Acyloxonium Ion Research Articles

Origins of Temperature-Dependent Anomeric Selectivity in Glycosylations with an L-Idose Thioglycoside.

L-Idose thioglycosides are useful glycosyl donors for the construction of glycosaminoglycan oligosaccharides. When activated with NIS and catalytic TMSOTf in the presence of methanol, the stereoselectivity of O-glycosylation displays an intriguing dependence on the reaction temperature, with an increased preference for formation of the α-glycoside at higher temperatures. Using a combination of vt-NMR spectroscopy and DFT calculations, we show how a simple mechanistic model, based on competing reactions of the iodinated thioglycoside, can explain the main features of the temperature dependence. In this model, the increased selectivity at high temperature is attributed to differences among the entropy and energy terms of the competing reaction pathways. Neighbouring-group participation (giving an intermediate acyloxonium ion) plays an increasingly dominant role as temperature is raised. The general features of this kinetic regime may also apply more broadly to other glycosylations that likewise favour α-glycoside formation at high temperature.

Effects of Endogenous Antioxidants in Camellia Oil on the Formation of 2-Monochloropropane-1, 3-diol Esters and 3-Monochloropropane-1,2-diol Esters during Thermal Processing.

2-Monochloropropane-1, 3-diol (2-MCPD) esters and 3-monochloropropane-1,2-diol (3-MCPD) esters, a class of substances potentially harmful to human health, are usually formed during the refining of vegetable oils under high temperature. The effects of endogenous antioxidants in vegetable oils on the formation of 2- and 3-MCPD esters is still unknown. In this study, the effects of endogenous antioxidants (α-tocopherol, stigmasterol and squalene) on the formation of 2- and 3-MCPD esters in model thermal processing of camellia oil were investigated. The possible formation mechanism of 2- and 3-MCPD esters was also studied through the monitoring of acyloxonium ions, the intermediate ions of 2- and 3-MCPD esters formation, and free radicals by employing infrared spectra and electron paramagnetic resonance (EPR), respectively. The results indicated that the addition of α-tocopherol had either promoting or inhibiting effects on the formation of 2- and 3-MCPD esters, depending on the amount added. Stigmasterol inhibited the formation of 3-MCPD ester and 2-MCPD ester at low concentrations, while promoting their formation at high concentrations. Squalene exhibited a promotional effect on the formation of 3-MCPD ester and 2-MCPD ester, with an increased promotion effect as the amount of squalene added increased. The EPR results suggested that CCl3•, Lipid alkoxyl, N3• and SO3• formed during the processing of camellia oil, which may further mediate the formation of chlorpropanol esters. This study also inferred that squalene promotes the participation of the free radical in chlorpropanol ester formation.

Pummerer Cyclization Revisited: Unraveling of Acyl Oxonium Ion and Vinyl Sulfide Pathways.

Two viable pathways (vinyl sulfide and acyl oxonium ion) for the Pummerer cyclization have been unraveled that expand the reaction scope and capabilities. Use of Brønsted- enhanced Lewis acidity was key to realization of the vinyl sulfide pathway, whereas selective complexation of the sulfur lone pair facilitated the unprecedented acyl oxonium ion pathway. Preliminary mechanistic investigations support these hypotheses. A range of substrates have been explored to understand the reaction parameters.

Glycosylations of Simple Acceptors with 2‐O‐Acyl l‐Idose or l‐Iduronic Acid Donors Reveal Only a Minor Role for Neighbouring‐Group Participation

Several l‐idose and l‐iduronic acid glycosyl donors (mostly thioglycosides but also halides and trichloroacetimidates) with acyl protecting groups at the C‐2 position were prepared and evaluated in glycosylation reactions with simple acceptors. In glycosaminoglycan oligosaccharide syntheses in the literature, the presence of C‐2 acyl protecting groups in l‐ido‐configured glycosyl donors generally results in exclusive formation of 1,2‐trans glycosidic linkages, a finding that has typically been attributed to neighbouring‐group participation. However, glycosylations of simple alcohols with l‐ido‐configured donors (particularly thioglycosides), reported here, generally displayed incomplete stereocontrol and gave mixtures of the 1,2‐trans and 1,2‐cis products, suggesting that neighbouring‐group participation has lesser importance in these reactions. Glycosyl donors and reaction conditions were identified that gave improved, but not exclusive, selectivity for the desired α‐l‐anomer (1,2‐trans) as the major product. Interestingly, glycosylations under the same reaction conditions with more complex monosaccharide acceptors gave exclusively the expected 1,2‐trans products. The role of neighbouring‐group participation in these glycosylations was explored with density functional theory (DFT) calculations, which revealed that the non‐stereoselective addition of the acceptor alcohol to the intermediate oxocarbenium ion is competitive with the stereospecific addition of the acceptor to the acyloxonium ion intermediate.

Formation of Glycidyl Fatty Acid Esters Both in Real Edible Oils during Laboratory-Scale Refining and in Chemical Model during High Temperature Exposure

In the present study, the formation mechanisms of glycidyl fatty acid esters (GEs) were investigated both in real edible oils (soybean oil, camellia oil, and palm oil) during laboratory-scale preparation and refining and in chemical model (1,2-dipalmitin (DPG) and 1-monopalmitin (MPG)) during high temperature exposure (160-260 °C under nitrogen). The formation process of GEs in the chemical model was monitored using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy. The results showed that the roasting and pressing process could produce certain amounts of GEs that were much lower than that produced in the deodorization process. GE contents in edible oils increased continuously and significantly with increasing deodorization time below 200 °C. However, when the temperature exceeded 200 °C, GE contents sharply increased in 1-2 h followed by a gradual decrease, which could verify a simultaneous formation and degradation of GEs at high temperature. In addition, it was also found that the presence of acylglycerol (DAGs and MAGs) could significantly increase the formation yield of GEs both in real edible oils and in chemical model. Compared with DAGs, moreover, MAGs displayed a higher formation capacity but substantially lower contribution to GE formation due to their low contents in edible oils. In situ ATR-FTIR spectroscopic evidence showed that cyclic acyloxonium ion intermediate was formed during GE formation derived from DPG and MPG in chemical model heated at 200 °C.

Characterization of Electron Ionization Mass Spectral (EIMS) Fragmentation Patterns of Chloropropanol Esters of Palmitic Acid Using Isotope Labeling Technique

Chloropropanol (CP) esters are a class of thermally-induced toxicants that are mainly formed in refined edible oils. The structural diversity of these esters presents significant analytical challenges which have often been overcome through analysis of their corresponding free alcohols after a hydrolysis step. Mass spectrometry-based methodologies incorporating characteristic fragmentation patterns of particular isomers of CP esters greatly facilitates their identification. The electron ionization mass spectra (EIMS) of various isomers of synthetic and commercially available (13)C- and (2)H-labeled CP ester standards of palmitic (C16) and other short chain fatty acids (C3 to C10) were generated and analyzed using GC/MS. Short chain CP esters were synthesized by reacting their respective acid anhydrides with the corresponding 3-chloro- and 2-chloro- propanediols in addition to 1,3-dichloro- and 1,2-dichloropropanols. Five fragmentation pathways were identified. Four of the five pathways, such as α-cleavage, McLafferty rearrangement, α-H rearrangement and cyclic acyloxonium ion formation, were characteristic of CP mono- and diesters. The remaining pathway generating chloronium ion was found only in dichlorinated isomers. The proposed fragmentation pathways for the palmitic acid esters were confirmed through the use of (13)C- and (2)H-labeled CP ester standards of palmitic acid, and the generality of identified fragmentation patterns was confirmed through the identification of equivalent ions in the mass spectra of short chain fatty acids (C3 to C16). Characteristic ions that were identified in this study retaining the chlorine atom in their structures can be considered as potential markers for the presence of CP esters.

Isotope Labeling Studies on the Electron Impact Mass Spectral Fragmentation Patterns of Chloropropanol Acetates

Chloropropanol (CP) esters are part of an emerging group of process-induced toxicants that are considered as potential health hazards particularly in palm oil. Mass spectrometry-based methodologies for identification of CP esters in food are critical in overcoming the challenges associated with direct detection methods. In the present study, a convenient strategy was employed to generate all possible CP acetates through reacting acetic anhydride with either glycerol in the presence of a chloride source or the corresponding CPs, such as 3-chloro-, 1,3-dichloro-, 2-chloro-, and 1,2-dichloropropanols, allowing for the identification of the individual CP acetates and assignment of their mass spectral fragmentations. Mass spectral fragmentations were confirmed through the use of the isotopic signature of chlorine in addition to the isotope labeling experiments performed using isotopically labeled precursors, such as [¹³C-U₃] glycerol, [¹³C-U₄] acetic anhydride, [¹³C-2,2'] acetic anhydride, and [d₅] 3-monochloropropane-1,2-diol (3-MCPD) as reactants. Such studies have indicated that all CP esters can undergo two general fragmentations under electron impact (EI) conditions, one generating the acylium ion at m/z 45 and the other generating a chlorinated cyclic acyloxonium ion at m/z 135.6. Considering the fact that such ions can also be generated from any fatty acid containing CP esters after undergoing McLafferty rearrangement, the ion at m/z 135.6 can therefore be considered as a universal marker for the presence of CP esters undergoing EI fragmentation. Furthermore, these studies have also indicated the formation of ions characteristic of CP diesters, monoesters, and dichloro esters.

Cyclic Acyloxonium Ions as Diagnostic Aids in the Characterization of Chloropropanol Esters under Electron Impact (EI), Electrospray Ionization (ESI), and Atmospheric Pressure Chemical Ionization (APCI) Conditions

During mass spectrometric analysis of various lipids and lipid derivatives such as the chlorinated counterparts of triacylglycerols, the detailed structure of the characteristic and common ions formed under electron impact (EI), electrospray ionization (ESI), and atmospheric pressure chemical ionization (APCI) conditions by the loss of a single fatty acid remains ambiguous. These ions are designated in the literature as "diacylglyceride ions" and are frequently depicted with a molecular formula without showing any structural features and sometimes represented as cyclic acyloxonium ions. Characterization of these ions is of considerable importance due to their utility in structural identification of lipid derivatives. This study provides complementary evidence on the cyclic nature of "diacylglyceride ions" through the use of the simplest 3-monochloropropanediol diester as a model and the use of isotope labeling technique. Tandem MS/MS studies have indicated that the ion at m/z 135.6 generated from 1,2-bis(acetoyl)-3-chloropropane through the loss of an acetyl group was identical to the ion at m/z 135.6 generated from 4-chloromethyl-2,2-dimethyl-1,3-dioxolane, the latter being generated from a cyclic precursor through the loss of a methyl radical, keeping the dioxolane ring structure intact, thus confirming the cyclic nature of these ions. The corresponding cyclic oxonium ions generated from longer chain chloropropanol diesters, such as the ion at m/z 331.2 originating from 3-monochloropropanediol (3-MCPD) diesters containing palmitic acid(s), could serve as chemical markers for the presence chloropropanol esters.

Formation mechanisms of Monochloropropanediol (MCPD) fatty acid diesters in refined palm (Elaeis guineensis) oil and related fractions

Monochloropropanediol (MCPD) fatty acid esters are process contaminants generated during the deodorisation of edible oils. In particular, MCPD diesters are found in higher abundance in refined palm oil than other edible oils. In the present study, a series of model reactions mimicking palm oil deodorisation has been conducted with pure acylglycerols in the presence or absence of either organic or inorganic chlorine-containing compounds. Results showed that the bulk of MCPD diesters are formed above 200°C through the reaction of organochlorines with triacylglycerols (TAG). Additional experiments confirmed that this reaction can be initiated during palm oil deodorisation by hydrogen chloride (HCl) gas evolved through the thermal degradation of organochlorines present in the oil. Therein, the majority of the ultimately produced MCPD diesters are the result of HCl reacting with TAG, via protonation, followed by the elimination of a fatty acid residue. Two possible MCPD diester formation mechanisms are highlighted, both of which involve acyloxonium ion reactive intermediates. Investigations with pure TAG regio-isomers showed that MCPD ester formation is regioselective and the sn-1(3) position of the glycerol backbone is favoured.

Monitoring cyclic acyloxonium ion formation in palmitin systems using infrared spectroscopy and isotope labelling technique

AbstractTo confirm the possible involvement of acyloxonium ions as reactive intermediates in food related lipids, their formation was monitored in triplamitin, 1,2 dipalmitin, 1‐monopalmitin and specifically labelled tripalmitin (1,1,1‐13C3) using Fourier‐transform IR spectroscopy (FTIR). Reactions were conducted at 100°C using a mixture of ZnCl2 and the lipids. When tripalmitin or 1,2‐dipalmitin samples were heated at 100°C in the presence of ZnCl2 a new band centred at 1651 cm−1 was formed and increased over time. When 13C‐labelled tripalmitin (1,1,1‐13C3) was studied the spectrum exhibited an expected 40 cm−1 shift from 1651 to 1611cm−1 indicating the involvement of the carbonyl carbon in the formation of the band. The 1‐monopalmitin generated a similar but weaker band at higher temperatures and requiring longer times. These observations may indicate that under hydrophobic environment acyloxonium ions are preferentially formed with neighbouring ester groups assisted by the catalytic action of a free hydroxyl group serving as a proton transfer site. In the absence of such a free hydroxyl group tripalmitin undergoes acyloxonium ion formation at a slower rate than 1,2‐dipalmitoyl glycerol, whereas, 1‐monopalmitoyl glycerol due to the absence of a neighbouring ester shows even slower transformation efficiencies. This order of reactivity may however change in the presence of water.

What do we know about the molecular mechanism of 3‐MCPD ester formation?

AbstractThe 3‐monochloropropane‐1,2‐diol (3‐MCPD) esters belong to a group of well known process‐induced contaminants derived from mono‐ and di‐chlorinated glycerols. The 3‐MCPD was first identified in 1978 in acid‐hydrolysed vegetable proteins and its corresponding esters in 1980 and since their discovery almost 30 years later the exact mechanism of their formation is still unknown. The recent renewed interest in their formation mechanism can be attributed to the realization that the ester content in real food systems often exceeds that of free 3‐MCPD content by many orders of magnitude. Presently, there are four proposed mechanisms all involving SN2 nucleophilic attack by chloride ions but differing from each other based on either the nature of the substrate or the leaving group. Two of the proposed mechanisms involve direct nucleophilic attack by the chloride ion at the glycerol carbon atoms carrying either an ester group or a protonated hydroxyl group. The other two pathways propose the formation of reactive intermediates such as acyloxonium ion or an epoxide ring in the form of glycidol prior to the nucleophilic attack by chloride ions.

Studies on the origin of stereoselectivity in the synthesis of 1,2-trans glycofuranosyl azides

The stereoselectivity of the 1,2-trans directed, Lewis acid-catalysed azidation of peracylated furanoses was found to depend on the reactivity of the azide donor (azide nucleophilicity) and the configuration at the anomeric centre relative to the neighbouring 2- O-acyl group. Reactions of 1,2-trans glycosyl esters with highly nucleophilic azide donors, generated from SnCl 4 and Me 3SiN 3, were stereospecific. The results are interpreted in terms of the rapid reaction of the azide species with bicyclic 1,2-acyloxonium (1,2- O-alkyliumdiyl- d-glycofuranose) ions, which were the primarily formed reactive intermediates. When using 1,2-cis glycosyl esters as starting materials the selectivity was reduced (90–94% de); the same is true with 1,2-trans counterparts if less nucleophilic Me 3SiN 3 in combination with Me 3SiOTf catalyst was used. This occurred due to the appearance of the more reactive but less selective oxocarbenium (glycofuranoxonium) ions either as primarily formed reactive intermediates in the former case or after equilibration with acyloxonium ions in the latter case. Protected 1,2-trans β- d-glycofuranosyl azides with ribo, xylo and 3-deoxy-erythro-pento configurations were best prepared from the corresponding glycosyl esters using 0.05 equivalents of SnCl 4, i.e., under anomerization-free conditions. Azidation of methyl glycofuranosides proceeds with inferior (80–90% de) and less predictable selectivity irrespective of the starting anomeric configuration.

Acyloxonium ions in the high-yielding synthesis of oxolanes from alditols, hexoses, and hexonolactones catalysed by car☐ylic acids in anhydrous hydrogen fluoride

Treatment of d-glucono-1,5- or d-mannono-1,4-lactone with anhydrous hydrogen fluoride catalysed by formic or acetic acid yields 3,6-anhydro- d-glucono- and - d-mannono-1,4-lactone, respectively. Similarly, d-mannitol is converted into 1,4-anhydro- d-mannitol and subsequently into the 1,4:3,6-dianhydride, whereas d-glucitol forms exclusively the 3,6-anhydride and, on further reaction, 1,4:3,6-dianhydro- d-glucitol. d-Glucose and 2-acetamido-2-deoxy- d-glucose are also converted into the corresponding 3,6-anhydrides by reaction with hydrogen fluoride and formic acid. 13C-N.m.r. spectroscopy indicates that the reactions involve intermediate dioxolanylium ions.

Equilibration of alditol anhydrides in acetic acid

Dehydration of pentitols in acetic acid containing an acidic catalyst parallels that in aqueous sulfuric acid; 1,4(2,5)-dehydration occurs with inversion of configuration at C-2 or C-4. Acetylated alditols undergo similar processes via intermediates having free hydroxyl groups. Configurational inversion of 1,4- or 1,5-anhydroalditols is attributed to intermediate acyloxonium ions that are also proposed as intermediates in the structural isomerisation. Drastic treatment of each alditol gives equilibrium mixtures. The equilibrium concentrations are used to calculate free-energy differences.

Competition of two participating groups in hypobromous acid addition to some 4-cholestene derivatives

Hypobromous acid addition to the 4,5-unsaturated hydroxy acetate VIII results in formation of the cyclic bromo ether XXIXa as a product of 5(O)n participation. Participation by hydroxy group is thus preferred over 5(O)π,n process by acetoxyl. Under the same conditions the 4,5-unsaturated diacetate IX afforded the diaxial bromohydrin XXXI arising from 4α,5α-bromonium ion with 5(O)π,n participation by the 3β-acetoxyl whereas an alternative 6(O)π,n participation by the 19-acetoxyl is not operative. The 3-epimeric diacetate XV reacts with hypobromous acid in a more complex way: the molecule is attacked by the electrophile from both α- and β-sites to give two diastereoisomeric bromonium ions XXXII and XXXIII. The former is simply cleaved with water as an external nucleophile to afford the diaxial bromohydrin XXXIV. The latter undergoes fission both with 5(O)π,n and 6(O)π,n participation: The first route leads to the trans-bromohydrin XXXVI. In the second pathway the acyloxonium ion XXXVII postulated as an intermediate is further cleaved with 6(O)π,n participation by 19-acetoxyl to give the acyloxonium ion XXXVIII, which is trapped by water to yield an unusual cis-bromohydrin XXXIX. The differences in the reaction course are discussed.

Ribosidierung von Pyrrolo[2,3‐d]pyrimidinen in Gegenwart starker Basen

Ribosidation of Pyrrolo[2,3‐d]pyrimidines in the Presence of Strong BasesGlycosidation of the pyrrolo[2,3‐d]pyrimidine derivative 3c with the tribenzylated halogenose 6b in strong alkaline medium under the conditions of phase transfer catalysis yields the anomers 9a and 10a. The latter are intermediates in the synthesis of the nucleoside Q as well as for preparation of 7‐methyl‐7‐deazanucleosides. By condensation of the 4‐chloro derivative 3a with the tribenzoylated halogenose 4b and sodium hydride, substitution at the carbon of the acyloxonium ion takes place and a reaction product with orthoamide structure is formed.

Ether cleavage of isomeric 2,3‐(dimethoxycarbonyl)‐7‐oxabicyclo[2.2.1]heptanes

AbstractThe ether cleavage of the three isomeric 2,3‐(dimethoxycarbonyl)‐7‐oxabicyclo[2.2.1]‐heptanes with acetic anhydride under influence of BF3 etherate or FeCl3 has been studied. A complex mixture of products was obtained, resulting from elimination, migration and substitution reactions. The results are interpreted in terms of reactions occurring via an acyloxonium ion and not via a ringopened carbenium ion intermediate.

Transformations of carboxonium compounds in carbohydrate and polyol chemistry

Abstract

Molecular orbital calculations relating to the mechanism of the reactions of sugar orthoesters: 1,2,4-orthoacetyl-α-D-xylopyranose

Quantum chemical studies of 1,2,4-orthoacetyl-α-D-xylopyranose and three protonated forms, four acyloxonium ions, and the glycosyl cation by means of the MINDO/2 method are reported. The protonated forms (oxonium ions) should not be considered as product-determining intermediates in acid-catalysed reactions of ortho-esters due to their fast rearrangement into isomeric acyloxonium ions. Of the latter, only 1,2- and 1,4-acyloxoniums, adopting a conformation close to that of starting orthoester (i.e. a distorted boat), were found to be relatively stable and reactive and so are considered to be the main product-determining intermediates. The distribution of the positive charge in these ions was interpreted as evidence of preferred nucleophilic attack on C-1 rather than on other centres of these ions. The isomerisation of the 1,2-acyloxonium ion into the glycosyl cation was found to be energetically very unlikely and so would be product determining only in fast, especially intramolecular, reactions. The results obtained were in good agreement with qualitative data on the chemistry of sugar orthoesters.

The acetolysis and benzolysis of some carbohydrate oxirans

A cyclic acyloxonium ion is formed as an intermediate when a carbohydrate oxiran bearing a vicinal trans-acyloxy-group is heated in acetic acid. In the presence of water the cyclic ion yields a cis-monoester. Under anhydrous conditions, using acetic acid or molten benzoic acid as solvent, three products are generally formed, corresponding to nucleophilic attack at each of the three carbon atoms of the cyclic ion. Possible mechanisms are discussed in the light of other published work on the properties of acyloxonium ions derived from polyols.