Model System 1: Amidinium and Benzimidazolium Ion

In order to prove the computational results, an aromatic amidinium and benzimidazolium ion was synthesized and the interaction with a (thio)carboxylate in different solvents investigated. The synthesis of compounds 3 and 5 as well as of the nucleophiles 7 and 9 is depicted in Scheme 13.

Scheme 13. Synthesis of amidinium iodide 3, benzimidazolium iodide 5, and tetrahexylammonium (thio)carboxylate 7 and 9 as model compounds for the zwitterionic dynamic covalent system, a) N,N-dimethylformamide dimethyl acetal, cat. AcOH, CHCl3, RT, o/n, b) dimethyl sulfate, THF, reflux, o/n, c) methyl iodide, K2CO3, MeCN, reflux, 5 h d) tetrahexylammonium chloride, organic solvents (benzene, chloroform, dimethylsulfoxide), ultrasound, 30 min.

Dimethylaniline 1 was converted into amidine 2 by N,N-dimethylformamide dimethyl acetal in acidic environment. Since the acetal is prone to hydrolysis, the mixture should be kept under

anhydrous conditions. Furthermore, to increase the overall yield, the reaction can be driven to the product side by removal of methanol, that is formed as a side product. Eventually, amidinium iodide 3 was obtained by methylation with dimethyl sulfate and subsequent anion exchange by means of sodium iodide. The direct methylation employing low-boiling methyl iodide was unsuccessful since higher temperatures and longer reaction times are necessary to achieve a sufficient conversion rate. In contrast, the exhaustive methylation of benzimidazole (4) by means of methyl iodide was successful yielding benzimidazolium iodide 5.

Due to the low solubility of commercially available potassium (thio)carboxylate in common organic solvents, an exchange for the tetrahexylammonium derivatives was performed. However, compound 9 is not stable under ambient conditions in solid or dissolved state. Therefore, a fresh solution was prepared for all experiments.

The first model compound 3 was analyzed by means of NMR spectroscopy in the pure form and in 1:1 mixtures with the carboxylate derivatives. Three solvents of different polarity were employed, i.e. benzene, chloroform, and dimethylsulfoxide. Chloroform was stirred with ground K2CO3 prior to use to neutralize potential acidic contaminations. In each case, the signals attributed to the amidinium and aromatic protons (Table 4, red) were compared before and after addition of the nucleophile. Especially the amidinium proton should exhibit a significant upfield shift when the charge is neutralized due to addition to the double bond. The remaining aliphatic signals are neglected as they strongly overlap with the ammonium hexyl chains. The results are summarized in Table 4.

Table 4. Addition of acetate 5 and thiocarboxylate 7 to amidinium 3, (+) indicates the appearance of new signals in the

1H-NMR spectrum while (-) denotes no change or minor shifts of the aromatic and/or amidinium protons (red), the remaining signals are neglected as they strongly overlap with the signals of ammonium hexyl chains.

Solvent Acetate 5 Thiocarboxylate 7

Benzene + +

Chloroform + -

Dimethylsulfoxide - -

While the addition of acetate 7 to amidinium 3 induces a change in the NMR spectrum in both non-polar solvents, regarding thiocarboxylate 9 only in benzene an effect is observed. These results support the computational analysis which indicated no reaction in polar media. However, the nature of the process is unknown since multiple new signals appear in the aromatic and

difficult, it is likely that more than one new species formed. An example spectrum before and after addition of compound 7 to compound 3 in chloroform is depicted in Figure 45. Three new major sets of signals appear in the region between 6.2 to 7.1 ppm. Each set consists of two signals that exhibit an integral ratio of 1 : 2. This ratio matches the aromatic protons in ortho (2) and para (1) position of amidinium 3, and suggests the presence of at least three species with an intact aromatic core after the addition of the nucleophile. However, the remaining three signals in the area between 8.3 to 9.5 ppm could not be assigned, as their integrals do not match the expected single amidinium proton.

Figure 45. ¹H-NMR (300 MHz, CDCl3) spectra of amidinium derivative 3 before (bottom, red) and after (top, blue) addition of 7, several new signals appear in the aromatic and stronger downfield shifted area indicating processes beyond the single addition of the nucleophile to the amidinium double bond, the displayed integral ratios of 1 : 2 for the three signal sets match the ortho and para protons of amidinium 3, which implies the presence of at least three species in the current system; consequently, the reaction was not further investigated as it does not fulfill the requirement of a clean reversible conversion between two species; the NMR solvent was rapidly stirred with ground K2CO3 and filtered prior to use to neutralize acidic contaminations.

Furthermore, the number, shape, and integrals of the NMR signals are different for every solvent and nucleophile. Hence, it is unlikely that the current system represents a dynamic covalent conversion of two species, but processes beyond the reversible addition of the nucleophile to the amidinium double bond seem to be the reason for the observation. However, deprotonation and formation of carbenes, a typical side reaction of amidinium compounds, can be excluded due to the low basicity of acetate.

The previous experiments were repeated with benzimidazolium derivative 5. However, due to the very low solubility of 5 in benzene as well as in chloroform, DCM and DMSO were employed for the NMR experiments. In contrast to the amidinium derivative 3 no reaction was observed with acetate 7 or thioacetate 9 in either of the solvents. In order to test the general electrophilic properties of compound 5 two last experiments with a stronger nucleophile, i.e. dimethylamine and benzyl amine, were conducted. Also in this case, no reaction was observed. The corresponding

1 : 2

1 : 2 1 : 2

NMR spectra are depicted in Figure 46. The downfield shift of the benzimidazolium proton in the green spectrum (after addition of acetate 7) might be attributed to non-covalent interactions. The addition of dimethylamine (blue spectrum) results in no significant change of the NMR spectrum.

The performed experiments do not support the computational data. While no indication for a reaction between benzimidazolium derivative 5 and a nucleophile is observed, amidinium derivative 3 shows a reaction. However, the process was not further investigated since the existence of a dynamic covalent equilibrium consisting of two species can be excluded. In order to avoid side reactions, a system exhibiting both reactive groups in one molecule might be beneficial due to the generally higher rate of intramolecular reactions. Furthermore, regarding the unreactive benzimidazolium compound, the resultant higher effective molarity might induce the targeted conversion to the uncharged state.

Figure 46. ¹H-NMR (300 MHz, DMC) spectra of benzimidazolium derivative 5 before (red) and after addition of acetate 7 (green) and dimethylamine (blue), the spectrum after addition of benzyl amine is not shown as it exhibits only minor changes in comparison to the blue one, no significant change is observed that can be attributed to the addition to the nitrogen double bond, the downfield shift of the benzimidazolium proton in the green spectrum might be attributed to non-covalent interactions.