How Torbjörn Lundstedt became achemometrician†

First of all I would like to congratulate Torbjörn to the HermanWold medal. He deserves this honour. Now, I wish to tell youthe story of how Torbjörn became a chemometrician. I know allthe details. He was my second graduate student. It all startedwhen I gave a lecture on infrared spectroscopy. Obviously, itwas an inspiring lecture and after it I was approached by astudent (Torbjörn) and he said that he wanted to do anundergraduate research project with me. I said OK. My firstsuggestion was in the field of enamine chemistry, but my firstgraduate student was also working in this field. Thus, I suggestedanother project, the Willgerodt reaction. Torbjörn found a paperpublished in JACS in 1946 by Carmack and DeTar[1]. He showedme the plots in the paper and said: ‘Do you see what I see?’ Ilooked at the plots too and I said: ‘It can be a response surface’.The paper contained enough data that could be read from thegraphs to permit response surface models for the variables takentwo by two. We could see that the response surface indicated amaximum yield. Experiments carried out in the calculatedoptimum domain afforded 91% yield, which was higher thanthe optimum yield (85.6%) reported by Carmack and DeTar inRef. [1]. Our results were published [2].

We then turned to the Willgerodt-Kindler modification of thereaction using primary or secondary amine to replace ammonia.The reaction is mentioned in almost all textbooks on organicchemistry, often as an embarrassing footnote because thereaction mechanism is not known with certainty, and allsuggested mechanisms are in conflict with experimentalobservation. The reaction has a bad reputation of being ratheruseless for synthesis; it usually gives poor yields (30–50%)isolated from black, tarry, and foul-smelling reaction mixtures.We thought that we could optimise the yields. The choice of thisreaction as a model reaction was very fortunate. It was foundthat the outcome was highly sensitive to the properties of theconstituents in the reaction mixture.

First, we wished to study the reaction with different substrates(para-substituted acetophenones). For each substrate theexperimental conditions were analysed by response surfacemethods to determine the conditions for maximum yield. Itwas possible to model the conditions for the optimum yield tothe properties of the para-substituents by PLS. It was alsopossible to use the PLS model to predict the optimum conditionsfor totally new substrates. The predictions were validated bydetermining the optimum conditions by response surfacemodels. The predictions were excellent. This was new. Nobodyhad ever predicted optimum experimental condition in thisway, and the results were published [3].Then, we wanted to study the reaction in different solvents.

We did not want to use ‘what-can-be-found-on-the-shelf’strategy for the selection of the solvent. We wanted a clear-cutcriterion for this. We thought that it might be possible to usetabulated properties of solvents and use a principal componentsanalysis to orthogonalize the property variables into principalcomponent scores, and then use the score plot for selection. Apaper on this was published [4] in which we suggested differentapproaches for selecting test candidates: Maximum spread whichtoday is called ‘diversity design’; Uniform spread, today called‘grid search’; selection by a Simplex search; selection by aD-optimal design. By running the Willgerodt-Kindler reaction insolvent selected by maximum spread design, and using responsesurface methodology to determine the conditions for maximumyield, it was possible to predict the outcome of the reaction inyet untested solvents [5]. By the same principles, different classesof compounds: aldehydes, ketones, amines, Lewis acid catalysts,were characterised by PCA[6]. Then, the editor of Acta Chem.Scand. said that we had to stop such characterisations. Weattracted no interest, whatsoever, with these papers. But he turnedout to be wrong. We were too much ahead of our time. 10 yearslater, the combinatorial chemistry exploded and then suddenlyour score plots of principal properties became highly interesting.In ourWillgerodt-Kindler studies, wewished to seewhether or not

we could determine the scope and limitation of the reaction with re-spect to variation of the substrate, amine reagent, and solvent, from asmall number of experiments. We used a fractional factorial designto select test items from different quadrants of the score plots forthe constituents, followed by response surface modelling for eachcombination. From only eight test systems in the calibration set, itwas possible to construct a PLS model and make good predictionsfor new combinations in a test set [7]. This was actually the very firstexample of a ‘combinatorial library’ in synthetic chemistry.Torbjörn summarised his finding in his PhD thesis[8] and I will

quote a part of his conclusions:

† A short text in celebration of Torbjörn Lundstedt’s actions within the fieldof chemometrics.

Editorial

Received: 7 May 2014, Accepted: 16 May 2014, Published online in Wiley Online Library: 23 July 2014

(wileyonlinelibrary.com) DOI: 10.1002/cem.2646

J. Chemometrics 2014, 28: 608–609 Copyright © 2014 John Wiley & Sons, Ltd.

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If all possible combinations of system descriptors studied inpapers II–V would have been simultaneously varied to spanthe reaction space, and if all reactions thus defined would havebeen optimised, a total of 9.600.000 individual experimentswould have been necessary. It would take one person around30.000 years to complete. This should be compared with the160 experiments needed by the proposed strategy. Of course,some information is lost. But 30.000years of work is saved,without systematic loss of information.

After his dissertation, Torbjörn went to the pharmaceutical in-dustry (Ferrosan in Malmö, a part of the Pharmacia Company).The company was interested in anti-schizophrenic pharmaceuti-cal. Torbjörn came across two types of psychiatric protocols inwhich different symptoms were graded and listed over the timeof treatment. Torbjörn used the protocols as the Y-block anddescriptors of the chemical structure of the pharmaceuticals asthe X-block, and by PLS, he was able to link the chemical structureto the pharmacological action. He could actually predict whatwould happen if a methyl substituent will be replaced by a chlo-rine: which symptoms will be relieved and which symptoms willbe aggravated. He presented his finding to the board of directors,and they realised immediately that this was completely new. Theydecided that Torbjörn should create a new centre, Structure-Property Optimization Center, SPOC, within Pharmacia, Uppsala. Thiscentre became highly successful. However, when Pharmacia wastaken over by Upjohn, they did not understand the merits ofchemometrics, so the centre was closed down. Torbjörn is nowleading a small pharmaceutical company, AcurePharma, and acompany specialising in metabolic profiling, Acureomics. And asfar as I know, they are doing very well. He is also a visiting professorat the school of pharmacy in Uppsala where he teaching studentsessentials of QSAR modelling.At the Second Symposium Scandinavian of Chemometrics in

Bergen, Norway 1991, I was approached by Luc Massart, andhe said that we should start a section for chemometrics in Swedenas a section of the Swedish Chemical Society. I said that I agreedand tried to coordinate this within the Swedish academia, withoutsuccess. Then, there was an initiative from industry (TorbjörnLundstedt at Pharmacia, Uppsala, and Bo Nordén at Astra Draco,Lund) to create a section for chemometrics in The SwedishChemical Society. I was the chairman of the Umeå section of theSwedish Chemical Society and I had a position as a member ofthe board. The question of starting a section for chemometricswas on the agenda at the board meeting. The president wasagainst the whole idea and he said that we first should initiate asection for organic chemistry. I pointed out that the initiative

actually came from the pharmaceutical industry and that it wouldbe very unwise not to accept the proposal. My arguments obviouslyconvinced the other members of the board, and the section forchemometrics was created. I assisted at the childbirth, and Ibecame the godfather. Torbjörn was elected as the chairman ifthe new section of the Swedish Chemical Society, a positionhe upheld for more than 20 years. He has done a good job.

When I saw that Torbjörn had been awarded the HermanWold Medal for outstanding contributions to chemometrics,my immediate reaction was: It was about time!

My sincere congratulations, Torbjörn, to the prestigious medal.SUMMA FELICITAS TIBI.

SEMPER TUUS

Rolf CarlssonProfessor emeritus

University of Tromsö, Tromsö, Norway

REFERENCES1. DeTar DF, Carmack M. Willgerodt Reaction II. A study of reaction

conditions with acetophenone and other ketone. J. Am. Chem. Soc.1946; 68:2025.

2. Carlson R, Lundstedt T, Phan-Tan-Luu R, Mathieu D. On the necessityof using multivariate methods for optimization in synthetic chemistry.an instructive example with the Willgerodt reaction. Nouv. J. Chim.1983; 7: 315.

3. Carlson R, Lundstedt T, Shabana R. Optimum conditions for theWillgerodt-Kindler Reaction 1. Reaction of substituted acetophenones.Prediction of optimum conditions for new substrates by multivariatecorrelation. Acta Chem. Scand. 1986; B 40: 534.

4. Carlson R, Lundstedt T, Albano C. Screening of suitable solvents fororganic synthesis, strategies for solvent selection. Acta Chem. Scand.1985; B 39: 79.

5. Carlson R, Lundstedt T Shabana R Optimum conditions for theWillgerodt-Kindler Reaction 2. A multivariate study on the influenceof different solvent on the optimum conditions. Acta Chem. Scand.1986; B 40: 694.

6. (a) Carlson R, Prochazka MP, Lundstedt T. Principal properties for syntheticscreening: ketones and aldehydes. Acta Chem. Scand. 1988; B 42: 145.(b) Carlson R, Prochazka MP, Lundstedt T. Principal properties forsynthetic screening: amines. Acta Chem. Scand. 1988; B 42: 157.(c) Carlson R, Lundstedt T, Nordahl Å Prochazka M Lewis acids inorganic synthesis: approach to a selection strategy for screeningexperiments. Acta Chem. Scand. 1986; B 40: 522.

7. Carlson R, Lundstedt T. Scope of synthetic reactions. Multivariatemethods for the exploration of the reaction space. An example withthe Willgerodt-Kindler reaction. Acta Chem. Scand. 1987; B 41: 164.

8. Lundstedt T. The Willgerodt-Kindler reaction. A multivariate approach.Diss. Umeå University: Umeå 1986. ISBN 91-7174-248-4.

How Torbjörn Lundstedt became a chemometrician

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