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Stereoselective Chemical Ionization Mass Spectrometry: Reactions of CH3OPOCH3+ with Cyclic Vicinal Diols Kami K. Thoen,† Lan Gao,† Thilini D. Ranatunga,† Pirjo Vainiotalo,‡ and Hilkka I. Kentta¨maa*,† Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393, and Department of Chemistry, University of Joensuu, P.O. Box 111, SF-80101 Joensuu, Finland Received May 23, 1997X
The phosphenium ion CH3OPOCH3+ readily attacks hydroxyl groups of neutral substrates in the gas phase in a Fourier-transform ion cyclotron resonance mass spectrometer. The electrophilic character of CH3OPOCH3+ is in agreement with molecular orbital calculations (Becke3LYP/6-31G(d) + ZPE) that predict a singlet electronic ground state for this species. The observed reactions provide a convenient synthetic route to various larger phosphenium ions in the gas phase. Most importantly, however, CH3OPOCH3+ was found to be extremely sensitive to the stereochemical structure of the neutral substrate. The dramatically different reaction product distributions obtained for diastereomeric cyclic vicinal diols suggest that CH3OPOCH3+ provides a powerful chemical ionization reagent for the mass spectrometric determination of the stereochemistry of diols. Introduction The biological action of a substance often greatly depends on its exact stereochemical structure. Obviously, access to fast and accurate methods for the determination of the stereochemistry of molecules is important to many areas of biomedical research, including drug development.1,2 Mass spectrometry has not proven to be generally applicable for the identification of the stereochemical structure of molecules. However, this technique could offer several advantages, including speed, sensitivity, and direct analysis of mixture components. Hence, an extensive amount of research has been devoted to the development of mass spectrometric approaches for stereoisomer differentiation.3 Electron ionization mass spectrometry is usually insensitive to the stereochemistry of molecules. For example, the spectra measured for cis- and trans-1,2cyclopentanediols are identical.3 Chemical ionization, e.g., via proton transfer or formation of an adduct with the ammonium ion, has shown more promise. This approach often produces fewer but more informative product ions. For example, cis- and trans-1,2-cyclopentanediols can be differentiated by using traditional chemical ionization methods3 since intramolecular hydrogen-bond formation results in a more abundant ionized molecule for the cis-diol. However most stereoisomers yield only minor quantitative differences upon chemical ionization. Hence, the analysis requires calibration with pure standards, the composition of isomer mixtures cannot be determined, and the stereochemistry of unknown compounds cannot be readily identified. Finally, differentiation of flexible diastereomers is often not possible. For example, the chemical ionization mass spectra reported for the cis- and trans-1,2-cyclohexanediols are nearly identical.3 †
Purdue University. University of Joensuu. Abstract published in Advance ACS Abstracts, November 1, 1997. (1) Wainer, I. W., Ed. Drug Stereochemistry. Analytical Methods and Pharmacology; Marcel Dekker: New York, 1993. (2) Stinson, S. S. Chem. Eng. News 1995, October 9, 44-74. (3) Plitter, J. S.; Turecek, F., Eds. Applications of Mass Spectrometry to Organic Stereochemistry; VCH Publishers: New York, 1994. ‡
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The chemical ionization reactions that have received most attention thus far involve protonation, proton abstraction, and formation of ionic adducts.3 However, intriguing results have been reported for some unusual reagent ions. Specifically, protonated trimethyl borate has been reported3 to react with cis-1,2-cyclopentanediol by addition followed by loss of two methanol molecules, while the trans-isomer mostly shows loss of one methanol. The differences observed for the flexible 1,2-cyclohexanediols were much less significant, however. Inspired by the above studies, we recently examined the gas-phase reactions of the ion CH3OBOCH3+ to probe its utility as a novel chemical ionization reagent. This ion is a very strong electrophile and readily attacks different types of nucleophiles, yielding simple but structurally diagnostic product distributions.4-8 Encouraged by this result, we proceeded to examine the reactions of the ion with cyclic diastereomeric diols. Small amounts of a diagnostic methanol elimination product were obtained for the cis-diols only; hence, qualitatively different spectra were measured for diastereomers. However, all the reactions are dominated by OH abstraction, which leads to loss of the stereochemical integrity of the neutral diol.6 Obviously, the ion CH3OBOCH3+ is too electrophilic to provide a useful tool for stereoisomer analysis. The above results suggest that a less aggressive electrophile with the key structural features of CH3OBOCH3+, i.e., two good leaving groups attached to a coordinatively unsaturated cationic center, might yield more abundant structurally informative products for stereo isomers. This could be accomplished by replacing the reactive boron center with a less electron deficient atom, such as phosphorus. We report here the results of the first systematic investigation of the chemical properties of the dimethoxyphosphenium ion (4) Ranatunga, T. D.; H. I. Kentta¨maa J. Am. Chem. Soc. 1992, 114, 860. (5) Ranatunga, T.; H. I. Kentta¨maa Inorg. Chem. 1995, 34, 18. (6) Leeck, D. T. Ranatunga, T. D.; Smith, R. L.; Partanen, T.; Vainiotalo, P.; H. I. Kentta¨maa Int. J. Mass Spectrom. Ion Processes 1996, 141, 229. (7) Ranatunga, T.; Kentta¨maa, H. I. J. Am. Chem. Soc. 1996, 118, 11893-11897. (8) Thoen, K. K.; Tutko, D. T.; Ranatunga, T. D.; H. I. Kentta¨maa J. Am. Soc. Mass Spectrom. 1996, 7, 1138.
© 1997 American Chemical Society
Reactions of CH3OPOCH3+ with Cyclic Vicinal Diols
J. Org. Chem., Vol. 62, No. 25, 1997 8703
CH3OPOCH3+. This ion yields dramatically different and predictable product distributions for cyclic diastereomeric diols in the gas phase. Even cis- and trans-1,2-cyclohexanediols, compounds that are notoriously difficult to distinguish due to their flexible cyclohexane skeleton,3 are readily distinguished on the basis of their reactions with CH3OPOCH3+. These results suggest that phosphenium ion chemistry may allow the mass spectrometric determination of the stereochemical structure of unknown compounds without extensive prior purification and derivatization, possibly in mixtures of isomers.
Experimental Section Trimethyl phosphite, dimethyl methylphosphonate, methanold4, ethanol, 2-propanol, 1-butanol, 1,2-propanediol, 1,3-butanediol, and cis- and trans-1,2-cyclopentanediol were obtained commercially and used as received. Trimethyl phosphite-d9, cis- and trans-1,2-cyclohexanediol, and cis- (diendo- and diexo-) and trans-2,3-trinorbornanediol were synthesized by standard literature procedures.9 The purity of all reagents was verified by mass spectrometry and by gas chromatography. The experiments were carried out in an Extrel FTMS 2001 Fourier-transform ion cyclotron resonance mass spectrometer. This instrument contains a dual cell that consists of two identical cubic 2-in. cells joined by a common wall (the conductance limit). The cell is aligned collinearly within the magnetic field produced by a 3.0 T superconducting magnet operated at approximately 2.5 T. The conductance limit and the two end trapping plates were held at +2.0 V unless otherwise specified. The cell was differentially pumped with two Balzers turbomolecular pumps (330 L/s), each of which was backed by an Alcatel 2012 mechanical pump. A nominal base pressure of
