MILESTONES

MILESTONE 7 Breaking down problems At its simplest, spectrometry gives The mass spectrum of styrene chlorohydrin, information about the atomic or molecular as reported by weight of an element or compound. Initial McLafferty. Reprinted with permission from applications of mass spectrometry focused McLafferty, F.W., Mass on confirming the weight of a known spectrometric analysis broad applicability to compound or analyzing elemental samples. chemical research, Anal. The next step was its use in determining Chem. 28, 306–316 molecular structures. (1956). In the 1950s, there was a pressing need for such techniques. NMR spectroscopy was adjacent to the in its infancy, with commercial machines ring. only beginning to emerge. Elemental Applied Society Chemical American ©1956, analysis could confirm the composition of a together, these rules sample, but it did not help with bond could distinguish connectivity. Crystallography only worked between closely related . As an collisions, allowing reaction rates and rate for that form single crystals. example, McLafferty examined styrene constants to be estimated. It was in this climate that scientists chlorohydrin, which has two possible The structural information that could be began to use mass spectra as a means to isomers depending on the location of the deduced from mass spectra continued to reveal all, or part, of a ’s structure. hydroxyl and chlorine . increase. Carl Djerassi was instrumental in Some methods for small-molecule structure Employing the general rule that major bond applying mass spectrometry analysis to determination were straightforward; the breakage occurs β to a ring, he natural products. In 1963, he and his simplest was to compare the molecule’s could predict the main characteristics of the co-workers performed a systematic study of spectrum with known reference spectra. By molecules’ expected spectra: fragmentation patterns in pentacyclic this time, laboratories at Dow Chemical, for 2-chloro-2-phenylethanol should generate triterpenes, describing fragmentation + example, had encoded reference spectra for large peaks corresponding to PhCHCH2OH behaviors and enabling unknown substances thousands of compounds onto IBM (loss of chloro) and PhCHCl+ (loss of to be assigned to a particular subclass. punched cards. These could be compared CH2OH). 2-Chloro-1-phenylethanol, in Key ion fragments and the reactions that rapidly with the significant peaks of an contrast, should result in peaks for gave rise to them could be deduced. Even + + unknown sample, thus allowing automated PhCHCH2Cl and PhCHOH , also from stereochemistry at carbon bridges could be matches to be made in many cases. β-bond cleavage. McLafferty observed the determined—a powerful demonstration of Even when reference spectra were not latter scenario and was able to assign the how much these techniques had progressed, available, scientists learned how to extract structural confidently. and foreshadowing their continued use increasingly greater amounts of information Mass spectra offer insight beyond today. from spectral peaks, through a combination structural assignments and have been Enda Bergin, Senior Editor, of empirical evidence and chemical employed to monitor gas-phase reactions of Nature Communications intuition. Fred McLafferty, John Beynon ions. Ionization techniques produce reactive and others examined many spectra, which gas-phase species within a mass ORIGINAL RESEARCH PAPERS McLafferty, F.W. Mass spectrometric analysis broad applicability to chemical research. led to a number of general observations. For spectrometer, and the products that arise Anal. Chem. 28, 306–316 (1956) | Beynon, J.H. The use of the example, they determined that when from collisions can subsequently be mass spectrometer for the identification of organic compounds. carbon-carbon double bonds are present, monitored by the instrument’s detector. Microchimica Acta 44, 437–453 (1956) | Field, F.H., Franklin, J.L. & Lampe, F.W. Reactions of gaseous ions. I. and including in aromatic rings, cleavage occurs F.H. Field, J.L Franklin and F.W. Lampe were . J. Am. Chem. Soc. 79, 2419–2429 (1957) | typically at the β-position. Molecules with instrumental in developing this field, starting Budzikiewicz, H., Wilson, J.M. & Djerassi, C. Mass spectrometry carbonyls fragment at the position α to the in the mid-1950s. They studied the in structural and stereochemical problems. XXXII. Pentacyclic triterpenes. J. Am. Chem. Soc. 85, 3688–3699 (1963) double bond. Saturated rings fragment secondary ions formed through gas-phase

NATURE MILESTONES | MASS SPECTROMETRY OCTOBER 2015