1-(2-Chlorobenzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-ol Derivatives: Synthesis, Characterization, and DFT-Based Descriptors Analysis

A novel series of 1-(2-chlorobenzyloxy)-3-[1,2,3]triazol-1-yl-propan-2-ol derivatives was designed and synthesized using copper catalyzed alkyne-azide cycloaddition in the key step. Theoretical investigation of molecular and electronic properties by means of global and local reactivity indexes of the synthetized compounds was carried out, using DFT (Density Functional Theory) at PBEPBE/6-31++G level.


Introduction
Depression and similar psychological disorders affect about 350 million people worldwide and represent one of the leading causes of disability and a major contributor to the burden of suicide and ischemic heart diseases [1,2]. This illness is associated with a decreased production of serotonin in conjunction with a decreased sensitivity of postsynaptic receptors to available serotonin [3]. Therefore, one of the most extended current therapies for this kind of diseases involve the use of commercially available drugs which work as selective serotonin reuptake inhibitors (SSRI) such as fluoxetine among other analogous compounds [4,5]. Although all these compounds are effective as antidepressants, some side effects are observed during their use. This reason has motivated the design and development of diverse molecules, which display good reuptake inhibiting activity [6][7][8].
A particular molecule that has attracted us is a derivative from chlorobenzyloxy-3,6-dihydropyridinyl propan-2ol named DJLDU-3-79, 1 [9]. This compound was designed from a hybridization of two active reuptake inhibitory molecules in order to improve the above-mentioned properties. However, a synthetic challenge in the preparation of this molecule is the tetrahydropyridine moiety prepared from 4-piperidone analogs, which in turn are obtained through several reaction steps [10,11]. In this regard, we propose a synthesis of a novel family of compounds 2 analogs to molecule 1 based on a substitution of tetrahydropyridine ring by 1,2,3-triazole which is easily synthesized by copper catalyzed alkyne-azide cycloaddition (CuAAC), the most powerful click reaction (Scheme 1).
On the other hand, DFT-based methods have already proven to be useful in determining molecular structure of organic compounds, as well as in elucidating their electronic structure and reactivity [12]. There are two kinds of DFTbased reactivity indexes: global and local quantities. The global parameters measure the electronic features of the molecules as a whole and the local quantity reflects the reactivity of particular regions or atoms. The properties calculated in this study have been successfully applied in to explain the reactivity of organic and inorganic molecules, proteins, solids, and others [13]. Several studies have confirmed closed relationships between the biological performance of a family of compounds and their chemical reactivity. The pharmacokinetic and pharmacodynamic properties of SSRI molecules are strongly influenced by their interactions to the body proteins [9]. Therefore, the electron transfer properties in proteinligand binding could be studied by using DFT reactivity indexes. To accomplish this goal, the use of global chemical reactivity parameters, chemical potential ( ), electron affinity ( ), chemical potential ( ), softness ( ), and electrophilicity ( ), could aid the understanding of the interaction process between SSRI and biological molecules. Also, the local parameters could give some light about which molecular moieties are most involved in the binding structure This report summarizes our most recent findings in the click chemistry area aiming to search and develop new molecules with high SSRI activity; also the theoretical characterization of the obtained molecules was carried out.

Experimental Section
2.1. Synthesis. The starting materials were purchased from Aldrich Chemical Co. and were used without further purification. Solvents were distilled before use. Silica plates of 0.20 mm thickness were used for thin layer chromatography. Melting points were determined with a Krüss Optronic melting point apparatus and they are uncorrected. 1 H and 13 C NMR spectra were recorded using a Bruker AVANCE 300; the chemical shifts ( ) are given in ppm relative to TMS as internal standard (0.00). For analytical purposes the mass spectra were recorded on a Shimadzu GCMS-QP2010 Plus in the EI mode, 70 eV, 200 ∘ C via direct inlet probe. Only the molecular and parent ions (m/z) are reported. IR spectra were recorded on a Bruker TENSOR 27 FT instrument. (4). A solution of 2-chlorobenzaldehyde (1.125 mL, 1.40 g, 10.03 mmol) in ethanol (15 mL) was added to a suspension of sodium borohydride (0.189 g, 4.97 mmol) in absolute ethanol (6 mL) maintaining the temperature below 25 ∘ C. The resulting mixture was heated at 50 ∘ C during 1.5 h. The solvent was removed in vacuo, and water (20 mL) was added; the mixture was acidified with diluted HCl (10%) to pH = 5. The product was extracted with CH 2 Cl 2 (3 × 15 mL), the organic phases were joined and dried over Na 2 SO 4 , and the solvent was removed in vacuo to yield a white solid (1.27 g, 90%), which was used without additional purification, m.p. 50 ∘ C; 1

2-Chlorophenyl-methanol
-benzyloxymethyl)-oxirane (5). A mixture of 40% aqueous solution of NaOH (6.5 mL) (2-chlorophenyl)-methanol 4 (0.71 g, 5 mmol) and tetrabutylammonium iodide (0.09 g, 0.25 mmol) was vigorously stirred at room temperature for 24 h. The mixture was cooled to 0 ∘ C and epichlorohydrin (1.55 mL, 1.83 g, and 19.9 mmol) was added dropwise. After completion, the reaction mixture was stirred at 0 ∘ C for 30 minutes and at room temperature overnight. The mixture was poured into ice cold water (20 mL). The product was extracted with CH 2 Cl 2 (3 × 15 mL), the organic phases were joined and dried over Na 2 SO 4 , and the solvent was removed in vacuo to yield a pale yellow oil (1.27 g, 90%), which was used without additional purification;

Theoretical Calculations.
All the electronic structure computations were carried out with NWChem package [14]. A frequency analysis was applied to the optimized geometries to verify the corresponding stability criterion. The PBEPBE [15] exchange and correlation functional was used with the 6-311++g * * Pople's basis set. All the reactivity parameters were computed from a finite differences approach.
Azido alcohol 6 was the starting material for the following CuAAC experiments. In a model reaction, compound 6 was treated with phenylacetylene in presence of diverse Cu(I) catalytic sources according to that described by Rostovtsev et al. [16], Tornøe et al. [17] and our group [18,19] (Scheme 3), obtaining compound 7 as only reaction product. From these experiments presented in Table 1, we selected CuI-DIPEA for CuAAC reaction because a best yield (85%) was reached using this catalytic system.
Taking these optimized conditions, a synthetic procedure was developed and a series of (2-chlorobenzyloxy)-1,2,3triazolyl-propan-2-ol derivatives was prepared from azido   Table 2 show that this process occurs with high efficiency and functional group tolerance; see Scheme 4.

DFT Characterization.
In order to compare triazoles 7-18 with compound 1 and to establish possible SSRI candidates, a theoretical study was carried out. The global reactivity indexes of studied compounds are presented in Table 3, electronic affinity ( ), ionization potential ( ), chemical potential ( ), chemical softness (S), and electrophilicity ( ).
The obtained results are gathered in Table 3. Ionization potential ( ) is defined as the energy needed to remove an electron from a molecule. According to obtained results, the molecule 12 showed the highest ionization potential value, and the molecule 15 has the closest value to 1, showing that electron-rich aromatic rings are necessary to mimic the properties of molecule 1. On the other hand, the presence of electron attracting groups in the aromatics increases the value of ; the aliphatic moieties have the same effect.
Electron affinity (EA) measures the ability of a molecule to accept electrons and form anions. There are some EA negative in the obtained values, because the molecules released energy in the process of electron acceptance. In a general view, only the half of the molecules has positive EA values like one. Nevertheless, the computed values are different compared with 1, with the molecules 16 with a behavior closest to 1.
Chemical potential ( ) measures the escaping tendency of an electronic cloud in the ground state system. The obtained results shown that molecule 1 has higher value (less negative) than synthesized triazolyl derivatives, making compound 1 a better electron donor than obtained compounds. Nevertheless, almost all the compounds have pretty close values to 1, except for compound 7 and in minor degree 12.
Chemical softness (S) is related to polarizability. The values S for compounds 14 and 18 are remarkably close to the value of compound 1, suggesting a similar facility to charge transfer; other compounds with similar values are 15-17, respectively. As matter of fact, the trifluorobenzyl group in compound 18 shows similar characteristics to indolyl moiety in compound 1.
Electrophilicity ( ) gives an idea of the stabilization energy when the system acquires electrons from the environment up to saturation. Since the electrophilicity power is computed through ( 2 /2 ), the differences in electrophilicity power ( ) between the compounds are mainly due to differences in their chemical potential. In this regard, the results suggest that triazole moiety is a better nucleophile for compounds 7-18 than tetrahydropyridine system in compound 1. In a general way all the parameters obtained by DFT calculations show the necessity of having an electronrich aromatic bond to mimic the indolyl moiety in compound 1.   Figure 1: Dual descriptor ± for the molecules studied in this work.
The local properties of synthesized compounds are hard to analyze due to the diverse nature of substituent groups used in this study. For this reason, the three nitrogen atoms in triazole ring were used as a probe for the local properties in the prepared molecules. As shown in Table 4, the highest values of − can be observed for N2 atom in all molecules, indicating that this atom is the most susceptible to a nucleophilic attack. In addition, a visible tendency for the case of + was not found. The local softness (s) followed the same tendencies as Fukui functions; nevertheless, this function could be comparable between molecules, being higher in compounds 14-18 on N2 atom. 8

Journal of Chemistry
Other important index is known as dual descriptor ± which contains information about the chemical philicity (electrophilicity/nucleophilicity). In this case, the graphic maps are generally sufficient for rationalizing the chemical reactivity. The maps of dual descriptor for the set of molecules studied in this work are represented in Figure 1, displaying the most probable sites for a possible nucleophilic-electrophilic attack. In a general way, the most electrophilic sites are found on the chlorobenzyl moiety, while the most nucleophilic sites are located on the opposite side of the molecule independent of the electronic nature of substituent group. These elements reveal some similarities between compound 1 and synthesized compounds with nearest values for compounds 14-18. The calculated parameters also allow establishing interaction sites in these molecules.

Conclusions
A new class of derivatives of chlorobenzyloxy triazolylpropan-2-ol was obtained from CuAAC reaction using commercially available raw materials through simple and efficient methods. Theoretical calculations indicate that a high similarity can be found between these products and the leading molecule 1; consequently, a good SSRI ability would be expected for these compounds, suggesting more studies about this topic. Also, DFT descriptors show that the presence of an electron-rich aromatic ring is necessary to mimic the indolyl moiety present in compound 1.

Conflicts of Interest
The authors declare that they have no conflicts of interest.