William J. Spillane

Semi-quantitative and quantitative structure–taste relationships for carboand hetero-sulphamate (RNHSO3–) sweeteners

Seventeen carbosulphamates (eight synthesised in this study) and 23 heterosulphamates (seven synthesised here) have been examined with a view to extending previously developed1,2 structure–taste relationships for sulphamates (RNHSO3–). Measurements of defined parameters x, y, z, and V(V=xyz) for R using Corey–Pauling–Koltun space-filling models for the 17 carbosulphamates have shown that their taste can be predicted in most cases using the previously developed semi-QSAR established. Predictions made from a recent pattern-recognition method study of sulphamate taste are shown to be partially incorrect.The heterosulphamates were also examined using CPK models and first-order molecular connectivity (1xv) measurements. The use of linear discriminant analysis on seven subsets of the five variables measured i.e. x, y, z, V, and 1xv showed that the subset, x, z, 1xV misclassified only three of the 23 heterocompounds, i.e. the percentage misclassified was 13%.Mapping of the sulphamate receptor site on the basis of the measurements carried out suggests that the carbo- and hetero-sulphamates use different sites to bind. This present work brings the database of taste-assessed sulphamates reported to over 120 compounds.

Basicity of nitrogen–sulphur(VI) compounds. Part 6. Ionization of NN′-di-and N-mono-substituted sulphamides and dihydro-2,1,3-benzothiadiazoline and benzothiadiazine 2,2-dioxides (cyclic sulphamides)

36 Di- and mono- and two tri-substituted sulphamides have been synthesised and their ionization equilibria in base (Schemes 1–3) have been studied. Many of the sulphamides are new materials. The pKa values obtained for each series have been correlated in Hammett and Taft plots. The Hammett ρ values obtained for the ionization of the proximate hydrogen are ca. 2.3. The Taft ρ* value obtained for ionization of the ‘remoter’ hydrogen is 1.68. The six-membered cyclic sulphamides are more acidic than their acyclic analogues by ca. 2.5 pKa units and the five-membered cyclic sulphamides are ca. 4 pKa units more acidic than model open-chain counterparts. Sulphur d-orbital involvement and ring-strain are suggested as possible sources of this ‘acid-strengthening’ effect.

Correlation of computed van der Waals and molecular volumes with apparent molar volumes (AMV) for amino acid, carbohydrate and sulfamate tastant molecules. Relationship between Corey–Pauling–Koltun volumes (VCPK) and computed volumes

Good linear correlations have been found between apparent molar volumes (AMV, φV) and GEPOL-generated van der Waals (Vw), molecular (Vm) and accessible (Va) volumes for 17 amino acids, 22 carbohydrates and 16 sulfamates. For a larger group of 24 sulfamates Corey–Pauling–Koltun measured volumes (VCPK) gave good linear correlations with Vw(r= 0.925) and Vm(r= 0.935).For the monosaccharides L-arabinose, D-glucose, L-lyxose, D-mannose and D-xylose the computer volumes and areas are slightly greater for the β- than for the α-anomers. However, for some methylated sugars the reverse occurs.The use of ‘effective’ Bondi, rather than Pauling, van der Waals radii has little effect on the computed volumes and areas for the sulfamates. The effect, on the computed volumes and areas, of using a number of different sets of van der Waals radii has been examined for sucrose, glycine and cyclamate. The effect of increasing the probe (sphere) radius from 1.4 A to 2.0 A has been examined and it is found that the van der Waals and molecular volumes and the corresponding areas remain virtually unchanged, but the accessible volumes increase by ca. 31% and the accessible areas by ca. 22%.The GEPOL program generally gives van der Waals volumes in good agreement with those available in the literature.

Further studies on the synthesis and tastes of monosubstituted benzenesulfamates. A semi-quantitative structure–taste relationship for the meta-compounds

Abstract Twenty-two new sodium monosubstituted phenylsulfamates XC 6 H 4 NHSO 3 − Na + have been prepared and characterized. These compounds, and also para -tolyl- and phenylsulfamate, have been tasted and their taste properties reported. Taste data are now available for 63 such compounds: 19 ortho- , 23 meta - (including phenylsulfamate) and 21 para -. Using CPK molecular models, measurements of the aromatic portion XC 6 H 4 – have been made. Exclusive/predominant sweetness and reduced sweetness is mainly found with the meta -compounds and a plot derived from the CPK measurements correctly classifies 20 of the 23 (including X=H) meta -compounds into sweet and bitter categories, 12 of the 13 sweet compounds (92%) and 8 of the 10 bitter compounds (80%). Using the PC SPARTAN PRO molecular modelling program, HOMO and LUMO electronic parameters and aqueous solvation energy E solv were calculated. Linear (LDA) and quadratic (QDA) discriminant analyses were carried out on the 23 compounds using various subsets of the CPK measurements and the above SPARTAN-calculated parameters. A 91% classification rate was achieved using QDA and the subset with the parameters LUMO, E solv , and the CPK measurements, x (length) and z (width) of XC 6 H 4 –. Apparently, for sweetness, the CPK measurement x of XC 6 H 4 – needs to be in the range ∼5.65⩽ x ⩽∼5.95 A. Using several of the methods developed, taste predictions were made on some unsynthesised meta -phenylsulfamates.

Synthesis and taste properties of sodium disubstituted phenylsulfamates. Structure-taste relationships for sweet and bitter/sweet sulfamates

Abstract Forty ring disubstituted phenylsulfamates have been synthesized as their sodium salts. These compounds display a variety of tastes including sweet, bitter and sour. Seven of them gave a predominantly sweet taste, twelve displayed a bitter taste followed by a sweet aftertaste, eleven showed predominant bitterness, five sourness and five gave an aniline- or hydrocarbon-like taste and were not assessed further by the panellists. A plot of z (width of molecule, measured using Corey-Pauling-Koltun (CPK) models) versus first-order molecular connectivity, 1xv placed the seven predominantly sweet compounds on the line described by z = 2·27 1 x v − 0·158 . Summation of Hammett sigma (σ) values for the X and Y substituents gives Σ σ, and with these the following structure-taste relationships were derived: Predominant sweetness: Σ σ ≥ 0·6, V CPK ≤ 300 A 3 and a meta-electron with drawing substituent, no para-substituent. Bitter/sweet aftertaste: Σ σ ≤ 0·22, V CPK ≤ 300 A 3 . Some of the starting disubstituted anilines have been reported to be sweet and sulfamation modifies or destroys this sweetness. This is also discussed.

Development of structure-taste relationships for thiazolyl-, benzothiazolyl-, and thiadiazolylsulfamates.

A total of 28 new five-membered aromatic ring thiazolyl-, benzothiazolyl-, and thiadiazolylsulfamates, as their sodium salts, have been synthesized and combined with 30 known similar heterocyclic sulfamates to create a database for the study of structure-activity (taste) relationships (SARs) in this heterocyclic subgroup, which is known to contain a somewhat disproportionate number of sweet compounds compared to other groups of tastants. A series of nine parameters (descriptors) to describe the properties of the sulfamate anions were calculated in Spartan Pro and HyperChem programs. These are the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), length of the molecule, dipole moment, area, volume, E(solv), sigma (from the literature), and log P. The taste data for all 58 compounds were categorized into three classes, namely, sweet (S), nonsweet (N), and nonsweet/sweet (N/S). Discriminant analysis only classified 44 of the 58 compounds correctly. Classification and regression tree analysis (CART) using the S_ Plus program proved highly effective, in that the derived tree correctly classified 46 compounds from a training set of 48 and, from a computer randomly selected test set of 10 compounds, 7 had their taste correctly predicted. A second tree was grown using the additional taste category N/S, and this tree also performed extremely well, with 8 of the 10 compounds in the test set correctly classified. These trees should be very reliable for predicting the tastes of other heterocyclic sulfamates, which belong to the subset used here.

Aminolysis of sulfamate esters in non-aqueous solvents. Evidence consistent with a concerted E2-type mechanism

Aminolysis of 4-nitrophenyl sulfamate, N-phenylmethylsulfamate and N-phenylsulfamate esters in chloroform and acetonitrile at 37 °C using a series of pyridine, quinuclidine and cyclic amine bases has been studied. Second-order kinetics were observed and k2 constants were obtained from plots of kobsvs. [amine]. Bronsted-type plots gave slopes of ∼ 0.27 for the pyridines and ∼ 0.5 for the stronger bases. The failure of the N,N-dimethylsulfamate, Me2NSO2OC6H4NO2-4, to react and the absence of steric effects when hindered pyridines were used support an elimination rather than a substitution mechanism and thus the amines act as general base catalysts. Negative entropies of activation support a bimolecular mechanism and an isokinetic temperature of 541 K was obtained from a plot of ΔH‡vs.ΔS‡. A β1g of –1.25 (ρ=+2.8) has been obtained for reaction of a series of five N-phenylmethyl esters, PhCH2NHSO2OC6H4X (X = 4-NO2, 3-NO2, 3-Cl, 4-Cl and H with tert-butylamine in chloroform and a ρacyl, of –0.91 for reaction of the phenyl esters, XC6H4NHSO2OC6H4X (X = 4-MeO, 4-Me, 3-Me, H and 3-Cl) with 4-dimethylaminopyridine in chloroform. These reactions are seen as being E2 type processes with some ElcB-like character but they are not thought to involve N-sulfonylamines, RNSO2.

Synthesis and taste properties of sodium monosubstituted phenylsulfamates

Abstract Thirty-four monosubstituted ortho-, meta- and para-phenylsulfamates have been synthesized, characterized and tasted. The compounds (as sodium salts) display all four primary tastes often in combination. Some structure-sweet taste relationships have been derived using measurements made with CPK models and using Hammett sigma values for the various substituents. For the 14 meta-substituted compounds (including five previously made) those having x (the length of the aromatic portion including the substituent) in the range 5·82 ± 0·12 A and V CPK (= x.y.z) ≤ 295 A 3 displayed some sweetness, this being much more pronounced and exclusive for those compounds with V CPK ≤ 170 A 3 . All the sweet meta-compounds had σm in the range −0·07 to + 0·56. The ortho-compounds that showed some sweet component in their taste generally had σo in the range −0·30 to + 0·81 and the para-compounds nine of which had a sweet aftertaste had σp in the range −0·27 to + 0·66.

Basicity of nitrogen–sulphur(VI) compounds. Part 4. Ionization of di- and tri-substituted sulphamides

Potentiometric and u.v. methods have been used to study the ionization equilibria of di- and tri-substituted sulphamides: RNHSO2NHR [graphic omitted] R[graphic omitted]SO2NHR [graphic omitted] R[graphic omitted]SO2[graphic omitted]R RNSHO2NME2 [graphic omitted] R[graphic omitted]SO2NMe2 pKa Values for equilibrium a have been determined for nine di- and five tri-substituted sulphamides, sulphamide, and phenylsulphamide in 60% v/v ethanol–water. Ionization data for equilibrium b have been measured for seven diarylsulphamides in aqueous potassium hydroxide. Since neither H– nor H2– acidity functions are suitable for describing the ionizations occurring a number of other methods, e.g. the modified Marziano–Cimino–Passerini method, have been used to obtain thermodynamic pKa values. The agreement between the pKa values obtained by the various methods is good. The effect of substituents on both equilibria (a and b) is similar.

Phase - transfer catalyser hydrogen-deuterium exchange in thiazoles.

Abstract phase transfer catalysis has been used for the first time in a reaction of hydrogen deuterium exchange in heterocyclic chemistry. The method provide a good synthetic path for the synthesis of D - 2 thiazoles by direct exchange. Moreover, even with substituents such as t-butyl, hydrogen exchange on positions adjacent to the alkyl group occured.