-(3,5-dinitrobenzoyl)-α-amino acids by NMR spectroscopy. CSA 4 was prepared simply by treating (1S,2S)-1,2diaminocyclohexane with ethyl isocyanate. CSA 4 thus prepared was used to see the H NMR chemical shift nonequivalence of the two enantiomers of N-(3,5-dinitrobenzoyl)phenylglycine. As shown in Figure 2, the chemical shift nonequivalence of the two enantiomers of N-(3,5-dinitrobenzoyl)phenylglycine was observed at the NMR peaks corresponding to the protons on the 3,5-dinitrophenyl ring (denoted by a in Figure 1). In addition the chemical shift nonequivalence of the two enantiomers of N-(3,5-dinitrobenzoyl)phenylglycine was observed to be greatest when the ratio of CSA 4 and N-(3,5-dinitrobenzoyl)phenylglycine is 2:1 at ambient temperature (22 ± 0.5 C). The H NMR experimental results for the chemical shift nonequivalences of the two enantiomers of five N-(3,5dinitrobenzoyl)-α-amino acids in the presence of two equivalents of CSA 4 are summarized in Table 1. As shown

Synthesis of Functionalized Chiral Phosphines and Chlorothiophosphonates

N-alkyl-2/4-aminocycloiminium salts of pyridine on reaction with dichlorophenyl-phosphine in the presence of triethylamine generated a novel series of tricoordinated chiral halophosphines, which, through its asymmetric phosphorus atom, induced diastereotopicity in the geminal N-methylene group. Halophosphines have been synthesized as a key precursor, which, in situ converted to stable tetracoordinated phosphorus by oxidation with elemental sulfur to obtain a new series of synthon compounds with an active chlorine atom. Chlorothiophosphonates have also exhibited a similar chemical-shift nonequivalence of geminal protons of NCH 2 . These compounds have been used for generation of variety of chiral bisamidothiophosphonates and investigated for insecticidal activity against Holotrichia consanguinea (whitegrub), which is an active pest of the crops of North India.

Observing the enantiomeric 1H chemical shift non-equivalence of several α-amino ester signals using tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]samarium(III): a chiral lanthanide shift reagent that causes minimal line broadening

The chiral lanthanide shift reagent, tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]samarium(III) [Sm(tfc) 3], was shown to resolve the 1H NMR signals of the enantiomers of α-amino esters without causing serious line broadening. This distinctive feature of Sm(tfc) 3 made it possible to examine the enantiomeric chemical shift non-equivalence of several protons in ester substrates, increasing the reliability of the empirical assignment of the absolute configuration as compared to earlier techniques.

Tryptophan chemical shift in peptides and proteins: a solid state carbon-13 nuclear magnetic resonance spectroscopic and quantum chemical investigation.

We have obtained the carbon-13 nuclear magnetic resonance spectra of a series of tryptophan-containing peptides and model systems, together with their X-ray crystallographic structures, and used quantum chemical methods to predict the (13)C NMR shifts (or shieldings) of all nonprotonated aromatic carbons (C(gamma), C(delta 2) and C(epsilon 2). Overall, there is generally good accord between theory and experiment. The chemical shifts of Trp C(gamma) in several proteins, hen egg white lysozyme, horse myoglobin, horse heart cytochrome c, and four carbonmonoxyhemoglobins, are also well predicted. The overall Trp C(gamma) shift range seen in the peptides and proteins is 11.4 ppm, and individual shifts (or shieldings) are predicted with an rms error of approximately 1.4 ppm (R value = 0.86). Unlike C(alpha) and N(H) chemical shifts, which are primarily a function of the backbone phi,psi torsion angles, the Trp C(gamma) shifts are shown to be correlated with the side-chain torsion angles chi(1) and chi(2) and appear to arise, at least in part, from gamma-gauche interactions with the backbone C' and N(H) atoms. This work helps solve the problem of the chemical shift nonequivalences of nonprotonated aromatic carbons in proteins first identified over 30 years ago and opens up the possibility of using aromatic carbon chemical shift information in structure determination.

Chiral resolution of diphenylalanine by high-performance liquid chromatography on a crown-ether-based chiral stationary phase and by NMR spectroscopy

The enantiomers of diphenylalanine (DPA) were well separated by chiral HPLC and NMR spectroscopy on the chiral stationary phase (CSP) derived from (18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA). The chromatographic parameters such as separation factors and retention times were greatly influenced by the mobile phase conditions. The (+)-18-C-6-TA used in the CSP was also employed as a chiral solvating agent for the enantiodiscrimination of the DPA enantiomers by NMR spectroscopy. The proton of the DPA analyte showing the chemical shift nonequivalences was used in determining the enantiomeric composition of the analyte.

An NMR Study of Chiral Recognition Relevant to the Liquid Chromatographic Separation of Enantiomers by a Cellulose Derivative

Abstract Chiral discrimination of enantiomers by cellulose tris(4-trimethylsilylphenylcarbamate) (CTSP) was studied by 1H NMR spectroscopy. The 1H NMR signals of trans-stilbene oxide and 2-butanol were enantiomerically separated into two sets of peaks in the presence of CTSP in CDCl3. The competition experiment with acetone suggests that trans-stilbene oxide may be adsorbed on the NH proton of carbamate residues of CTSP. Chemical shift non-equivalence in enantiotopic methyl groups of 2-propanol was observed in the presence of CTSP.

Correlation of fluorine-19 chemical shielding and chemical shift nonequivalence

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCorrelation of fluorine-19 chemical shielding and chemical shift nonequivalenceJoseph D. Augspurger and Clifford E. DykstraCite this: J. Am. Chem. Soc. 1993, 115, 25, 12016–12019Publication Date (Print):December 1, 1993Publication History Published online1 May 2002Published inissue 1 December 1993https://doi.org/10.1021/ja00078a045RIGHTS & PERMISSIONSArticle Views91Altmetric-Citations17LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (459 KB) Get e-Alerts Get e-Alerts

CHEMICAL SHIFT NON-EQUIVALENCE IN THE NMR SPECTROSCOPY OF DIALKYLα-HYDROXYBENZYL-AND DIALKYLα-METHOXYBENZYLPHOSPHONATES AND THE CRYSTAL STRUCTURE OF DIMETHYLα-CHLOROMETHYL-αHYDROXYBENZYLPHOSPHONATE

Abstract Single crystal X-ray diffraction of dimethyl α-chloromethyl-α-hydroxybenzylphosphonate shows the compound to exist as hydrogen-bonded dimers in the solid state. In solution, 1H and 13C nmr spectroscopy reveal chemical shift non-equivalence of the corresponding nuclei in the two alkoxy groups of dialkyl α-hydroxybenzyl-and dialkyl α-methoxybenzylphosphonates, an effect that is attributed primarily to the presence of the chiral α-carbon atom, although restriction of rotation about the P—C α bond by intermolecular hydrogen-bonding may also be a factor in the α-hydroxy compounds. Chemical shift non-equivalence of the α-halogenomethyl protons in dimethyl α-halogenomethyl-α-hydroxyben-zylphosphonates is significantly greater for the chloro-than for the bromo-compound.

Recognition of enantiomers by Chirasil-Val and oligopeptide analogues as studied by gas-phase calorimetry and 1H NMR spectroscopy in solution

A series of oligopeptides, l-Val n -NH t Bu ( n = 1–4), were linked to poly(β-methyl)siloxy-α-methylpropanoic acid copolymer; the resulting chirally modified polydimethylsiloxanes were used for the resolution of enantiomers by gas chromatography. Chiral recognition proved most effective for n = 1 (known as Chirasil-Val), as judged from the resolution factors (α) and the thermodynamic parameters ΔΔ H, ΔΔ S and x = ΔΔ H/Δ H′, where Δ H′= Δ H Chir-Δ H SE30· Likewise, 1H NMR spectroscopy in carbon tetrachloride solution revealed a maximum chemical shift non-equivalence of the amide N-H signal of racemic N-TFA-amino acid methyl esters on addition of the chiral polymer, for n = 1. From circular dichroism spectroscopy of l-Val n ,-NH t Bu ( n = 2, 3, 4 and 6) and polyoxyethylene-bound pivaloyl- l-Val n -Gly-NH-POE 3000 ( n = 2–8), it is concluded that the peptide moiety of the stationary phase mostly adopts the unfavourable random coil conformation, whereas the β-sheet structure was only partially found and only for n⪖6.

Chemical Shift Nonequivalence of Enantiomers of Amino Acid Derivatives in 1H NMR and 19F NMR Spectroscopy Induced by L-Chirasil- Val.

Enantiomers of N-trifluoroacetyl-amino acid methyl esters in CC14 solution, after addition of the chiral polysiloxane (L)-Chirasil-Val, display a chemical shift nonequivalence ΔΔδ in both 1H NMR and 19F NMR spectroscopy. The effects found for the leucine and valine derivatives can be correlated with the thermodynamic parameters of interaction in the undiluted system, as determined by gas chromatography. In CDC13 solution, no peak splitting was observed. The method is potentially useful for the determination of the enantiomeric purity of substrates of low volatility.