AbstractDerivatives of amides belong to a very attractive group of compounds due to a broad spectrum of different biological activities. The type of molecule activity significantly depends on its interactions with the environment, which on the other hand largely depends on the nature of the substituent attached to the basic molecule as well as of solvents properties. In this work, the influence of the mentioned parameters on the interaction ability of the group of N‐(4‐phenylsubstituted) cyanoacetamides is investigated by using multivariate methods, based on the results obtained by reverse‐phase thin‐layer chromatography and ultraviolet absorption spectroscopy. Results obtained by the used chemometrics methods are very similar, within which the principal component analysis has provided the most detailed information. The obtained results suggest that the interactions of the investigated compounds are dominantly regulated by the polarity of the used solvents and their proton donor ability inside the chromatographic measurements, while in the case of the spectrophotometric data, the solvent's hydrogen bond ability has the greatest impact on the future interaction capability of the investigated cyanoacetamides. In the case of the substituent effect which is attached to the benzene ring, the greatest impact on the future interaction ability of the investigated cyanoacetamides is the orientation effect of ring substituent. Based on all the obtained results, it can be noticed that the used multivariate methods are able to detect effects of the substituent and solvent properties on the future interaction ability of the investigated derivatives. Copyright © 2015 John Wiley & Sons, Ltd.