Activation of Ligand Reaction on an Iron Complex: H/D Exchange Reaction of a Low-Spin Bis[2-(Pyridylmethylidene)-1-(2-pyridyl)methylamine]iron(II) Complex

Abstract

With the aim of shedding some light on the still scarcely investigated mechanism of transformation of imines in metal complexes, this study describes the investigation of the hydrogen–deuterium (H/D) exchange reaction of a bis[2-(pyridylmethylidene)-1-(2-pyridylmethylamine]iron(II) complex ([Fe(PMAP)₂]²⁺), following our previous work on a low-spin iron(II) complex bearing two molecules of S-2-pyridylmethylidene-1-(2-pyridyl)ethylamine. This complex has been proven to undergo successive transiminations in acetonitrile, yielding a bis[1-(2-pyridyl)ethylidene-2-pyridylmethylamine]iron(II) complex. In the analogous [Fe(PMAP)₂]²⁺ complex, a 1,3-hydrogen rearrangement occurs in a 10% deuterium oxide-acetonitrile-d₃ (D₂O–CD₃CN) solution. The H/D exchange reaction of [Fe(PMAP)₂]²⁺ was examined in the presence of various concentrations of 2,6-dimethylpyridine as a base in a 10% D₂O–CD₃CN solution at 45 °C, and the reaction mechanism was investigated.

Introduction

The transfer of hydrogen from one group to another within a molecule or between molecules is one of the most important and fundamental chemical reactions¹⁾ involved in processes such as transamination and racemization of α-amino acids. Many of the biochemical transformations occurring in the latter processes are often catalyzed by pyridoxal (vitamin B₆).^2–5) In such reactions, aldimines are formed from the aldehydes of pyridoxal and the amino groups of the substrate. The subsequent transimination from aldimines to ketimines is the central process of the biochemical reaction. It is well known that metal ions accelerate these reactions compared to H⁺, and can catalyze pyridoxal-dependent reactions.

Meanwhile, metal complexes containing imines can be easily obtained by reacting a carbonyl group (ketone or aldehyde) with an amine in the presence of a metal precursor.^6,7) Consequently, the mechanism of formation of imine bonds in the presence of metal ions has been well studied.^6–15)

Previously, we prepared an imine-containing low-spin iron(II) complex bearing two molecules of S-2-pyridylmethylidene-1-(2-pyridyl)ethylamine ([Fe(S-PMPE)₂](ClO₄)₂), which was isolated as a diastereomeric mixture, Λ- and Δ-[Fe(S-PMPE)₂]²⁺¹⁶⁾(Fig. 1). Moreover, the analysis of hydrogen–deuterium (H/D) exchange was performed to investigate transimination because transformation occurred via the proton exchange. We found that [Fe(S-PMPE)₂]²⁺ underwent successive transiminations, yielding bis[1-(2-pyridyl)ethylidene-2-pyridylmethylamine]iron(II) as a mixture of Λ- and Δ-[Fe(PEPM)₂]²⁺ in acetonitrile¹⁶⁾ (Fig. 1).

Fig. 1. Transimination Pathway of Λ- and Δ-[Fe(S-PMPE)₂]²⁺

Following our studies on the transformations of imine-containing complexes, we prepared an iron(II) complex bearing two molecules of 2-(pyridylmethylidene)-1-(2-pyridyl)methylamine, [Fe(PMAP)₂](ClO₄)₂ (Fig. 2), which is similar to [Fe(S-PMPE)₂]²⁺. Herein, we describe the investigation of the H/D exchange reaction of [Fe(PMAP)₂]²⁺ in the presence of various concentrations of 2,6-dimethylpyridine as a base in a 10% deuterium oxide-acetonitrile-d₃ (D₂O–CD₃CN) solution at 45°C using NMR spectroscopy. Furthermore, the dependency of the H/D exchange rate on the concentration of 2,6-dimethylpyridine is evaluated, and its reaction mechanism is investigated in detail.

Fig. 2. Chemical Structure of [Fe(PMAP)₂](ClO₄)₂

Results and Discussion

[Fe(PMAP)₂](ClO₄)₂ was prepared according to the method previously reported by Lions and Martin.¹⁷⁾ Figure 3a shows the time-dependent changes in the ¹H-NMR of [Fe(PMAP)₂]²⁺ in the presence of various concentrations of 2,6-dimethylpyridine in a 10% D₂O–CD₃CN solution at 45°C. Figure 3b shows an enlarged view of the change in the methylene area of the spectrum.

Fig. 3. (a) ¹H-NMR Spectral Changes of [Fe(PMAP)]²⁺ in the Presence of 7.89 mM 2,6-Dimethylpyridine in a 10% D₂O–CD₃CN Solution at 45°C

(b) Expansion of the methylene area.

In the early reaction stage, the methylene protons appeared as an AB pattern signal centered at approx. δ = 6.59 ppm, whose peaks are denoted as q1, q2, q3, and q4, starting from the low magnetic field side, in Fig. 3. The signal of the singlet azomethine proton, which is denoted as s1, appeared at δ = 10.20 ppm. As can be seen in the figure, the intensity of the q1 and q3 signals gradually diminished with time. On the other hand, the q2 signal decreased at a lower rate than q1 and q3. A new signal (denoted as n2) appeared near q4 over time (see 6 and 15 min in Fig. 3b). In the spectrum recorded at 70 min (Fig. 3b), n2 and another signal n1, which would be most likely overlapped with q2, were clearly observed close to q2 and q4. The intensity of both n1 and n2 signals decreased until it almost disappeared at 1350 min (Fig. 3b). From these observations, it can be inferred that the two newly appearing signals n1 and n2 are owing to the H/D exchange of one of the methylene hydrogens (CH₂).

On the other hand, the azomethine signal at δ = 10.25 ppm was still present at 1350 min, although its intensity diminished similarly to that of q1–q4. These results suggest that the H/D exchange reaction occurred with two different reaction rates.

Next, we estimated the H/D exchange rate using the signal areas of q1–q4, n1, n2, and s1 (See Supplementary Materials for details of the analysis method). Figures 4a and 5a show examples of the time course of the H/D exchange reaction at the methylene and azomethine signals in the presence of 7.89 mM 2,6-dimethylpyridine. As can be extracted from Figs. 4b, c, the H/D exchange at the methylene protons followed successive first-order reactions with rate constants of 0.118 and 0.021 min⁻¹ (see Table S2), indicating that the exchange of one of the methylene hydrogens occurred in the initial stage, followed by the exchange of the remaining hydrogen (described above).

Fig. 4. (a) Time Course of the H/D Exchange at the Methylene Protons of [Fe(PMAP)]²⁺ in the Presence of 7.89 mM 2,6-Dimethylpyridine in a 10% D₂O–CD₃CN Solution at 45°C

Four methylene proton peaks were denoted by q1, q2, q3, and q4, starting from the low magnetic field side. Solid lines were generated by a nonlinear least-squares fit of the data to Eqs. 1 and 2 in Supplementary materials. (b) Dependency of first-order rate constants for the H/D exchange reaction of q1 and q3 on the concentration of 2,6-dimethylpyridine. (c) Dependency of first-order rate constants for the H/D exchange reaction of q2–q1 and q4–q3 on the concentration of 2,6-dimethylpyridine.

Fig. 5. (a) Time Course of the H/D Exchange at the Azomethine Proton of [Fe(PMAP)]²⁺ in the Presence of 7.89 mM 2,6-Dimethylpyridine in a 10% D₂O–CD₃CN Solution at 45°C

Solid lines were generated by a nonlinear least-squares fit of the data to equation 3 in Supplementary materials. (b) Dependency of first-order rate constants for a slow reaction of the azomethine proton on the concentration of 2,6-dimethylpyridine. (c) Dependency of first-order rate constants for a fast reaction of the azomethine proton on the concentration of 2,6-dimethylpyridine.

In contrast, the intensity decay of the azomethine proton resonance proceeded more slowly compared to that of the methylene protons (Fig. 5a). Assuming that the kinetics of the H/D exchange reaction of the azomethine proton obey two first-order reactions composed of fast and slow phases, the decay rate can be expressed as A₁ exp(−k_fastt) + A₂ exp(−k_slowt), with k_fast = 0.027 min⁻¹ and k_slow = 0.0016 min⁻¹ (see Table S3).

We envisaged a plausible mechanism for the H/D exchange reaction of [Fe(PMAP)]²⁺, which is shown in Fig. 6, taking into account that the rate of the H/D exchange reaction increased with the concentration of 2,6-dimethylpyridine as extracted from Figs. 4b, c and Figs. 5b, c, and deriving the second-order rate constants from the slope of the lines in Figs. 4b, c and Figs. 5b, c. As can be seen in Fig. 6, species (1) disappears to yield species (2) with a second-order rate constant of 0.015 min⁻¹ mM⁻¹. Subsequently, species (2) disappears to yield species (3) or (4) with a second-order rate constant of 0.0028 min⁻¹ mM⁻¹.

Fig. 6. Proposed Pathway for the H/D Exchange of [Fe(PMAP)]²⁺ in the Presence of 2,6-Dimethylpyridine as a Base in a 10% D₂O–CD₃CN Solution

With regard to the azomethine proton, it is necessary to consider the process via species (3) because the decrease in the signal of the azomethine proton at 10.20 ppm is composed of two first-order reactions. The fast H/D exchange process of the azomethine protons proceeds from species (1) → species (2) → species (4) with k_fast = 0.0042 min⁻¹ mM⁻¹, whereas in the slow H/D exchange process the transition state is reached from (2) via species (3) and then through species (4) with k_slow = 0.00034 min⁻¹ mM⁻¹.

Conclusion

We investigated the H/D exchange reaction of [Fe(PMAP)₂]²⁺ in the presence of various concentrations of 2,6-dimethylpyridine as a base in 10% D₂O–CD₃CN at 45°C by using NMR spectroscopy. The occurrence of two reaction processes, one fast and one slow, during the H/D exchange reaction of [Fe(PMAP)₂]²⁺ was revealed, indicating that deuteration of the azomethine group was slower than that of the methylene group. It is worth noting that only one methylene proton was abstracted by 2,6-dimethylpyridine. The reaction mechanism of the 1,3-hydrogen rearrangement was therefore elucidated.

Acknowledgments

We thank Yasumi Matsuda (Kumamoto University) for her contribution in ¹H-NMR measurements. This work was supported in part by the Kinjo Gakuin University-Parent Teacher Association Research Grant.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References

• 1) Bertini I., Luchinat C., “The Reaction Pathways of Zinc Enzymes and Related Biological Systems,” Chapter 2, ed. by Bertini I., Gray H. B., Lippard S. J., Valentine J. S., University Science Books, California, 1994, pp. 96–101.
• 2) Zabinski R. F., Toney M. D., J. Am. Chem. Soc., 123, 193–198 (2001).
• 3) Nagata Y., Yoda R., Matsushima Y., Chem. Pharm. Bull., 46, 1849–1852 (1998).
• 4) Constable E. C., “Metals and Ligand Reactivity: An Introduction to the Organic Chemistry of Metal Complexes,” VCH, Weinheim, 1996, pp. 116–119.
• 5) Martell A. E., Acc. Chem. Res., 22, 115–124 (1989).
• 6) Chavez-Gil T., de Faria D. L. A., Toma H., Vib. Spectrosc., 16, 89–92 (1998).
• 7) Cabral J. D. O., Cabral M. F., Drew M. G. B., Esho F. S., Nelson S. M., J. Chem. Soc., Chem. Commun., 1068–1069 (1982).
• 8) Black D. S. C., “Comprehensive Coordination Chemistry,” ed. by Wilkinson G., D. G. R., McCleverty J. A., Pergamon Press, Oxford, 1987, pp. 415–462.
• 9) Busch D. H., Farmery K., Goedkin V., Katovic V., Melnyk A. C., Sperati C. R., Tokel N., Adv. Chem. Ser., 100, 44–78 (1971).
• 10) Curry J. D., Busch D. H., J. Am. Chem. Soc., 86, 592–594 (1964).
• 11) Karn J. L., Busch D. H., Nature (London), 211, 160–162 (1966).
• 12) Karn J. L., Busch D. H., Inorg. Chem., 8, 1149–1153 (1969).
• 13) Fleischer E. B., Hawkinson A. J., Inorg. Chem., 7, 2312–2316 (1968).
• 14) Nelson S. M., Busch D. H., Inorg. Chem., 8, 1859–1863 (1969).
• 15) Fleischer E., Hawkinson S., J. Am. Chem. Soc., 89, 720–721 (1967).
• 16) Chavez-Gil T. E., Yasaka M. T. S., Sumimoto M., Kurosaki H., Goto M., Chem. Commun., 2388–2389 (2001).
• 17) Lions F., Martin K. V., J. Am. Chem. Soc., 79, 2733–2738 (1957).