RSC Advances View Article Online PAPER View Journal | View Issue Physical organic studies and dynamic covalent chemistry of picolyl heterocyclic amino aminals† Cite this: RSC Adv., 2020, 10,40421 Ji-Ming Ciou,a Hong-Feng Zhu,b Chia-Wen Chang,a Jing-Yun Chena and Ya-Fan Lin *ab A dynamic covalent system of the picolyl heterocyclic amino aminals has been studied. The aminals are characterized as a metastable species and easily switch to other forms via external stimuli. The solvent, temperature, acid–base and substituent effects have been examined to evaluate the dynamic covalent system. The results reveal that a more polar solvent, a lower temperature, basic conditions and an electron-withdrawing moiety contribute to the stabilities of aminals. The existence of the n / p* interaction between acetonitrile and the C]N moiety makes the N-pyrimidyl imine (4c and 4d) yield higher in CD3CN. In a similar fashion, all aminals tend to convert to the corresponding hemiaminal Received 7th October 2020 ethers in a methanol environment. According to these findings, we successfully synthesized the Accepted 30th October 2020 following species: (a) N-2-picolylpyrimidin-2-amine 6c obtained by reduction using acetonitrile as the Creative Commons Attribution-NonCommercial 3.0 Unported Licence. DOI: 10.1039/d0ra08527h specific solvent; (b) a picolyl aromatic amino aminal 3e prepared from 2-pyridinecarboxaldehyde and the rsc.li/rsc-advances electron withdrawing 2-methoxy-5-nitroaniline. Introduction Herein, we re-examined the physical organic properties and the dynamic covalent chemistry (DCC) of a series of picolyl Dynamic covalent chemistry is dened as a covalent bond that heterocyclic amino aminals.46 Although the synthesis and forms or breaks reversibly.1–7 Several components undergo characterization of this system have been reported,47 the continuous exchange and reach an equilibrium in a stable dynamic behaviours such as the equilibria between aminals This article is licensed under a distribution.8–11 A dynamic covalent system can respond to and the corresponding imines remain unclear. To explore the external stimuli to achieve adaption, bringing dynamic diversity molecular properties of aminals more deeply, we decided to to allow variation and selection.12–17 As a result, if the transition investigate the responsiveness of this system to the external – Open Access Article. Published on 06 November 2020. Downloaded 9/28/2021 5:27:52 PM. of the different states can be controlled via external stimuli, the stimuli such as solvent, acid base, substituent and temperature chemical system can be considered as a kind of molecular effect. It was found that the entity of the heterocyclic amine switch.18–21 Imine is one of the known dynamic covalent would be predominant to the molecular behaviours. Further- systems, which have been widely utilized in several elds, such more, since the switch of the equilibrating states in this system as many enzymatic processes and development of dynamic can be well-controlled by an environmental stimulus, we materials.22–26 Although dynamic imine formation processes are therefore presented aminal reduction and the synthesis of known to include several reversible reactions such as hydro- a novel picolyl aromatic amino aminal in accordance with the lysis,27 transimination28–32 and imine metathesis,33–35 limited different tuning factors. studies have reported the observation and isolation of the cor- responding intermediates such as aminals, hemiaminals and hemiaminal ethers.36–45 To develop new functions by under- Results and discussion standing the thermodynamic and bonding properties, there is Synthesis of picolyl heterocyclic amino aminals still a great demanding to explore suitable systems which can be Treatment of a methanol solution of 2-pyridinecarboxaldehyde successfully detected intermediates. (1) with 2 equivalent of 2-amino-heterocyclic 2a–d at room temperature (301 K) gives 3a–d (Scheme 1). Changing the aDepartment of Fragrance and Cosmetic Science, Kaohsiung Medical University, 100 reactant ratio only varies the yields but not the products. For the Shi-Chuan 1st Rd., San-Ming Dist., Kaohsiung, 80708, Taiwan. E-mail: yafan@kmu. solid state characterization, elemental analysis of 3a–d agrees edu.tw with the aminal formulas (Table 1). Single crystal diffraction b Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, analysis reveals 3a and 3c crystallize as an aminal structure with Kaohsiung 80708, Taiwan space groups of Pbcn and P21/n, respectively (Fig. S1†). All † Electronic supplementary information (ESI) available. CCDC 1961718–1961721. For ESI and crystallographic data in CIF or other electronic format see DOI: structural parameters show similar values to the literature 10.1039/d0ra08527h data.48 This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,40421–40427 | 40421 View Article Online RSC Advances Paper covalent properties for 3a and 3b. The equilibrium constant Keq is dened as eqn (1): ½aminal K ¼ eq ½imine½amine (1) Various ratios of 2a/3a or 2b/3b respectively dissolved in CDCl3, acetone-d6,CD3CN and DMSO-d6 were prepared and monitored by 1H NMR spectroscopy at 301 K using 1,3,5- trimethyl-2,4,6-trinitrobenzene as the internal standard. The Keq values listed in Table 2 were obtained by a plot of [aminal] Scheme 1 Synthesis route for 3a–d. vs. [imine][amine] (Fig. S14–S21†). The results reveal that the formation of aminal is generally favoured in the more polar environment. In both cases, Keq values derived from the DMSO- 3 ¼ 3 ¼ d6 ( 47.8) and CD3CN ( 37.5) systems are larger than that Table 1 Elemental analysis of aminals 3a–d 3 ¼ from CDCl3 ( 4.7). The more polar environment would make Calculated, % Found, % the carbon on the imine group more electrophilic. As a result, nucleophiles such as amines attack the imine group more No. Formula CHNCHNeasily, increasing the yields of aminals. Quite the opposite, the more electron-donating amino moiety of 4b would push elec- 3a C H N 69.29 5.45 25.25 69.15 5.43 25.29 16 15 5 tron density toward the electrophilic carbon atom and stabilize 3b C18H19N5 70.80 6.27 22.93 70.76 6.28 23.06 3c C14H13N7 60.20 4.69 35.10 60.16 4.73 35.37 the imine group. Indeed, a comparison between the two 3d C18H21N7 64.46 6.31 29.23 64.20 6.25 29.36 systems shows that 3b, the more electron-donating aminal, has Creative Commons Attribution-NonCommercial 3.0 Unported Licence. a greater tendency to shi the equilibrium to imine. To understand whether aminals 3c and 3d exhibit dynamic Interestingly, the molecular structures of 3c and 3d in solu- covalent properties or not, we examined their solution behav- tion are consistent with those characterized in solid state, whilst iours by NMR in six different solvents (listed in the order from 3 ¼ it shows an imine-aminal equilibrium when 3a and 3b are lowest to highest dielectric constant: CDCl3, pyridine-d5 ( 1 3 ¼ dissolved in CDCl3 (Scheme 2). The HNMRspectraof3c and 12.4), acetone-d6,CD3NO2 ( 35.9), CD3CN and DMSO-d6). 3d in CDCl3 reveal no peak at the typical imine regions (7.7–9.5 Although the N-pyrimidyl substituted imines 4c and 4d cannot ppm). Meanwhile, a triplet around 7.1 ppm attributed to the be detected in CDCl3, pyridine-d5 and DMSO-d6, small amounts This article is licensed under a methine (–CH–)groupwasobservedinbothcasesof3c and 3d. of them can be observed in acetone-d6,CD3NO2 and CD3CN. 1 In contrast, when 3a and 3b were dissolved in CDCl3,the H The aminal/imine ratios of 3c/4c and 3d/4d were found as 96/4 NMR spectra showed two sets of distinct picolyl signals. The and 97/3 in acetone-d6, 95/5 and 90/10 in CD3NO2, and 90/10 † characteristic aldimine signals of 4a and 4b were observed at and 84/16 in CD3CN (Table S3 ). The less yields of 4c and 4d Open Access Article. Published on 06 November 2020. Downloaded 9/28/2021 5:27:52 PM. 9.17 and 9.08 ppm, respectively. Interestingly, when the can be attributed to the more electron withdrawing pyrimidyl measurements were carried out in DMSO-d6,both3a/4a and substituent on the N atom, leading to the formation of the more 3b/4b ratios were increased to 74/26 and 55/45, respectively reactive C]N group easily attacked by a nucleophile. (Table S3†). Since preliminary results showed that aminals 3a and 3b C]N group stabilized by the n / p* interaction exhibit dynamic covalent properties in solution, we further Since the aminal/imine ratio depends on the reactivity of the examined how the reaction is responsive to the environmental C]N group, aminal forms should be more favoured in the more stimuli. polar solvents. However, the result does not follow the order of (a) Solvent effect. The equilibrium constants of 3a/4a and 3b/ the solvent polarity. We wondered the non-covalent intermo- 4b in various solvents were determined to evaluate the dynamic lecular forces such as n / p* or p / p* interaction generated from the overlapping of the n or p orbital (from the solvent) and Table 2 Equilibrium constants of 3a/4a and 3b/4b in different solvents at 301 K 3 d-solvent Dielectric constant ( ) Keq for 3a/4a Keq for 3b/4b CDCl3 4.81 31.70 Æ 0.49 22.87 Æ 0.46 Acetone-d6 20.7 56.21 Æ 0.13 32.05 Æ 0.25 Æ Æ CD3CN 37.5 63.38 0.75 40.14 0.74 DMSO-d6 46.7 88.42 Æ 0.40 38.06 Æ 0.57 Scheme 2 Equilibrating states for 3a and 3b in CDCl3.