Amino alcohol based chiral solvating agents: synthesis and applications in the NMR enantiodiscrimination of carboxylic acids

Four optically active amino alcohols were synthesized via the ring opening of (R)-N-(2,3-epoxypropyl)phthalimide with (R)-2-phenyl glycinol, (1R,2S)-cis-1-amino-2-indanol, (R)-2-amino-1-butanol and (S)-phenyl ethylamine in 73-93% yields. The enantioselective recognition of these receptors towards the enantiomers of racemic carboxylic acids was studied by ¹H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of the guests were determined by using Job plots and a non-linear least-squares fitting method, respectively. Large non-equivalent chemical shifts (up to 30.0 Hz) can be achieved in the presence of chiral amino alcohols 2 and 5. Amongst the chiral receptors used, compound 5 was found to be the best chiral shift reagent, and was effective in the determination of the enantiomeric excess of chiral carboxylic acids.     

New chiral solvating agents for carboxylic acids: discrimination of enantiotopic nuclei and binding properties

New chiral hosts for carboxylic acids have been synthesized and their capacity for discrimination of enantiotopic nuclei explored by NMR. In addition, binding properties were examined by ¹H NMR titration experiments and molecular mechanics calculations.     

C-hexaphenyl-substituted trianglamine as a chiral solvating agent for carboxylic acids

Chiral hexaazamacrocycles with a trianglamine structure and C(3)-symmetry, containing six ring substituents and twelve stereocenters have been tested as chiral solvating agents (CSAs) for α-substituted carboxylic acids. Excellent results have been obtained with a hexaphenyl-substituted macrocycle. The optimal ratio between the macrocycle and racemic acid, allowing for baseline separation of the enantiomers' signals in the (1)H NMR spectrum, was dependent on the type of acid, in particular on its degree of acidity. The analyte and the CSA could be separated and recovered by a simple acid-base extraction and reused without purification. The conformations of the free and protonated hexaamino macrocycles were inferred by CD spectroscopic studies and DFT calculations.     

Chiral ionic liquids based on nicotine for the chiral recognition of carboxylic acids

The synthesis of enantiopure ionic liquids based on (?)-nicotine is discussed. The desired compounds were prepared in good yields from (?)-nicotine via quaternization of the pyridine ring of (?)-nicotine with MeI and EtBr. After anion metathesis the ionic liquids were investigated as chiral solvating agents and showed a splitting of the signals of Mosher’s acid and mandelic acid in the ¹H and ¹⁹F NMR spectra. In addition to aprotic solvents it was also possible to use methanol in the experiments.     

New chiral auxiliaries derived from (S)-α-phenylethylamine as chiral solvating agents for carboxylic acids

The two new diastereoisomeric chiral auxiliaries 1a and 1b were synthesized conveniently and effectively. ¹H NMR was employed to investigate their chiral recognition ability. Compared with (S)-PEA, these new chiral auxiliaries exhibited better enantioselectivity towards the carboxylic acids we had chosen.     

An azamacrocyclic receptor as efficient polytopic chiral solvating agent for carboxylic acids

The efficient use of a polyazamacrocycle as chiral solvating agent (CSA) for the determination of the enantiomeric excess of different carboxylic acids has been studied. All the data agree with the formation of multimolecular diastereomeric complexes in solution, which render good splitting of the NMR signals for the enantiomers of the acids (up to ΔΔδ = 0.20 ppm) using a small amount (even 0.125 equiv) of the receptor.     

Chiral bis(amino amides) as chiral solvating agents for enantiomeric excess determination of α-hydroxy and arylpropionic acids

A family of bis(amino amides) derived from natural amino acids has been synthesized and tested for the NMR enantiodiscrimination, as chiral solvating agents, for enantiomeric excess determination of some carboxylic acids. Those bis(amino amide) receptors contain different structural modifications and the splitting of the signals of the acids, after addition of the corresponding CSAs, depends on those structural variables. The influence of aminoacid side chain and the nature of the aliphatic spacer are important parameters to obtain good chiral discriminations. The results obtained clearly show the chiral recognition abilities of these bis(amino amide) ligands and suggest their advantageous use as chiral solvating agents for carboxylic acids. The binding between bis(amino amides) and carboxylic acids has been studied by ESI-MS, NMR, DSC, and molecular modeling. The data suggest that enantiodiscrimination involves the formation of an ionic pair after proton transfer from the carboxylic substrate to the bis(amino amides).     

Amphiphilic chiral receptor as efficient chiral solvating agent for both lipophilic and hydrophilic carboxylic acids

Two amphiphilic chiral receptors 2a and 2b were designed and synthesized. Both are efficient chiral solvating agents for chiral carboxylic acids. In particular, 2a is an excellent CSA not only for lipophilic guests, but also for some hydrophilic guests. It is the first CSA for the direct determination of the enantiomeric composition of hydrophilic chiral hydroxylated acid in protic polar solvent.     

Cycloalkane-1,2-diamine derivatives as chiral solvating agents. Study of the structural variables controlling the NMR enantiodiscrimination of chiral carboxylic acids

A family of pincer-like receptors (2-5) has been synthesized and tested for the NMR enantiodiscrimination (CSA) of chiral carboxylic acids. Starting from a previous design (1), different structural variables have been mapped on the receptor frame. The splitting of the signals of the acids upon the addition of the CSAs largely depends on these structural variables. Thus, we concluded that the C₂ symmetrical pyridine-2,6-biscarboxamide moiety is a key structural feature for the efficiency of the CSA. Structural studies by NMR and molecular modeling showed that this moiety promotes the U-shape-folded pincer-like conformation by intramolecular H-bonds. On the other hand, we also observed that the cyclohexane-1,2-diamine derivative 5 is a more versatile CSA than its cyclopentane analogue 1, as 5 shows a better performance for more structurally different acids. However, the original cyclopentane derivative (1) remained the best for the arylpropionic acids. Finally, combination of NMR and modeling studies allowed us to propose a reasonable model for the interaction and, accordingly, for the observed NMR enantiodiscrimination.     

Novel NMR chiral solvating agents derived from (1R,2R)-diaminocyclohexane: synthesis and enantiodiscrimination for chiral carboxylic acids

A series of new compounds, (1R,2R)-1-(1′,8′-naphthalimide)-2-aminocyclohexane 1 and its 4′-derivatives 2 and 3 derived from (1R,2R)-1,2-diaminocyclohexane have been synthesized conveniently and efficiently. ¹H NMR spectroscopy was employed to investigate their enantiodiscriminating ability. Compared with α-phenylethylamine, a commercially available chiral solvating agent (CSA), these compounds exhibited better enantiodiscriminating ability toward the chiral carboxylic acids we had chosen, distinguishing them as promising and practical CSAs.     

Extraction of aromatic carboxylic acids and phenols by strongly solvating organophosphorus compounds and sulfoxides

Summary This paper contains a systematic comparison of the extracting power and selectivity of tri-n-butylphosphate (TBP), di-n-octylsulfoxide (DOSO) and tri-n-octylphosphinoxide (TOPO) in the extraction of aromatic carboxylic acids and phenols from aqueous perchloric acid solutions of varying pH. Organophosphorus compounds and sulfoxides form hydrogen bonds to proton-donating molecules. This rather specific interaction can be used for solvent extraction of acidic compounds or for Chromatographic separations. A simple model describes the influence of the main experimental parameters on the liquid-liquid distribution behaviour.The most interesting Chromatographic phase systems for the separation of acidic compounds by column liquid chromatography are liquid-liquid systems which contain a strongly solvating reagent in the liquid stationary phase and liquid-solid systems with strongly solvating compounds adsorbed on the hydrophobic adsorbent surface.

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Extraktion aromatischer Carbonsäuren und Phenole mit stark solvatisierenden Organophosphorverbindungen und Sulfoxiden

Zusammenfassung Das Extraktionsvermögen und die Selektivität von Tri-n-butylphosphat (TBP), Di-n-oktylsulfoxid (DOSO) und Tri-n-oktylphosphinoxid (TOPO) gegenüber aromatischen Carboxylsäuren und Phenolen aus wäßrigen perchlorsauren Lösungen mit verschiedenen pH-Werten wurde systematisch verglichen. Organophosphorverbindungen und Sulfoxide bilden zu Molekülen, die Protonendonatoren sind, Wasserstoffbrückenbindungen aus. Diese ziemlich spezifische Wechselwirkung kann zur Lösungsmittelextraktion saurer Verbindungen oder bei chromatographischen Trennungen eingesetzt werden. Der Einfluß der wichtigsten Versuchsparameter auf das Flüssig-flüssig-Verteilungsverhalten läßt sich durch ein einfaches Modell beschreiben.-Die zur Trennung saurer Verbindungen durch Säulen-Flüssigkeits-Chromatographie interessantesten Phasensysteme sind Flüssig-flüssig-Phasensysteme, in denen die stationäre Flüssigkeit eine stark solvatisierende Verbindung enthält, sowie Flüssig-fest-Systeme, in denen stark solvatisierende Verbindungen an der Oberfläche eines hydrophoben Adsorbens adsorbiert sind.

     

Chiral amines as reagents for HPLC-MS enantioseparation of chiral carboxylic acids

Mass spectrometry (MS) has become a popular analytical technique because of its high sensitivity and specificity. Therefore, the use of a chiral derivatization reagent for the MS detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis is very limited. The applicability of commercially available chiral amines as the derivatization reagents for the enantiomeric separation of chiral carboxylic acids is reported in this paper by using non-steroidal anti-inflammatory drugs (NSAIDs), i.e. ibuprofen, flurbiprofen, and loxoprofen. The efficiency of the chiral reagents was evaluated in terms of tagging easiness, separation by reversed-phase chromatography, and detection sensitivity by electrospray ionization (ESI)-MS/MS. Among the tested eight chiral amines, i.e. (R)-(+)-4-(3-aminopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-APy), (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (PMP), L-prolinamide, (3R)-(-)-1-benzyl-3-aminopyrrolidine, (S)-(+)-1-cyclohexyl-ethylamine, (3R)-(+)-3-(trifluoroacetamido)-pyrrolidine (TFAP), (R)-(-)-1-aminoindan (AI), and (S)-(+)-tetrahydrofurfuryl-amine, DBD-APy, PMP, AI, and TFAP could be used as the chiral reagents for the enantiomeric separation of the NSAIDs. The Rs values and the detection limits of the derivatives were in the range of 1.29-3.85 and 0.57-0.96 fmol, respectively. These four reagents were applied for the determination of the NSAIDs in rat plasma.     

Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety

An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.     

Amphoteric ion-exchangers based on pyridine carboxylic acids

Conclusions Amphoteric ion-exchangers have been prepared by the reaction of styrene and divinylbenzene copolymers of conventional and macroporous structure with pyridine carboxylic acids.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya. No. lO, pp. 2366–2367,October, 1970.     

Na+ triggered fluorescence sensors for Mg2+ detection based on a coumarin salen moiety

Two coumarin salen-based sensors CS1 and CS2 can exhibit a pronounced fluorescence enhancement response toward Mg(2+) as high as 36-fold (CS1) and 111-fold (CS2) in the presence of Na(+) as a synergic trigger. More importantly, the fluorescent color of CS1 was bright green instead of weak yellow after the addition of Mg(2+) and Na(+) together, which can be easily detected by the naked eye.     

Chiral mono boronic acid as fluorescent enantioselective sensor for mono alpha-hydroxyl carboxylic acids

New mono boronic acid was found to be an enantioselective fluorescent chemosensor for mono alpha-hydroxyl carboxylic acids, such as mandelic acid and lactic acid. The chiral sensor shows lower background fluorescence, higher fluorescence enhancement, and enantioselective recognition kinetics toward mandelic acids and lactic acids.     

Friedel-Crafts acylation reaction using carboxylic acids as acylating agents

Dehydrative Friedel-Crafts acylation reaction of aromatic compounds with carboxylic acids as acylating agents was investigated in the presence of Lewis acid- or Brønsted acid-catalyst. Various metal triflates and bis(trifluoromethanesulfonyl)amides showed catalytic activity at high temperature, among which Eu(NTf₂)₃ proved to be the most effective and efficiently catalyzed the acylation reaction of alkyl- and alkoxybenzenes with aliphatic and aromatic carboxylic acids at 250 °C. Bi(NTf₂)₃ was more effective than Eu(NTf₂)₃ at lower temperature, but proved to be hydrolyzed in the presence of a small amount of water to give HNTf₂ and [Bi₆O₄(OH)₄(H₂O)₆](NTf₂)₆. The structure of the latter compound was confirmed by a single crystal X-ray analysis. Among five Brønsted acids, HOTf, HNTf₂, HCTf₃, TsOH, and Nafion^® SAC-13, HNTf₂ has proved to be the most efficient catalyst and more effective than Eu(NTf₂)₃ for the acylation of p-xylene with heptanoic acid at 220 °C or lower temperature. HNTf₂ catalyzed the acylation of anisole with carboxylic acids in high yields in refluxing toluene with azeotropic removal of water.     

Synthesis of various acylating agents directly from carboxylic acids

Abstract

A straightforward synthesis of acylating reagents such as Weinreb and MAP amides from aromatic, aliphatic carboxylic acids, and amino acids using PPh₃/NBS combination is described. A chemo-selective modification of the carboxylic acid group into Weinreb amide in the presence of more reactive aldehydes and ketones is presented. All reactions were performed at ambient temperature under air using undried commercial grade solvent. Furthermore, the present methodology could be performed at a gram scale under inert-free reaction conditions. In addition, 7-azaindoline amide auxiliary (used for catalytic asymmetric aldol- and Mannich-type reactions), which behaves like Weinreb amide is also synthesized under similar reaction conditions.     

Structurally simple, modular amino alcohols for the recognition of carboxylic acids. Application to the development of a new chiral solvating agent

[structure: see text] Two flexible receptors for carboxylic acids, based on 1-amino-3-fluoro-2-alcohol functional arrays and built on aminomethylpyridine platforms, are described. The C(2)-symmetric one [from 2,6-bis(aminomethyl)pyridine] has been shown to be an efficient CSA due to its ability to form geometrically different diastereomeric complexes enabling the discrimination between the enantiomers of a series of carboxylic acid in the (1)H NMR spectra.