Product distortion: chemical yields exaggerated by uncalibrated instrumentation

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  • Published: Dec 15, 2010
  • Author: David Bradley
  • Channels: Chemometrics & Informatics
thumbnail image: Product distortion: chemical yields exaggerated by uncalibrated instrumentation

Synthetic boost, to be or not?

A critique by chemists at Brock Universty of how synthetic product yields are reported suggests that a lack of calibration could be distorting data from nuclear magnetic resonance spectroscopy, chromatography and mass spectrometry.

Martina Wernerova and Tomas Hudlicky of the Department of Chemistry and the Centre for Biotechnology, at Brock University, in St. Catharines, Ontario, Canada, believe that anyone who has read the chemical literature over the last few years will have noticed a worrying trend. In the field of organic synthesis, they suggest, whether in methodology reports, catalytic developments or the total synthesis of complex natural products, the isolated product yields, ratios of diastereomers, and enantiomeric excess values have been going up steadily. "A comparison of papers published during the period 1955 to 1980 with those published between 1980 and 2005 reveals that those from the more recent period frequently report isolated product yields of reactions greater than 95%," the team says.

A generous interpretation of such a trend might be that technology and techniques have been improving in organic synthesis so much recently that chemists are genuinely attaining much better yields. A less generous, and altogether more worrying, explanation is that something is awry with the way in which organic chemists are determining their yields and excesses. One clue as to the possibility that the latter explanation is the valid one is that such large yields and excesses were rarely found in the older literature and, add Wernerova and Hudlicky, such values, "are all but absent in Organic Syntheses." This journal publishes synthetic procedures that have been reproduced independently by other chemists and so, essentially validates the true yields achievable for a given reaction sequence.

Talk about synthetic inflation

Of course, the gossip on the conference circuit that takes place between lectures, would suggest that most synthetic chemists are only too aware of the issue and that most generally reject the ego-inflating yields reported by others. There are several pressures that might lead to synthetic inflation, including community and peer pressure that correlate high yield with high value, inept analytical technique or poor instrument calibration or sample preparation.

Whether or not the yields are deliberately boosted or enhanced by inadequate measurements is a moot point that Wernerova and Hudlicky hoped to address through a detailed analysis of yields and the instrumentation used to report them. The researchers also hoped to demonstrate that, despite the scandals of recent years regarding scientific fraud and discrepancies between patent reports and literature reports, that instrumentation or inadequate technique are more generally to blame. Whatever the cause of inflated yields, the value of today's chemical literature is reduced significantly and could be disregarded by future chemists altogether as the issue becomes more apparent.

The researchers have now carried out careful experiments in order to determine whether more accurate yields can be extracted from published chromatographic and spectroscopic data. They have examined the limits of accuracy in reporting isolated product yields from total mass from chromatography or extractions, as well as ratios of isomers determined by HPLC, GC, or NMR methods. The researchers have directed their attention to the magnitude of errors encountered in the HPLC or GC measurements of such ratios, particularly when instrumentation is not calibrated with precision. They carried out their own measurements on accurately defined mixtures of compounds (prepared by volumetric means) and looked at the measurements obtained under different conditions and compared those with the known composition.

Illustrious results tarnished

Their results offer a new perspective on all those illustrious yields reported in recent years and point to ways chemists might avoid inaccurate reporting of experimental parameters in future. The authors hope that their findings will push editorial policy to include a disclosure when calibration of data has not been validated for yields and excesses. Indeed, they suggest policy should be nudged one step further so that diastereomeric and enantiomeric excesses are no longer reported given their spurious nature and poor definition in modern chemistry.

 

Credit: Synlett/Thieme A critique by US chemists of how synthetic product yields are reported suggests that a lack of calibration could be distorting data from nuclear magnetic resonance spectroscopy, chromatography and mass spectrometry.
Wernerova and Hudlicky

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