Approaches to the Synthesis of Dicarboxylic Derivatives of Bis(pyrazol-1-yl)alkanes

Carboxylation of bis(pyrazol-1-yl)alkanes by oxalyl chloride was studied. It was found that 4,4′-dicarboxylic derivatives of substrates with electron-donating methyl groups and short linkers (from one to three methylene groups) can be prepared using this method. Longer linkers lead to significantly lower product yields, which is probably due to instability of the intermediate acid chlorides that are initially formed in the reaction with oxalyl chloride. Thus, bis(pyrazol-1-yl)methane gave only monocarboxylic derivative even with a large excess of oxalyl chloride and prolonged reaction duration. An alternative approach involves the reaction of ethyl 4-pyrazolecarboxylates with dibromoalkanes in a superbasic medium (potassium hydroxide–dimethyl sulfoxide) and is suitable for the preparation of bis(4-carboxypyrazol-1-yl)alkanes with both short and long linkers independent of substitution in positions 3 and 5 of pyrazole rings. The obtained dicarboxylic acids are interesting as potential building blocks for metal-organic frameworks.


Introduction
Bis(pyrazol-1-yl)alkanes are bidentate ligands widely used for the synthesis of the coordination compounds [1], some of which were shown to exhibit catalytic [2][3][4][5][6], anticancer [7,8], antibacterial [9] and SOD-like activity [10,11], and electroluminescent properties [12,13]. The properties of the ligands can be varied by introducing the functional groups into the pyrazole rings [14][15][16][17], besides, carboxylic groups themselves can act as donor groups for the formation of coordination bond with the metal ions. Carboxysubstituted pyrazoles were used for the construction of highly porous metal-organic frameworks [18][19][20][21]. Carboxylic acids based on bis(pyrazol-1-yl)alkanes are much less explored and only a few research papers were published so far [22][23][24][25]. In addition, a series of works devoted to the synthesis of metal-organic frameworks based on structurally related bis(4-carboxyphenylpyrazol-1-yl)methane was carried out by Sumby et al., the presence of the free chelating units in the structure of the framework allowed them to prepare catalysts with single metal sites [26,27].
In this contribution we report a facile synthesis of a series of 4,4 -dicarboxy-substituted bis(pyrazol-1-yl)alkanes with varied linker length and substitution in positions 3 and 5 of the pyrazole rings.

Results and Discussion
To introduce carboxyl groups into bis(pyrazol-1-yl)alkanes, a reaction with oxalyl chloride was used, in which it was both a reagent and a solvent. Previously oxalyl chloride was successfully used for the carboxylation of 1-phenyl-and 1-alkylpyrazoles [28]. In this reaction, a pyrazole-containing derivative of oxalic acid chloride is initially formed, which is converted to a carboxylic acid chloride with the release of carbon monoxide. The acid chloride is hydrolyzed without isolation to form a carboxylic acid. Other methods for the introduction of carboxylic groups into pyrazole rings include oxidation of alkyl [29,30] or formyl [31] groups, substitution of halogens via intermediate organolithium derivatives [32], and hydrolysis of trichloromethyl derivatives [33].
Carboxylation by oxalyl chloride proved to be poorly suitable for bis(pyrazol-1yl)alkanes without electron-donating methyl groups. Thus, only in the case of 1,3-bis(pyrazol-1-yl)propane 3d a dicarboxylation product could be isolated, while bis(pyrazol-1-yl)methane 1d gave solely a monocarboxylated product 7 (Scheme 3). Even a large excess of oxalyl chloride and prolonged heating did not lead to the formation of the dicarboxylic acid. For derivatives with longer spacers (four to six methylene groups) only traces of carboxylation products (after conversion to methyl esters) were detected (for substrate 4c) but were not isolated (Scheme 3).
In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-yl)methane 1d, DFT calculations of charge distribution in the starting compound 1d and compounds 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid chlorides formed during the first electrophilic substitution step were carried out. The structures were optimized at the B3LYP 6-31G(d) level of theory and absence of imaginary frequencies confirmed that the found stationary points correspond to minima on the potential energy surface. In order to get a more precise electron density distribution, MP2 6-31G(d) single point calculations were carried out for the found structures. Next, charges on carbon atoms (q C ) in position 4 of the pyrazole ring (since an electrophilic attack is directed at this position) and the hydrogen atom bound to it (q H ,) were calculated using the Bader's theory of atoms in molecules [34]. The calculation results are presented in Table 1.  In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-1d, DFT calculations of charge distribution in the starting compound 1d and c 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid formed during the first electrophilic substitution step were carried out. The were optimized at the B3LYP 6-31G(d) level of theory and absence of imagina cies confirmed that the found stationary points correspond to minima on th energy surface. In order to get a more precise electron density distribution, MP single point calculations were carried out for the found structures. Next, char bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attack at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Tab   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivatives. In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-1d, DFT calculations of charge distribution in the starting compound 1d and c 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid formed during the first electrophilic substitution step were carried out. The were optimized at the B3LYP 6-31G(d) level of theory and absence of imagina cies confirmed that the found stationary points correspond to minima on th energy surface. In order to get a more precise electron density distribution, MP single point calculations were carried out for the found structures. Next, char bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attack at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Tab   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivatives. In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-1d, DFT calculations of charge distribution in the starting compound 1d and c 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid formed during the first electrophilic substitution step were carried out. The were optimized at the B3LYP 6-31G(d) level of theory and absence of imagina cies confirmed that the found stationary points correspond to minima on th energy surface. In order to get a more precise electron density distribution, MP single point calculations were carried out for the found structures. Next, char bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attack at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Tab   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivatives.

Scheme 3. Carboxylation of bis(pyrazol-1-yl)alkanes.
In order to gain insight into the reasons for low reactivity of bis(pyrazol-1 1d, DFT calculations of charge distribution in the starting compound 1d and 1a, 3a, and 3d for comparison and the corresponding monosubstituted ac formed during the first electrophilic substitution step were carried out. Th were optimized at the B3LYP 6-31G(d) level of theory and absence of imagin cies confirmed that the found stationary points correspond to minima on t energy surface. In order to get a more precise electron density distribution, M single point calculations were carried out for the found structures. Next, cha bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attac at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Ta   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivative In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-1d, DFT calculations of charge distribution in the starting compound 1d and c 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid formed during the first electrophilic substitution step were carried out. The were optimized at the B3LYP 6-31G(d) level of theory and absence of imagina cies confirmed that the found stationary points correspond to minima on th energy surface. In order to get a more precise electron density distribution, MP single point calculations were carried out for the found structures. Next, char bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attack at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Tab   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivatives. In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-1d, DFT calculations of charge distribution in the starting compound 1d and c 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid formed during the first electrophilic substitution step were carried out. The were optimized at the B3LYP 6-31G(d) level of theory and absence of imagina cies confirmed that the found stationary points correspond to minima on th energy surface. In order to get a more precise electron density distribution, MP single point calculations were carried out for the found structures. Next, char bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attack at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Tab   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivatives. In order to gain insight into the reasons for low reactivity of bis(pyrazol-1-1d, DFT calculations of charge distribution in the starting compound 1d and c 1a, 3a, and 3d for comparison and the corresponding monosubstituted acid formed during the first electrophilic substitution step were carried out. The were optimized at the B3LYP 6-31G(d) level of theory and absence of imagina cies confirmed that the found stationary points correspond to minima on th energy surface. In order to get a more precise electron density distribution, MP single point calculations were carried out for the found structures. Next, char bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attack at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Tab   Table 1. Selected atomic charges in some bis(pyrazol-1-yl)alkanes and their monoacid chloride derivatives. In order to gain insight into the reasons for low reactivity of bis(pyrazol-1 1d, DFT calculations of charge distribution in the starting compound 1d and 1a, 3a, and 3d for comparison and the corresponding monosubstituted ac formed during the first electrophilic substitution step were carried out. Th were optimized at the B3LYP 6-31G(d) level of theory and absence of imagin cies confirmed that the found stationary points correspond to minima on t energy surface. In order to get a more precise electron density distribution, M single point calculations were carried out for the found structures. Next, cha bon atoms (qC) in position 4 of the pyrazole ring (since an electrophilic attac at this position) and the hydrogen atom bound to it (qH,) were calculated using theory of atoms in molecules [34]. The calculation results are presented in Ta The following conclusions can be drawn from the obtained charge distribution:

Structure
(1) The introduction of methyl groups into pyrazole rings (in pairs of compounds 1a-1d and 3a-3d) noticeably increases the negative charge at position 4 of the heterocycle, i.e., makes it more active in the electrophilic substitution reaction, and the effect of electron-donor groups is best manifested when comparing the sum of charges on carbon and hydrogen atoms; (2) An increase in the length of the linker from one to three methylene groups also increases the excess negative charge at position 4, which is apparently associated with the negative inductive effect of the pyrazole ring; (3) The introduction of an electron-withdrawing acid chloride group into one of the pyrazole rings deactivates the other cycle in the electrophilic substitution reaction, and to a greater extent, deactivation manifests itself in pyrazole derivatives without methyl substituents, and with a short methylene linker.
Based on the charge distribution, bis(pyrazol-1-yl)methane 1d is the least active in electrophilic substitution reactions, the charge on the 4-CH group in which is close to the charge on this group in the acid chloride of the propane derivative 3d . Experimental data show that monochloro anhydride 3d can undergo carboxylation with the formation of dicarboxylic acid 3e. At the same time, bis(pyrazol-1-yl)methane 1d at the first step of electrophilic substitution gives acid chloride 1d , in which position 4 of the other pyrazole ring is so deactivated by the electron-withdrawing effect of the already substituted heterocycle that the reaction halts on monochloroanhydride 1d , the hydrolysis of which gives monocarboxylic acid 7. Therefore, the pyrazole ring with an electron-withdrawing functional group (i.e., chlorocarbonyl) is a substituent with a strong negative inductive effect, which affects the reactivity of the neighboring pyrazole ring located even across two aliphatic bonds.
Taking into account the limitations of direct carboxylation of bis(pyrazol-1-yl)alkanes, an alternative approach involving the double alkylation of 4-pyrazolecarboxylic acid and its 3,5-dimethylderivative by α,ω-dibromoalkanes was evaluated. Ethyl esters of 4pyrazolecarboxylic acid and 3,5-dimethyl-4-pyrazole carboxylates were smoothly alkylated by α,ω-dibromoalkanes in a superbasic KOH-DMSO system and gave the corresponding diethyl dicarboxylates in high yields (Scheme 4). Alkaline hydrolysis of the diesters and subsequent neutralization gave the target dicarboxylic acids, including the ones with longer spacers, unavailable by direct carboxylation (Scheme 4). Unfortunately, derivatives of 1,2-bis(pyrazol-1-yl)ethane cannot be prepared by this route, since, as it is known, the reaction of pyrazole and its derivatives with 1,2-dibromoethane leads to the formation of 1-vinylpyrazoles, which undergo hydrolysis to the starting materials upon isolation [35]. Since both alkylation and ester hydrolysis take place under basic catalysis, we explored the possibility to carry out the synthesis of diacid 1e in a one-pot process. Indeed, after the alkylation was complete (TLC control), two additional equivalents of KOH and excess of water were added to the reaction mixture, which gave the hydrolysis product in several minutes in 92% overall yield.

Materials and Methods
Gas chromatography-mass spectrometry analysis was performed using Agilent 7890A gas chromatograph (Santa Clara, CA, USA) equipped with Agilent MSD 5975C massselective detector with quadrupole mass-analyzer (electron impact ionization energy 70 eV). NMR spectra were recorded on Bruker DRX400 and Bruker Advance 500 instruments (Billerica, MA, USA), solvent residual peaks were used as internal standards. Elemental analyses were carried out on a Vario Micro-Cube analyzer (Elementar Analysensysteme GmbH, Langenselbold, Germany). IR-spectra of solid samples were recorded on Agilent Cary 630 FT IR (Santa Clara, CA, USA) spectrophotometer equipped with diamond ATR accessory. Melting points of compounds 1b, 3b, and 1d (with melting points higher than 300 • C) were determined in helium atmosphere on NETZSCH TG 209 F1 thermoanalyzer (NETZSCH TAURUS Instruments GmbH, Weimar, Germany) with the heating rate of 10 • /min.
The calculations were performed using the Gaussian 09 package, revision D.01 [36]. Atomic charges were calculated using the AIMAll Professional 10.05.04 package.

Conclusions
In summary, approaches to the synthesis of 4,4 -dicarboxy-substituted bis(pyrazol-1-yl)alkanes were evaluated. It was found that direct carboxylation by oxalyl chloride is feasible only for the preparation of bis(3,5-dimethylpyrazol-1-yl)methane derivates due to electron-donating methyl groups and short methylene linker. Longer linkers lead to significantly lower product yields, which is probably due to the instability of the intermediate acid chlorides that are formed in the reaction with oxalyl chloride. A more universal method is based on the reaction of ethyl 4-pyrazolecarboxylates with dibromoalkanes in a superbasic medium and is applicable for the preparation of bis(4-carboxypyrazol-1-yl)alkanes with both short and long linkers. The obtained dicarboxylic acids are interesting as potential building blocks for metal-organic frameworks.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.