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Review
. 2023 Oct 26;28(21):7282.
doi: 10.3390/molecules28217282.

On Prototropy and Bond Length Alternation in Neutral and Ionized Pyrimidine Bases and Their Model Azines in Vacuo

Ewa Daniela Raczyńska  1
Affiliations
Review

On Prototropy and Bond Length Alternation in Neutral and Ionized Pyrimidine Bases and Their Model Azines in Vacuo

Ewa Daniela Raczyńska. Molecules. .

Abstract

In this review, the complete tautomeric equilibria are derived for disubstituted pyrimidine nucleic acid bases starting from phenol, aniline, and their model compounds-monosubstituted aromatic azines. The differences in tautomeric preferences for isolated (gaseous) neutral pyrimidine bases and their model compounds are discussed in light of different functional groups, their positions within the six-membered ring, electronic effects, and intramolecular interactions. For the discussion of tautomeric preferences and for the analysis of internal effects, recent quantum-chemical results are taken into account and compared to some experimental ones. For each possible tautomer-rotamer of the title compounds, the bond length alternation, measured by means of the harmonic oscillator model of electron delocalization (HOMED) index, is examined. Significant HOMED similarities exist for mono- and disubstituted derivatives. The lack of parallelism between the geometric (HOMED) and energetic (ΔG) parameters for all possible isomers clearly shows that aromaticity is not the main factor that dictates tautomeric preferences for pyrimidine bases, particularly for uracil and thymine. The effects of one-electron loss (positive ionization) and one-electron gain (negative ionization) on prototropy and bond length alternation are also reviewed for pyrimidine bases and their models.

Keywords: bond length alternation; complete tautomeric mixtures; consequences of positive and negative ionization; internal effects; pyrimidine nucleic acid bases; quantum-chemical data in vacuo; tautomeric aromatic azines; tautomeric preferences.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Prototropic equilibria in phenol (X = O) and aniline (X = NH). The labile proton is indicated in bold red color.
Figure 2
Figure 2
Isomeric equilibria possible for 2- (2HOPY) and 4-hydroxypyridines (4HOPY), and 2- (2HOPM) and 4-hydroxypyrimidines (4HOPM). The labile proton shown in bold red color. Tautomeric equilibria and rotation about C–OH indicated by ⇌ and ⇄ arrows, respectively.
Figure 3
Figure 3
Isomeric equilibria possible for 3-hydroxypyridine (3HOPY) and 5-hydroxypyrimidine (5HOPM). The labile proton shown in bold red color. Tautomeric conversions indicated by ⇌ arrows, while zwitterion formation and rotation about C–OH by ⇄ arrows.
Figure 4
Figure 4
Isomeric equilibria for 2- (2APY) and 4-aminopyridines (4APY), and 2- (2APM) and 4-aminopyrimidines (4APM). The labile proton shown in bold red color. Tautomeric equilibria and configurational isomerism about =NH indicated by ⇌ and ⇄ arrows, respectively.
Figure 5
Figure 5
Tautomeric equilibria in pyrimidine bases: uracil (U with X, Y = O, R = H), thymine (T with X, Y = O, R = CH3), cytosine (C with X = O, Y = NH, R = H), and isocytosine (iC with X = NH, Y = O, R = H). The two labile protons indicated in bold red color. The number of atoms shown in 78.
Figure 6
Figure 6
Eighteen tautomers-rotamers possible for U (R = H) and T (R = CH3). The two labile protons shown in bold red color. Abbreviations of tautomers refer to the number of atoms possessing the two labile protons and those of rotamers to the two extreme positions of the exo hydroxy H atom at 2- (a or b) and/or 4-position (a or b).
Figure 7
Figure 7
Twenty-one tautomers-rotamers possible for C. The two labile protons indicated in bold red color. Abbreviations of tautomers refer to the number of atoms possessing the labile protons and/or those of rotamers to the two extreme positions of the exo hydroxy H atom at 2-position (a or b) and/or the imino H atom at 4-position (a or b).
Figure 8
Figure 8
Intramolecular interactions between neighboring exo and endo groups/atoms in selected conformational and configurational isomers of model azines. The labile proton indicated in red color, and H atoms engaged in intramolecular interactions in black color.
Figure 9
Figure 9
Intramolecular interactions between neighboring exo and endo groups/atoms in selected conformational (a) and configurational (b) isomers of pyrimidine bases (X, Y: O or NH). The labile protons indicated in red color and H atoms engaged in intramolecular interactions in black color.
Figure 10
Figure 10
DFT-calculated relative Gibbs energies for selected tautomers–rotamers of pyrimidine bases. The numbers 1–9 correspond to the favored isomers of 13, 17, 18, 37, 38, 78, 35, 57, and 58. For 6 (favored isomer of 78), ΔG = 0 kcal mol−1. Data taken from refs. [62,64,65].
Figure 11
Figure 11
Variations of HOMEDs estimated for selected isomers of model azines and pyrimidine bases. HOMED for the six-membered ring included in the ring and that for the entire molecule placed near formula. DFT-calculated HOMED data taken from refs. [28,49,57,58,59,60,61,62,63,64,65].
Figure 12
Figure 12
Linear trends for monosubstituted azines including parent systems (a) and disubstituted pyrimidine bases (b) between HOMEDs (for entire molecule) and ΔGs for isomers containing labile proton(s) at N and/or C atoms. DFT-calculated geometric and energetic data taken from refs. [18,22,28,49,57,58,59,60,61,62,63,64,65].
Figure 13
Figure 13
Linear relations between HOMED6s estimated for tautomers–rotamers of mono-amino and mono-hydroxy aromatic derivatives (a) and for isomers of disubstituted pyrimidine bases (b). DFT-calculated HOMED6s for the six-membered ring taken from refs. [18,22,28,49,57,58,59,60,61,62,63,64,65].
Figure 14
Figure 14
Consequences of positive and negative ionization on composition of isomeric mixtures and electron delocalization for phenol and aniline. DFT-estimated percentage contents given below formula, HOMED6s included in the ring, and HOMED7s placed near the ring. Data taken from refs. [18,22].
Figure 15
Figure 15
Consequences of positive and negative ionization on isomeric-mixture composition and electron delocalization for mono-hydroxy (2HOPY, 4HOPY, 2HOPM, and 4HOPM) and mono-amino azines (2APY, 4APY, 2APM, and 4APM). DFT-estimated percentage contents given below formula, HOMED6s included in the ring, and HOMED7s placed near the ring. Data taken from refs. [49,58,59,60,61].
Figure 15
Figure 15
Consequences of positive and negative ionization on isomeric-mixture composition and electron delocalization for mono-hydroxy (2HOPY, 4HOPY, 2HOPM, and 4HOPM) and mono-amino azines (2APY, 4APY, 2APM, and 4APM). DFT-estimated percentage contents given below formula, HOMED6s included in the ring, and HOMED7s placed near the ring. Data taken from refs. [49,58,59,60,61].
Figure 16
Figure 16
Variations in tautomeric-mixture composition and electron delocalization for neutral and ionized uracil. DFT-estimated percentage contents given below formula, HOMED6s included in the ring, and HOMED8s placed near the ring, all taken from refs. [62,63].
Figure 17
Figure 17
Variations of isomeric preferences and electron delocalization when proceeding from neutral to ionized cytosine. DFT-estimated percentage contents given below formulae, HOMED6s included in the ring, and HOMED8s placed near the ring, all taken from ref. [64].
Figure 18
Figure 18
Variations of isomeric preferences and electron delocalization when proceeding from neutral to ionized isocytosine. DFT-estimated percentage contents given below formulae, HOMED6s included in the ring, and HOMED8s placed near the ring, all taken from refs. [28,57,65].
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