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Lars F. Gram - One of the best experts on this subject based on the ideXlab platform.
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Sparteine oxidation polymorphism in Denmark.
Acta pharmacologica et toxicologica, 2009Co-Authors: Kim Brosen, S V Otton, Lars F. GramAbstract:Sparteine oxidation was polymorphic among 301 healthy Danish volunteers. Hence 22 subjects or 7.3% were phenotyped as poor metabolizers (PM) whereas 279 subjects were classified as extensive metabolizers (EM). The metabolic ratio (MR) between Sparteine and 2- and 5-dehydroSparteine (% of dose) in 12 hrs urine ranged from 0.11-12.6 in EM and from 30-394 in PM. Urinary excretion of 2- and 5-dehydroSparteine also discriminated between PM and EM. Age, sex, and smoking habits did not influence the MR. This study confirms that Sparteine is a useful probe drug in pharmacogenetic investigations.
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pharmacokinetics of citalopram in relation to the Sparteine and the mephenytoin oxidation polymorphisms
Therapeutic Drug Monitoring, 1993Co-Authors: Soren Hein Sindrup, M G J Hansen, Tove Aaesjorgensen, K. Fredricson Overø, Kim Brosen, Lars F. GramAbstract:Summary The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the Sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of Sparteine and mephenytoin (n = 10), poor metabolizers of Sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the Sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of Sparteine, contrasting measurable serum levels in all Sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in Sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in Sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of Sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the Sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
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Moclobemide treatment causes a substantial rise in the Sparteine metabolic ratio. Danish University Antidepressant Group.
British journal of clinical pharmacology, 1993Co-Authors: Lars F. Gram, Kim BrosenAbstract:A Sparteine test was carried out immediately before (n = 37) and during (n = 33) moclobemide treatment (200 mg twice daily) in 37 patients participating in a controlled clinical trial. The Sparteine metabolic ratio (MR) did not correlate with the plasma concentration of moclobemide and/or its oxidized metabolite Ro 12-8095, and four Sparteine poor metabolisers (PM, MR > 20) had plasma moclobemide concentrations similar to those in extensive metabolisers (EM, MR < 20). The Ro 12-8095/moclobemide ratio tended to correlate negatively with the Sparteine MR before and during treatment (rs = -0.32, -0.37). During moclobemide treatment the Sparteine MR rose substantially by a factor of 1-103 (median 4.7), and two EM became phenotypically PM. In the PM subjects as well as in one EM patient on cimetidine during both tests, no change in Sparteine MR occurred.
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The relationship between paroxetine and the Sparteine oxidation polymorphism.
Clinical pharmacology and therapeutics, 1992Co-Authors: Soren Hein Sindrup, Erik Skjelbo, Lars F. Gram, Kim Brosen, Jesper Hallas, Ann Allen, Graham D Allen, Steven M Cooper, Graham Mellows, Tim C G TaskerAbstract:The relationship between the selective serotonin reuptake inhibitor paroxetine and the Sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of Sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol · hr/L), whereas at steady state the median AUCsst interphenotype difference was only twofold (4410 versus 2550 nmol · hr/L). Plasma half-life and steady-state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of Sparteine/de-hydroSparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with Sparteine MRs of 5.7 to 16.5. The inhibition of Sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and Sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the Sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of Sparteine oxidation by CYP2D6 in vivo. Clinical Pharmacology and Therapeutics (1992) 51, 278–287; doi:10.1038/clpt.1992.23
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the mephenytoin oxidation polymorphism is partially responsible for the n demethylation of imipramine
Clinical Pharmacology & Therapeutics, 1991Co-Authors: Erik Skjelbo, Kim Brosen, Jesper Hallas, Lars F. GramAbstract:The metabolism of imipramine in six poor metabolizers of mephenytoin was compared with the metabolism of 16 extensive metabolizers of mephenytoin from an earlier study. Each subject was given single doses of 100 mg imipramine hydrochloride and 100 mg desipramine hydrochloride on separate occasions. Imipramine demethylation clearance was 0.74 L · min−1 (mean; range, 0.31–1.24) in poor metabolizers of mephenytoin compared with 1.43 L · min−1 (mean; range, 0.61–3.81) in extensive metabolizers of mephenytoin (p = 0.01, Mann-Whitney U test). It has previously been shown that the imipramine clearance by way of other pathways and desipramine oral clearance, both largely representing 2-hydroxylation, are considerably lower in poor metabolizers of Sparteine than in extensive metabolizers of Sparteine. In contrast, five subjects who were poor metabolizers of mephenytoin and extensive metabolizers of Sparteine and a control group of 11 subjects who were extensive metabolizers of mephenytoin and Sparteine showed no statistically significant difference with regard to these parameters. One subject who was a poor metabolizer of mephenytoin and Sparteine had the lowest imipramine oral clearance of all 22 subjects studied. In conclusion, this and an earlier study show that the oxidation of imipramine is mediated by means of two different polymorphic P450 isozymes, 2-hydroxylation by way of the Sparteine oxygenase (P450IID6) and demethylation by way of the mephenytoin oxygenase (P450IIC8). Clinical Pharmacology and Therapeutics (1991) 49, 18–23; doi:10.1038/clpt.1991.4
Kim Brosen - One of the best experts on this subject based on the ideXlab platform.
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Sparteine oxidation polymorphism in Denmark.
Acta pharmacologica et toxicologica, 2009Co-Authors: Kim Brosen, S V Otton, Lars F. GramAbstract:Sparteine oxidation was polymorphic among 301 healthy Danish volunteers. Hence 22 subjects or 7.3% were phenotyped as poor metabolizers (PM) whereas 279 subjects were classified as extensive metabolizers (EM). The metabolic ratio (MR) between Sparteine and 2- and 5-dehydroSparteine (% of dose) in 12 hrs urine ranged from 0.11-12.6 in EM and from 30-394 in PM. Urinary excretion of 2- and 5-dehydroSparteine also discriminated between PM and EM. Age, sex, and smoking habits did not influence the MR. This study confirms that Sparteine is a useful probe drug in pharmacogenetic investigations.
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pharmacokinetics of citalopram in relation to the Sparteine and the mephenytoin oxidation polymorphisms
Therapeutic Drug Monitoring, 1993Co-Authors: Soren Hein Sindrup, M G J Hansen, Tove Aaesjorgensen, K. Fredricson Overø, Kim Brosen, Lars F. GramAbstract:Summary The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the Sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of Sparteine and mephenytoin (n = 10), poor metabolizers of Sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the Sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of Sparteine, contrasting measurable serum levels in all Sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in Sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in Sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of Sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the Sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
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Moclobemide treatment causes a substantial rise in the Sparteine metabolic ratio. Danish University Antidepressant Group.
British journal of clinical pharmacology, 1993Co-Authors: Lars F. Gram, Kim BrosenAbstract:A Sparteine test was carried out immediately before (n = 37) and during (n = 33) moclobemide treatment (200 mg twice daily) in 37 patients participating in a controlled clinical trial. The Sparteine metabolic ratio (MR) did not correlate with the plasma concentration of moclobemide and/or its oxidized metabolite Ro 12-8095, and four Sparteine poor metabolisers (PM, MR > 20) had plasma moclobemide concentrations similar to those in extensive metabolisers (EM, MR < 20). The Ro 12-8095/moclobemide ratio tended to correlate negatively with the Sparteine MR before and during treatment (rs = -0.32, -0.37). During moclobemide treatment the Sparteine MR rose substantially by a factor of 1-103 (median 4.7), and two EM became phenotypically PM. In the PM subjects as well as in one EM patient on cimetidine during both tests, no change in Sparteine MR occurred.
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pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine nonlinearity and relation to the Sparteine oxidation polymorphism
Clinical Pharmacology & Therapeutics, 1992Co-Authors: Soren Hein Sindrup, Kim Brosen, L F GramAbstract:Steady-state plasma concentrations of paroxetine were studied at five or more paroxetine dose levels (10 to 70 mg/day) in each of 13 extensive metabolizers of Sparteine and at three or four dose levels (10 to 40 mg/day) in each of three poor metabolizers of Sparteine, all treated for diabetic neuropathy symptoms. On a dose of 30 mg/day there was a 25-fold variation in steady-state concentrations (25 to 670 nmol/L). The upper extreme of this variation was made up by the poor metabolizers of Sparteine and the lower extreme by some fast extensive metabolizers. Further, within the extensive metabolizer group, steady-state levels showed a significant, positive correlation with Sparteine metabolic ratio at all dose levels. On increasing doses, a disproportionate increase in plasma drug levels was observed in the majority of patients. In nearly all extensive metabolizers the concentration-dose data were best described by a pharmacokinetic model assuming elimination by at least two kinetically distinct processes, one a high-affinity saturable process and one a low-affinity linear process. Estimates of clearance at low drug levels of the high-affinity process showed a significant negative correlation with the Sparteine metabolic ratio. Clearance of the low-affinity process was not related to the metabolic ratio and was of the same magnitude in extensive and poor metabolizers. The data thus confirmed that the metabolism of paroxetine and Sparteine cosegregates and indicated that the enzyme responsible for a high-affinity saturable paroxetine elimination process is identical with CYP2D6, the source of the Sparteine oxidation polymorphism. Clinical Pharmacology and Therapeutics (1992) 51, 288–295; doi:10.1038/clpt.1992.24
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The relationship between paroxetine and the Sparteine oxidation polymorphism.
Clinical pharmacology and therapeutics, 1992Co-Authors: Soren Hein Sindrup, Erik Skjelbo, Lars F. Gram, Kim Brosen, Jesper Hallas, Ann Allen, Graham D Allen, Steven M Cooper, Graham Mellows, Tim C G TaskerAbstract:The relationship between the selective serotonin reuptake inhibitor paroxetine and the Sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of Sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol · hr/L), whereas at steady state the median AUCsst interphenotype difference was only twofold (4410 versus 2550 nmol · hr/L). Plasma half-life and steady-state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of Sparteine/de-hydroSparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with Sparteine MRs of 5.7 to 16.5. The inhibition of Sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and Sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the Sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of Sparteine oxidation by CYP2D6 in vivo. Clinical Pharmacology and Therapeutics (1992) 51, 278–287; doi:10.1038/clpt.1992.23
Peter O'brien - One of the best experts on this subject based on the ideXlab platform.
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Revisiting the Sparteine surrogate: development of a resolution route to the (−)-Sparteine surrogate
Organic & biomolecular chemistry, 2014Co-Authors: James D. Firth, Peter O'brien, Leigh FerrisAbstract:The improved performance of the Sparteine surrogate compared to Sparteine in a range of applications has highlighted the need to develop an approach to the (-)-Sparteine surrogate, previously inaccessible in gram-quantities. A multi-gram scale, chromatography-free synthesis of the racemic Sparteine surrogate and its resolution via diastereomeric salt formation with (-)-O,O'-di-p-toluoyl-l-tartaric acid is reported. Resolution on a 10.0 mmol scale gave the diastereomeric salts in 33% yield from which (-)-Sparteine surrogate of 93 : 7 er was generated. This work solves a key limitation: either enantiomer of the Sparteine surrogate can now be readily accessed.
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Use of copper(II)/diamine catalysts in the desymmetrisation of meso -diols and asymmetric Henry reactions: comparison of (−)-Sparteine and (+)-Sparteine surrogates
Tetrahedron, 2014Co-Authors: Steven J. Canipa, Annika Stute, Peter O'brienAbstract:Abstract Four new copper(II)/diamine complexes comprising some (+)-Sparteine surrogates and a cyclohexane-derived diamine were prepared and evaluated as chiral catalysts in desymmetrisation of meso-diols and asymmetric Henry reactions. Mono-benzoylation reactions generated two products with high enantioselectivity (90:10 to 97:3 er). Asymmetric Henry reactions gave nitro alcohols in 90:10 to 98:2 er. Notably, the sense of induction with the (+)-Sparteine surrogates was opposite to that obtained using the copper(II)/(−)-Sparteine complex. One of the nitro alcohol products was utilised in a concise synthesis of a chiral morpholine.
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A New Sparteine Surrogate for Asymmetric Deprotonation of N-Boc Pyrrolidine
Organic letters, 2008Co-Authors: Darren Stead, Peter O'brien, Adam J. SandersonAbstract:The s-BuLi complex of a cyclohexane-derived diamine is as efficient as s-BuLi/(−)-Sparteine for the asymmetric deprotonation of N-Boc pyrrolidine. This is the first example of high enantioselectivity using a non-Sparteine-like diamine in such reactions. The (S,S)-diamine is a useful (+)-Sparteine surrogate and was utilized in short syntheses of (−)-indolizidine 167B and an intermediate for the synthesis of the CCK antagonist (+)-RP 66803.
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Basic instinct: design, synthesis and evaluation of (+)-Sparteine surrogates for asymmetric synthesis.
Chemical Communications, 2008Co-Authors: Peter O'brienAbstract:(–)-Sparteine, a naturally occurring lupin alkaloid, is widely used as a chiral ligand for asymmetric synthesis. To address the limitation that Sparteine is only available as its (–)-antipode, our group introduced a family of (+)-Sparteine surrogates that are structurally similar to (+)-Sparteine but lack the D-ring. After briefly summarising the design aspect, this feature article provides an overview of synthetic routes to the Sparteine surrogates and a detailed comparison with (–)-Sparteine in a range of asymmetric reactions. The main conclusions are: (i) the (+)-Sparteine surrogates are most easily prepared starting from (–)-cytisine extracted from Laburnum anagyroides seeds; (ii) in nearly all examples, use of the (+)-Sparteine surrogates produced essentially equal but opposite enantioselectivity compared to (–)-Sparteine and (iii) the N-Me-substituted (+)-Sparteine surrogate is the most useful and versatile of those investigated.
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Evaluation of Sparteine-like chiral diamines in the enantioselective lithiation–electrophilic trapping of an O-alkyl carbamate
Organic & Biomolecular Chemistry, 2006Co-Authors: Cedric Genet, Matthew J. Mcgrath, Peter O'brienAbstract:Seven (+)-Sparteine-like diamines and (−)-Sparteine were evaluated in the diamine-mediated asymmetric lithiation–trapping of an O-alkyl carbamate. The (+)-Sparteine-like diamines (≥98 : 2 er by chiral shift NMR spectroscopy) were prepared from (−)-cytisine (>99 : 1 er by chiral HPLC of N-benzyl cytisine) and two new (+)-Sparteine-like diamines containing N-CD3 substituents were included as part of this study. The following results from the ligand evaluation study were obtained: (−)-Sparteine is unrivalled in its ability to induce near-perfect enantioselectivity (99 : 1 er); N-methyl diamine and the two N-CD3-substituted diamines are the optimal (+)-Sparteine surrogates (up to 96 : 4 er); sterically more hindered N-alkyl substituents gave reduced enantioselectivity (N-iso-propyl: 86 : 14 er; N-CH2tBu: 54 : 46 er). From a synthetic point of view, these results show that either enantiomer of α-substituted O-alkyl carbamates can be obtained by enantioselective lithiation–trapping using (−)-Sparteine and the N-methyl (+)-Sparteine surrogate.
Gigosos Pérez, Marco Antonio - One of the best experts on this subject based on the ideXlab platform.
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Rotational Spectra of Tetracyclic Quinolizidine Alkaloids: Does a Water Molecule Flip Sparteine?
RSC, 2017Co-Authors: Lesarri Gómez, Alberto Eugenio, Pinacho Gómez Ruth, Enríquez Giraudo, María Lourdes, Rubio García, José Emiliano, Jaraíz Maldonado Martín, Abad, José L., Gigosos Pérez, Marco AntonioAbstract:Producción CientíficaSparteine is a quinolizidine alkaloid used as chiral auxiliary in asymmetric synthesis. We examine whether hydration by a single molecule can flip Sparteine from the most stable trans conformation to the bidentate cis arrangement observed in catalytic complexation to a metal center. Sparteine and the dimer Sparteine-water were generated in a supersonic jet expansion with H216O and H218O, and characterized by broadband chirped-pulse microwave spectroscopy. Despite the bidentate water dimer was predicted with larger binding energy, a single isomer was observed for the monohydrated cluster, with Sparteine retaining the trans conformation observed for the free molecule. The absence of the bidentate dimer is attributed to kinetic control of the cluster formation, favoring the pre-expansion most abundant monomer. The structural properties of the O-H···N hydrogen bond in the dimer are compared with complexes of other secondary and tertiary amines.2018-07-21MINECO-FEDER (CTQ2015-68148-C2-2-P
Marco A. Gigosos - One of the best experts on this subject based on the ideXlab platform.
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Rotational spectra of tetracyclic quinolizidine alkaloids: does a water molecule flip Sparteine?
Physical chemistry chemical physics : PCCP, 2017Co-Authors: Alberto Lesarri, R. Pinacho, L. Enriquez, J. E. Rubio, Martín Jaraíz, José L. Abad, Marco A. GigososAbstract:Sparteine is a quinolizidine alkaloid used as a chiral auxiliary in asymmetric synthesis. We examine whether hydration by a single molecule can flip Sparteine from the most stable trans conformation to the bidentate cis arrangement observed in catalytic complexation to a metal center. Sparteine and the Sparteine-water dimer were generated in a supersonic jet expansion with H216O and H218O, and characterized by broadband chirped-pulse microwave spectroscopy. Even though the bidentate water dimer was predicted with larger binding energy, a single isomer was observed for the monohydrated cluster, with Sparteine retaining the trans conformation observed for the free molecule. The absence of the bidentate dimer is attributed to the kinetic control of cluster formation, favoring the pre-expansion most abundant monomer. The structural properties of the O-HN hydrogen bond in the dimer are compared with those of complexes of other secondary and tertiary amines.
