William J. Spillane

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Organization: National University of Ireland , Ireland

Department: Department of Chemistry

Title: Emeritus Professor(PhD)

TOPICS

Organic Chemistry

Chemicals
References

Sulfamic Acid and Its N- and O-Substituted Derivatives

Co-reporter:William Spillane and Jean-Baptiste Malaubier

Chemical Reviews 2014 Volume 114(Issue 4) pp:2507

Publication Date(Web):December 17, 2013

DOI:10.1021/cr400230c

Mechanisms of hydrolysis of phenyl- and benzyl 4-nitrophenyl-sulfamate esters

Co-reporter:William J. Spillane, Sergio Thea, Giorgio Cevasco, Michael J. Hynes, Cheryl J. A. McCaw and Neil P. Maguire

Organic & Biomolecular Chemistry 2011 vol. 9(Issue 2) pp:523-530

Publication Date(Web):25 Oct 2010

DOI:10.1039/C0OB00362J

The kinetics of hydrolysis at medium acid strength (pH interval 2–5) of a series of phenylsulfamate esters 1 have been studied and they have been found to react by an associative SN2(S) mechanism with water acting as a nucleophile attacking at sulfur, cleaving the S–O bond with simultaneous formation of a new S–O bond to the oxygen of a water molecule leading to sulfamic acid and phenol as products. In neutral to moderate alkaline solution (pH ≥ ∼ 6–9) a dissociative (E1cB) route is followed that involves i) ionization of the amino group followed by ii) unimolecular expulsion of the leaving group from the ionized ester to give N-sulfonylamine [HNSO2] as an intermediate. In more alkaline solution further ionization of the conjugate base of the ester occurs to give a dianionic species which expels the aryloxide leaving group to yield the novel N-sulfonylamine anion [−NSO2]; in a final step, rapid attack of hydroxide ion or a water molecule on it leads again to sulfamic acid. A series of substituted benzyl 4-nitrophenylsulfamate esters 4 were hydrolysed in the pH range 6.4–14, giving rise to a Hammett relationship whose reaction constant is shown to be consistent with the E1cB mechanism.

Mechanism of the hydrolysis of the sulfamate EMATE—an irreversible steroid sulfatase inhibitor

Co-reporter:William J. Spillane, Jean-Baptiste Malaubier

Tetrahedron Letters 2010 Volume 51(Issue 15) pp:2059-2062

Publication Date(Web):14 April 2010

DOI:10.1016/j.tetlet.2010.02.065

The kinetics of hydrolysis of the medicinally important sulfamate ester EMATE have been probed over a wide pH range and into moderately strong base (H_ region). Analysis of the pH/H_-rate profile, measurements of pKas, solvent-reactivity, kinetic isotope effects and determination of activation data reveal that in the pH range from ∼1 to ∼8 an SN2 (S) solvolytic mechanism is followed and after the pKa of EMATE (pKa ∼9) is passed, a second pathway showing a first-order dependence on base operates and an E1cB mechanism is supported.Two hydrolysis pathways for the biologically-important sulfamate ester EMATE have been established.

The effect on taste upon the introduction of heteroatoms in sulphamates

Co-reporter:William J. Spillane, Emer F. Thompson

Food Chemistry 2009 Volume 114(Issue 1) pp:217-225

Publication Date(Web):1 May 2009

DOI:10.1016/j.foodchem.2008.09.042

The effect on taste of introducing a heteroatom(s) in place of a carbon atom(s) in sulphamate tastants has been examined in this work. Seventy sets of heterosulphamates and their corresponding carbon analogues (130 compounds in total) were examined. This interesting database was assembled by bringing together series of heterocompounds and suitable nonhetero analogues from the literature, by the synthesis in this work of 15 new heterosulphamates and two new carbosulphamates, which was necessary “to match up” with known carbosulphamate analogues and by making taste predictions for ten carbosulphamates which are unknown, using existing well-established structure-taste relationships (SARs). A sulphur atom replaced a carbon atom in 18 cases, either oxygen or an –OH group replaced carbon in 16 cases, and there are 29 examples where a nitrogen atom or an –NH group replaced carbon. Finally, there are six instances of a “double carbon–carbon, nitrogen–nitrogen substitution” and one of a treble carbon, nitrogen substitution. The overall picture shows that in 33 instances no change in taste was found when substitution occurred, in 29 instances sweet taste (S) was removed giving a nonsweet compound (N), and in eight instances a nonsweet material (N) became sweet (S). Replacement of oxygen by sulphur resulted in the introduction of sweetness in three cases out of four examined. Several important findings were made and a number of new structure-taste relationships have been derived for heterosulphamates.

Development of Structure−Taste Relationships for Thiazolyl-, Benzothiazolyl-, and Thiadiazolylsulfamates

Co-reporter:William J. Spillane, Catherine M. Coyle, Brendan G. Feeney and Emer F. Thompson

Journal of Agricultural and Food Chemistry 2009 Volume 57(Issue 12) pp:5486-5493

Publication Date(Web):May 20, 2009

DOI:10.1021/jf9002472

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, Esolv, σ (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.

Elimination Mechanisms in the Aminolysis of Sulfamate Esters of the Type NH2SO2OC6H4X Models of Enzyme Inhibitors

Co-reporter:William J. Spillane;Andrew O'Byrne ;Cheryl J. A. McCaw

European Journal of Organic Chemistry 2008 Volume 2008( Issue 24) pp:4200-4205

Publication Date(Web):

DOI:10.1002/ejoc.200800366

Abstract

The kinetics of the reaction of 4-nitrophenyl sulfamate NH₂SO₂OC₆H₄NO₂-4 (1a) in acetonitrile (ACN) with a series of pyridines (pK_a range ca. 8 units) and alicyclic amines (pK_a range ca. 3.6 units) has been studied in the presence of excess amine at various temperatures. The compounds 1a–1f are important as model substrates for the medicinally important sulfamate esters 667-coumate and emate and analogues. Pseudo-first-order rate constants (k_obsd.) have been obtained mainly by the release of 4-nitrophenol/4-nitrophenoxide. Slopes of plots of k_obsd. vs. [amine] gave second-order rate constants (k₂), and Brönsted plots were biphasic for the aminolysis (with alicyclic amines) with an initial slope β₁ = 0.53 and a subsequent slope β₂ = 0.19. The change in slope occurs near the first pK_a of 1a (17.9) in ACN. Leaving-group effects were probed by using the same series of phenyl sulfamates, i.e. 1a–f and the alicyclic amines N-formylpiperazine and pyrrolidine. The reactions were considered to be dissociative in nature involving E2- and E1cB- type mechanisms with the phenyl sulfamate anion 2 being involved in pyridine and in the weaker alicyclic amines (β₁ segment) and a phenyl sulfamate dianion 3 being involved with the stronger alicyclic bases (β₂ segment). The calculation of Leffler indices (α) for bond-forming (base···H⁺) and bond-breaking (S–OAr) steps allows fuller interpretation of the mechanisms occurring, which are seen as having the N-sulfonylamines, HN=SO₂ and ^–N=SO₂ on the reaction pathways leading to products. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Kinetic and mechanistic studies on sulfamate esters: models of enzyme inhibitors

Co-reporter:Cheryl J. A. McCaw

Journal of Physical Organic Chemistry 2006 Volume 19(Issue 8‐9) pp:512-517

Publication Date(Web):3 JUL 2006

DOI:10.1002/poc.1050

Many compounds containing a sulfamate moiety, such as NH₂SO₂O are now known to be medicinally important. However, very little is known about their mechanisms of reaction even under non-biological conditions. In this work the various types of elimination mechanisms that may occur have been probed by studying the kinetics of the reactions of model sulfamate substrates with amines (bases) that act as models for the enzymes involved. The principal mechanistic tool employed has been Brönsted plots and both ‘normal’ rectilinear and two types of biphasic plots have been found for the decomposition of the esters in acetonitrile (ACN). The mechanisms operating are seen as being of the E2 and E1cB types. Copyright © 2006 John Wiley & Sons, Ltd.

Apparent specific volumes and tastes of cyclamates, other sulfamates, saccharins and acesulfame sweeteners

Co-reporter:Gordon G. Birch, Kieran A. Haywood, Gary G. Hanniffy, Catherine M. Coyle, Wm.J. Spillane

Food Chemistry 2004 Volume 84(Issue 3) pp:429-435

Publication Date(Web):February 2004

DOI:10.1016/S0308-8146(03)00262-0

Measurements of apparent specific volume (ASV) for a series of alternative sweeteners (cyclamates, sulfamates, saccharins, acesulfames and anilinomethanesulfonates) have been made. Taste data have been obtained for many of the new compounds unless the toxicity of the associated metals precluded this. Apparent molar volume (AMV), isentropic specific (IASC) and isentropic molar (IAMC) compressibilities were also measured. Sixteen metallic cyclamates cyc-C6H11NHSO3M and two phenylsulfamates ArNHSO3Na, namely 3,5-dimethyl- and 3,4-dimethoxyphenylsulfamates have been examined. When the ASVs for these are combined with those for 15 aliphatic, aromatic and alicyclic sulfamates from a previous study, many of the values are seen to fall into the region that was previously identified as being the “sweet area”, i.e. the ASVs lay between ∼0.5 and ∼0.7 (a few sweet compounds fall below this range and it is suggested that it could be extended slightly to accommodate these). Interestingly, the anilinomethanesulfonates, ArNHCH2SO3Na (Ar=C6H5-, 3-MeC6H4- and 3-ClC6H4-) lie clearly in the sweet region but only one of them shows slight sweetness showing that the molecular structural change made (compared with the ‘parent’ sulfamate–NHSO3−) cannot be accommodated at the receptor site.

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

Co-reporter:William J Spillane, Brendan G Feeney, Catherine M Coyle

Food Chemistry 2002 Volume 79(Issue 1) pp:15-22

Publication Date(Web):October 2002

DOI:10.1016/S0308-8146(02)00169-3

Twenty-two new sodium monosubstituted phenylsulfamates XC6H4NHSO3−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 XC6H4– 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 Esolv 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, Esolv, and the CPK measurements, x (length) and z (width) of XC6H4–. Apparently, for sweetness, the CPK measurement x of XC6H4– needs to be in the range ∼5.65⩽x⩽∼5.95 Å. Using several of the methods developed, taste predictions were made on some unsynthesised meta-phenylsulfamates.

Mechanisms of hydrolysis of phenyl- and benzyl 4-nitrophenyl-sulfamate esters

Co-reporter:William J. Spillane, Sergio Thea, Giorgio Cevasco, Michael J. Hynes, Cheryl J. A. McCaw and Neil P. Maguire

Organic & Biomolecular Chemistry 2011 - vol. 9(Issue 2) pp:NaN530-530

Publication Date(Web):2010/10/25

DOI:10.1039/C0OB00362J