## 4 Discussion and Conclusions
On the G4 method and alternatives, [PERSON] and [PERSON] concluded [52] that 'If one is restricted to using a single method, statistical measures indicate that the best methods are in the rank order G3 \(\approx\) G4 > W1 BD > CBS-APNO > CBS-QB3'. The comparison of theoretical quantum methods was made with reference to the experimental data from the Active Thermochemical Tables compilation though limited to 45 CxHyOz molecules. Moreover, it should be verified whether the experimental data are the truly correct ones with chemical accuracy. In another study [53], the authors combined artificial intelligence with quantum methods in order to obtain a faster method but retaining good performance. The heat of formation of around 130 organic CHNO species was found, among a larger number of methods, still best represented by the G4 method: a mean absolute deviation of 0.74 kcal/mol vs. 0.85 kcal/mol for the AI method (AIQM1), the best of all approaches tested. Our conclusion is that the G4 results are more likely the more reliable results than the experimental values in the cases referred to. Moreover, the good performance of the GC model for butylisobutylamine, for which we do not expect any specific electronic or steric effects, supports this view, and the GC model value agrees very well with the G4 value. Contrary to other related works, we applied conformational averaging to obtain a slightly more realistic G4 result. Although the difference is generally only a few kJ/mol, this may still be relevant when attempting the development of a model with chemical accuracy, e.g., 4.2 kJ/mol. Secondly, discrepancies are observed for molecules due to the presence of steric interactions such as nearest neighbour substituents on a benzene ring. Such steric effects cannot be accounted for by a Group Contribution method. The fact that we could come up with interaction parameters between neighbouring methoxy Groups in Section 3.3.4 was perhaps some form of good luck, but it will be obvious that, in general, it will not be possible to establish such parameters for many types of substituents. One aspect is the lack of sufficient experimental data to support this, but there might also be a more fundamental problem to be solved to make this work in a generic sense. Moreover, the mere number of possible combinations of neighbouring substituents would make it practically impossible. The conclusion is that when neighbours are near and steric effects expected, the GC model result should be considered insufficiently reliable when looking for chemical accuracy. The G4 method could be applied to obtain a reliable value, assuming the tools and expertise to perform such calculations are available. Finally, as the likelihood to find appropriate experimental data to further expand the GC model becomes more and more distante, relying on the G4 method seems to be the method of choice for further development. This is what we already found for the aliphatic esters. Selected experimental data should be used to verify the correctness of the G4 method for other classes of molecules. This applies to, e.g., various classes of heterocycles. It might also be investigated whether G4 calculations are capable of quantitatively capturing the correct heat of formation of fragments involving high steric congestion. An extension of our GC model using G4 data could be advanced using the larger set of G4 data reported by [PERSON] c.s. [19]. More G4 data are available in the literature including data on polyprismanes [54] and mono- through tetra-substituted hydro, fluoro, chloro, bromo,methyl, ethynyl, and cyano carbon tetrahedrane derivatives [55]. These are particularly useful as few experimental data are available. For cubane, excellent agreement between the G4 value and the only available experimental value was reported [54]. Finally, cations might be investigated using the G4 method [56], which is useful as for ions and radicals even fewer experimental data are available.