Effect of mono- and di-hydration on the stability and tautomerisms of different tautomers of creatinine: A thermodynamic and mechanistic study

doi:10.1016/j.comptc.2015.03.008

Computational and Theoretical Chemistry

Volume 1061, 1 June 2015, Pages 27-35

https://doi.org/10.1016/j.comptc.2015.03.008 Get rights and content

Highlights

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Amino and imino isomers of creatinine exist in aqueous and gas phase, respectively.
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In the mono-hydrated form, imino and amino isomers have considerable abundances.
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When creatinine is di-hydrated, only its amino form is the most stable isomer.
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H₂O catalyzes the proton transfers in creatinine and decreases the energy barriers.

Abstract

Relative stabilities of nine tautomers of creatinine in gas and aqueous phases and hydrated forms were studied by M062X, MP2 and B3LYP computational methods. It was found that two tautomers (an amino and an imino) have significant stability and relative abundances among all. The imino tautomer is more stable in gas phase while the amino form is more stable in aqueous phase and in di-hydrated form. The stability and relative abundances of the both amino and imino tautomers in mono-hydrated form were approximately the same. Activation energies and Gibbs free energies of isomerizations in creatinine, including intramolecular proton transfers and internal OH rotations, were calculated. The energy barriers of rotations of hydrogen atom of OH group around C–O bond were smaller than 40 kJ/mol. Two types of proton transfer reactions including imine ↔ amine and keto ↔ enol tautomerisms were considered. The activation energies of keto–enol tautomerisms, in which the proton is transferred between oxygen and carbon atoms, were in the range 270–300 kJ/mol. Catalysis effect of one and two water molecules on the intramolecular proton transfers was studied. It was found that the activation energies are decreased by about 130 and 150 kJ/mol in the presence of one and two water molecules, respectively.

Graphical abstract

Introduction

Intermolecular and intramolecular proton transfer are important reactions in biological and chemical systems [1], [2]. Keto–enol and amino–imino tautomerisms are two types of intramolecular proton transfers which have been well studied [3], [4], [5], [6], [7]. Tautomerism occurs in molecules that have both proton acceptor and proton donor sites. Creatinine is one the molecules that have different tautomers and exists in anino-, imino-, keto and enol forms.

Creatinine is a byproduct of muscle metabolism which is excreted unchanged by the kidneys, therefore, it is used to diagnose renal diseases [8], [9], [10]. Detection of creatinine in urine is based on some chemical reactions or spectrometric and spectroscopic methods. Creatinine has different tautomers which may have different properties and reactivity, therefore, they affect the results of the measurements in different ways. Several research groups have studied creatinine tautomers and their structural properties by theoretical methods and experimental techniques [11], [12], [13], [14], [15], [16], [17]. Creatinine can have different tautomers, however, there are two tautomers that are more stable than others. The amino tautomer of creatinine (2-amino-1-methyl-2-imidazoline-4-one, tautomer II in Fig. 1) is the most stable tautomer in aqueous phase [13], [14], [15], [17], while in the gas phase, the imino tautomer (2-imino-1-methyl-imidazoline-4-one, tautomer I in Fig. 1) is more stable [13], [14], [18]. Although creatinine can have more than these two tautomers, only its amino and imino tautomers have been considered in the literature [12], [13], [14], [18], [19]. A theoretical study on the creatinine structure showed that the imino tautomer is more stable than the amino form by 8.3 kJ/mol, in gas phase while the amino tautomer is preferred in aqueous phase by 10.8 kJ/mol [13]. Also, there are some studies on the calculation of internal rotations in creatinine. Craw et al. [18] calculated the barrier of rotation about C–NH₂ bond in amino form of creatinine using NMR spectroscopy and computational methods in aqueous phase. They obtained the rotation barrier to be about 54 and 37 kJ/mol using experimental and theoretical methods, respectively. Kotsyubynskyy et al. [14] performed another study on the C–NH₂ rotation in creatinine by NMR spectroscopy in DMSO-d6 solution and obtained the same results.

As mentioned, stability of the two tautomers creatinine has been studied in gas phase and solution. In this work, thermodynamic and structural properties of nine tautomers of creatinine are studied in gas and aqueous phases as well as in mono- and di-hydrated forms. Furthermore, simple and water catalysis tautomerisms in creatinine are investigated and their activation energies are calculated using MP2 and B3LYP methods.

Section snippets

Computational details

M062X [20], B3LYP and MP2 computational methods were employed to optimized the structures of the different tautomers of creatinine in isolated and hydrated forms. The 6-311++G(3df, 3pd) and 6-311++G(d, p) basis sets were used for the calculations which involve enough polarization and diffuse functions for hydrogen and heavy atoms. Frequency calculations were performed by the same methods and basis sets to obtain the thermodynamic quantities of the structures. The interaction energies between

Relative stability of creatinine tautomers

Structures of nine tautomers of creatinine optimized at B3LYP level of theory are shown in Fig. 1. Geometrical parameters of the tautomers structures have been collected in Supplementary Information A. The tautomers I, II and IX are keto forms of creatinine while the others are enolic tautomers. Another classification can be applied according to the –NH_n (n = 1 or 2) group so that tautomers I, V, VI and IX are amino tautomers and the other tautomers are imino forms of creatinine.

The energetic

Conclusion

Creatinine has different tautomers whose stabilities are different in gas phase and aqueous solutions. In this work, structures of nine tautomers of creatinine (I–IX) were studied in gas and aqueous phases using computational methods. The tautomer I is the most stable form of creatinine in gas phase while the tautomer II has the most relative abundance in aqueous phase. When creatinine is mono-hydrated, the relative abundances of the tautomers I and II are the same. As the hydration increases

Acknowledgment

The authors wish to express thanks to the Center of Excellency in Chemistry of Isfahan University of Technology.

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Effect of mono- and di-hydration on the stability and tautomerisms of different tautomers of creatinine: A thermodynamic and mechanistic study

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Computational details

Relative stability of creatinine tautomers

Conclusion

Acknowledgment

Atmos. Environ.

Vib. Spectr.

Comput. Theor. Chem.

Comput. Theor. Chem.

Neurosci. Biobehav. Rev.

J. Mol. Struct. THEOCHEM

Chem. Phys.

Chem. Phys.

J. Mol. Graph. Modell.

Stair motifs at protein–DNA interface. Nonadditivity of H-bond, stacking, and cation-pi interactions

J. Am. Chem. Soc.

Tautomersim of purines. 2. Amino–imino tautomerism in 1-alkyladenines

J. Am. Chem. Soc.

Tautomeric equilibria in relation to pi-electron delocalization

Chem. Rev.

Recommendations for improving serum creatinine measurement: a report from the laboratory working group of the national kidney disease education program

Clin. Chem.

Relating structure to mechanism in creatine kinase

Crit. Rev. Biochem. Mol. Biol.

Solvation and solid state effects on the structure and energetics of the tautomers of creatinine

J. Chem. Phys.

Creatinine and creatininium cation in DMSO-d6 solution. Structure and restricted internal rotation of NH2 group

Magn. Reson. Chem.

Tautometric preferences among glycocyamidines

J. Am. Chem. Soc.

A two-dimensional self-assembled proton transfer compound containing pyridiunium-2,6-bis(monothiocarboxylates) and creatinine ion pair: synthesis, characterization, crystal structure, solution and ab initio studies

J. Iran. Chem. Soc.

Creatinine and creatininium cation in DMSO-d₆ solution. Structure and restricted internal rotation of NH₂ group