Intramolecular Diels-Alder reactions of pyrimidines, a synthetic and computational study

W.A.W. Stolle

Research output: Thesisinternal PhD, WU


This thesis deals with an investigation on the ringtransformation reactions of 2and 5-(ω-alkynyl)pyrimidine derivatives, which undergo upon heating an intramolecular Diels-Alder reaction and subsequently a spontaneous retro Diels- Alder reaction. To get a better insight into the applicability and the mechanistic aspects of these conversions synthetical organic experiments were carried out and computational chemistry methods were used to explain the obtained results.

In Chapter 1 a historical overview, a classification of the Diels-Alder reactions and a general introduction on computational chemistry is given, because the latter is a relatively unknown field within the organic chemistry. Finally the scope of this thesis is given.

In Chapter 2 the synthesis and ringtransformations of 2-(2- trimethylsilylethynylphenyl-X)pyrimidines (X= O, S, NAc, CH 2 , CO, NH) are described. In case of X= O, S, NAc, CH 2 and CO this yields new tricyclic annelated heteroaromatic systems. Because the reaction rate of these compounds (t 1/2 : CO < NAc < O < CH2 < S << NH) is not as was expectated, a computational study towards the reactivity of some specific analogs was performed in Chapter 3.

From semi-empirical calculations (MNDO) it appeared that the heat of activation of the intramolecular Diels-Alder reactions is not the rate determining factor. Therefore the origin of the differences in reactivity has to be found in the sterical (e.g. conformational) properties of the molecules. To investigate a methodology was developed in which the reactivity of a conformation is coupled to the probability of the molecule to be in that conformation. By means of a "Rigid Rotor" approximation a large number of conformations can be generated and their energies calculated (Molecular Mechanics). Then it is possible to determine the probability of the molecule to be in each generated conformation by means of the "Bolzmann" distribution equation. As a measure for the reactivity of a conformation the distance between the diene and dienophile was taken. From the combination of reactivity and probability of the conformations it could be concluded that the reactivity of the molecules under study is determined by the probability of the molecules to be in a conformation which is able to undergo an intramolecular Diels-Alder reaction.

By means of this methodology and the previously mentioned semi- empirical calculations the enhanced reactivity of α,α-dicyano-2-(pent-4-yn-l-yl)pyrimidine as compared to its α,α-dihydro analog was investigated (Chapter 4). Starting with the crystal structures of 5- p -nitrophenyl-2-(pent-4-yn-l-yl)pyrimidine and 2-(1,1-dicyanopent-4-yn-l-yl)-5-nitropyrimidine the heats of activation and the probability-reactivity relationships were determined. Analysis of these data revealed that the enhanced reactivity by introduction of the two cyano groups is caused by: i) a decrease of the heat of activation, due to the electron withdrawing capacity of the cyano groups, ii) a rotamer effect, iii) the so called "Thorpe-Ingold"/ gem -dialkyl effect.

Chapter 5 deals with an investigation towards the reactivity and selectivity of 2en 5-(ω-alkynyl)pyrimidines. In the synthetic part it appears that 2-(prop-2-ynyloxycarbonyl)pyrimidine gives a Diels-Alder reaction under the applied reaction conditions (nitrobenzene, 210 °C), whereas the isomeric 5-(prop-2-ynyl- oxycarbonyl)pyrimidine does not react. Likewise, it appeared that 5 -phenyl-2- (2(1-prop-2-ynyl)pyrrolidinyl)pyrimidine does react, wherease its aromatic analog 5-phenyl-2-(2-(1-prop -2-ynyl)pyrryl) pyrimidine does not. On the other hand, the aromatic 2-(2-prop-2ynyloxyphenyl)pyrimidines do react under relatively mild conditions. It was determined that the observed differences in reactivities could not be explained by the differences in the heats of activation. By application of the previous mentioned computational technics, it appeared that the differences in reactivity between often closely related molecules were determined by the (im)possibilities of the molecules to be in conformations in which the diene and dienophile can react.

In Chapter 6 the synthesis of 5-propynyloxycycloalkanepyrimidine derivatives is presented and their reactivity and selectivity in intramolecular Diels-Alder reactions. Upon introduction a methyl, ethyl or phenyl substituent alfa according to the pyrimidine moiety the reactivity of the molecules under study increase 4 - 10 times. The selectivity of the retro Diels-Alder reaction appears to be determined mainly by the size of the cycloalkane ring: cyclohexane ring, cycloheptane ring or no ring at all. In case of the last two the expulsion of HCN is favoured, whereas in the first case mainly the expulsion of -X-CH 2 CN is observed. Besides, the ringtransformation of 2-phenyl-S-propynyloxy-5,6,7,8-tetrahydroquinazoline and the two 5- H -S-R-2phenyl-S-propynyloxy-6,7,8,9-tetrahydrocyclohepta- [b]pyrimidines yielded two hitherto unknown ringsystems: 4-phenyl-2 H -6,7,8,8a-tetrahydrofuro[4,3,2- de ]quinoline and 2 H -1,6,7,8,9,9a-hexahydro-4-phenyl-9a-R-5- aza-1-oxo-benz[c,d]azulenes.

From computations towards the differences in selectivity and the reactivity of the 5-propynyloxycycloalkanepyrimidine derivatives, as presented in Chapter 7, it appeared that both properties were determined by differences in the heats of activation. Determination of the energies and dipole moments of the transition states of the different reaction pathways revealed that the ratio of the product formation was determined by the polarity of the transiton states as represented by their dipole moments in combination with the polarity of the reaction medium. Also the reactivity of the compounds under study appeared to depend on the polarity of the transition state of the initial Diels-Alder reaction. The differences in dipole moments of the different TS's are ascribed to the geometry of the molecules in the TS's. Furthermore, a comparison of the heats of activation of the initial Diels-Alder reaction and the subsequent retro Diels-Alder reaction showed that the first one is the rate determining step.

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
  • Marcelis, A.T.M., Promotor
Award date16 Apr 1992
Place of PublicationS.l.
Publication statusPublished - 1992


  • pyrimidines
  • synthesis
  • addition reactions


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