2-Iodopyridin-3-yl acetate

Abstract

The title compound 2-iodopyridin-3-yl acetate was obtained by acetylation of the OH group of 2-iodo-3-hydroxypyridine. Knowing that the hydroxyl group, as a strong H-bond donor in halogenated hydroxypyridines, usually directs supramolecular packing and might enforce possible halogen–halogen contacts, we crystallized 2-iodo-3-acetoxypyridine with the aim of disrupting the most important H-bond donor and assessing the propensity of the iodine for halogen bond formation. Indeed, in the compound 2-iodopyridin-3-yl acetate, the crystal packing is characterized by infinite 3D chains bonded through I···O=C and C-H···I contacts between adjacent molecules. These chains are interconnected by weak C-H···O contacts, implying the presence of oxygen in the ester. The I···H contact with the C-H axis perpendicular to the electron belt of the iodine atom can enhance the σ-hole of the iodine and act cooperatively in crystal cohesion. No halogen–halogen contacts were present.

1. Introduction

Pyridines are considered to be among the privileged structures in pharmaceutical chemistry [1,2,3] and are present as substructures of important building blocks of living beings [1,4]. Also, substituted pyridines, as single uncondensed molecules, present a wide range of pharmaceutical activities [5,6,7] and are present in the structures of blockbuster drugs (Figure 1) such as omeprazole, imatinib, etc.

Halogenated pyridines are important in pharmaceuticals but the ones containing bromine or iodine atoms, were investigated to a lesser extent [8,9]. However, iodinated pyridines were found to be effective templates for the study of halogen bonds [10,11,12,13,14] and other important supramolecular features.

Our specific interest in studying the tendency of halogen bond formation in nitrogen-containing halogenated heterocycles [15,16,17,18], as well as the above considerations, led us to investigate the supramolecular properties of 2-iodopyridin-3-yl acetate.

Herein we present the synthesis, structural characterization and interesting supramolecular properties of 2-iodopyridin-3-yl acetate.

2. Results and Discussion

A quick search of the 2-halogenated pyridines in the CCDC database gave ~2000 structures. Among these structures, 63 were 2-iodinated pyridines and only eight were 2-iodo-3-ORpyridines. One of these was 2-iodo-3-hydroxypyridine (R = H) [19] and two of them contain the 2-iodo-3-methoxypyridine framework (R = Me) [20,21]. These structures are presented in the Supplementary Material (Table S1). All these structures imply the presence of a halogen bond. Thus, the significance of iodinated pyridines as supramolecular synthons [14,15,16,17,18] and the scarcity of 2-iodinated pyridines with 2-iodo-3-hydroxypyridine as the parent (Table S1) led us to investigate another functionalized analogue: 2-iodopyridin-3-yl acetate.

2-iodopyridin-3-yl acetate was synthesized by an adaptation of a known method [22,23] using acetic anhydride instead of acetyl chloride for the O-acylation reaction. Thus, 2-iodo-3-hydroxypyridine was reacted under reflux with acetic anhydride (Scheme 1) in the presence of triethylamine (TEA). The synthesis steps are detailed in the Supplementary Materials.

Compound 3 was structurally investigated by ATR-IR, NMR and X-ray diffraction analysis.

2.1. Structural Description

The IR spectrum of compound 3 (Figure S1) presents specific bands at 1757 cm⁻¹ for the carbonyl C=O group, at 1554 cm⁻¹, attributed to C=C bonds in the pyridine moiety, and at 1438 cm⁻¹, attributed to the C=N bonds. At 1182 cm⁻¹, the simple C-O bond stretch is present.

The NMR spectra for compound 3 (Supplementary Material—Figures S2–S4) are in good agreement with the structure. The ¹H-NMR spectrum presents the relevant signals for Me hydrogen atoms at 2.40 ppm. The aromatic protons appear as a doublet of doublets with corresponding coupling constants. The protons H-4 and H-5 present an AMX coupling system (Figure 2) with a “roof” shape. The ¹³C-NMR spectrum presents all the expected signals, with the most shielded aromatic C-2 atom due to direct bonding to iodine at 115 ppm and the most deshielded C=O at 168 ppm. All the signals are in the expected ranges.

It appears that, in solution and in the presence of DABCO as a base, no halogen bond complex between the iodine and DABCO is formed, as no change in the chemical shift of C-2 was observed [24]. The ¹³C-NMR spectra are presented in Figure 3.

Even though this first evaluation was not satisfactory, we still performed crystallization experiments and obtained suitable crystals from CH₂Cl₂/EtOH for the X-ray diffraction analysis.

2.2. X-Ray Diffraction Analysis

The results of single crystal X-ray diffraction are illustrated in Figure 4 (and reported in

Table 1. Relevant contacts in the structure of compound 3.

D-X···A	D-X (Å)	D···A (Å)	X···A (Å)	DXA (◦)	Symmetry Op.
C1-I1···O2=C	2.11	N/A	3.191(8)	172.5(3)	0.5 + x, 0.5 − y, 0.5 − z
C7-H7A···I1	0.97	4.077(10)	3.18	155.2	1/2 + x, 1/2 − y, 1 − z
C7-H7B···O1	0.97	3.428(12)	2.50	159.5	2 − x, −1/2 + y, 3/2 − z
C3-H3···O2 *	0.93	3.467	2.79	130	1 − x, −1/2 + y, 3/2 − z
C7-H7C···N6 *	0.97	3.397	2.79	121	3/2 − x, 1 − y, −1/2 + z

* distance is 10% larger than the sum of the vdW radii of the respective atoms and less favorable angles.

). The values of bond distances and angles are summarized in Table S2. As it turned out, compound 3 crystallizes in the P-1 space group of a triclinic system with one molecule in the asymmetric unit (ASU), as shown in Figure 4a. No co-crystallized interstitial solvate molecules were found in the crystal. The acetoxy group is rotated almost perpendicular with respect to the plane of the pyridine ring with a C6-O1-C2-C3 torsion angle of 84.2°. Despite the absence of conditions for classical hydrogen bonds, there are other specific intermolecular interactions such as C-O···I, C-H···O, C-H···I and C-H···π involving the pyridine ring, which play a crucial role in crystal packing. An iodine atom is involved as a donor in the C1-I1···O2ⁱ halogen bond toward the acetoxy oxygen atom (C1-I1 2.11 Å, I1···O2ⁱ 3.19 Å, ∠C1-I1-O2 172°, (i) 0.5 + x, 0.5 − y, 0.5 − z). These interactions determined the formation of a 1D array along the a axis, which can be considered the main structural motif of the crystal (Figure 4b). Additionally, the C7-H···I1ⁱ (C7-H 0.97 Å, H···I1ⁱ 3.18 Å, ∠C7-H-I1 155°) intermolecular hydrogen bonds between the same pairs of neighboring molecules strengthen the 1D supramolecular module. In the crystal, the parallel packed 1D modules further interact through C7-H···O1ⁱ hydrogen bonds (C7-H 0.97 Å, H···O1ⁱ 2.50 Å, ∠C7-H-O1ⁱ 159°, (i) 2 − x, y − 0.5, 1.5 − z) and C7-H···π contacts of 3.28 Å to form a 3D supramolecular network, as illustrated in Figure 4c. The C5-H···π interactions between aromatic C-H groups and pyridine rings, which occur within the 3D network, are illustrated in Figure 4d.

2.3. Hirshfeld Analysis

The Hirshfeld analysis reveals the important contacts, and the fingerprint plots present red spots characteristic of contacts with lengths less than the sum of the vdW radii for I1···O2 contacts and for H7B···O1 contacts (Figure 5).

Fingerprint plots reveal that the crystalline network is dominated by H···H dispersive contacts and O···H, I···H and C···H weak contacts (Figure 6). Contacts are reciprocal, as can be observed by the symmetry of the fingerprint plots. N···H contacts of ~10% are present as weak.

The strong I···O contacts account only for 5.2% of the Hirshfeld surface. It must be noted that fingerprint plots represent a quantitative and not qualitative view of the forces acting in the supramolecular structure. However the 8.0% attributed to I···C contacts suggests we should look at this interaction closely (Figure 7).

The C-I···π contact (I···C) of 3.76 Å (sum of vdW radii of C atom and I atom: 3.55 Å) and an angle of 120° are not quite satisfactory for a strong halogen–π interaction going through the σ-hole of the iodine atom, which would require an angle closer to 180°.

To our knowledge, 2-iodopyridine does not exist in CCDC for use as a comparison. However, the parent compound 2-iodo-3-hydroxypyridine 1 still was crystallized (Ref. code: YELQUC [19]) and a brief comparison can be made. Of course, the hydroxyl group in YELQUC will influence the formation of strong hydrogen bonds with the nitrogen in the pyrimidine ring, and the iodine atom will lack a strong electronegative oxygen such in the case of acetyl. Thus, for compound 1, a type II iodine–iodine bond strengthened by lp-π (lp: lone pair) iodine–pyridine bonds will lead to a stair-like arrangement of the molecules (Supplementary Material—Figure S5) with an enhancing effect on the halogen bond similar to the one discussed by Frontera et al. [25].

The percentage interactions between the two compounds YELQUC and 3 are presented in Figure 7. The most significant differences between the two molecules are the halogen bond type and the percentage in the supramolecular network, which for molecule 3 are I···O (5.2%) and for YELQUC are I···I (6.1%). For YELQUC we can observe an I···C percentage of 5.2% compared to 8% in 3, but this is due to an lp···π type of contact and not a halogen σ-hole interaction like the one depicted in Figure 6. This latter contact can be enforced by π···π (C···C 5.6%—green color in Figure 8)-type interactions which are not present in compound 3.

3. Materials and Methods

Single-crystal X-ray diffraction data for compound 3 were collected with an XCALIBUR E CCD diffractometer (Rigaku, Tokyo, Japan) equipped with graphite-monochromated MoKα radiation. The unit cell determination and data integration were carried out using the CrysAlisPro (1.171.44.136a)package from Oxford Diffraction [26]. The structure was solved with the SHELXT program using the intrinsic phasing method and refined by the full-matrix least-squares method on F² with SHELXL [27,28]. Olex2 was used as an interface to the SHELX programs [29]. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were added in idealized positions and refined using a riding model. The molecular plots were obtained with the Olex2 program. Selected crystallographic data and structure refinement details are provided in

Table 2. Crystallographic data and refinement details for 3.

Empirical Formula	C7H6INO2
Formula weight	263.03
Temperature/K	240
Space group	P212121
a/Å	7.3660(4)
b/Å	8.0857(5)
c/Å	14.5894(7)
α/°	90
β/°	90
γ/°	90
Volume/Å3	868.93(8)
Z	4
ρcalc g/cm3	2.011
μ/mm−1	3.636
Crystal size/mm3	0.06 × 0.06 × 0.02
2Θ range/°	5.584 to 49.996
Refs collected	3032
Indep. refls	1505, 0.0387
Data/restrs/params	1505/0/101
GOF on F2	0.999
R1, wR2 (all data)	0.0488, 0.0495
CCDC No.	2521105

and the corresponding CIF-file. Deposition Number 2521105 contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe at http://www.ccdc.cam.ac.uk/structures (31 December 2025).

NMR spectra were measured on Varian Gemini 300 BB instrument (Palo Alto, CA, USA), operating at 300 MHz for ¹H-NMR and 75 MHz for ¹³C-NMR.

Hirshfeld analysis was done using Crystal Explorer 17 [30]. Fingerprint plots represent statistical contacts distribution and were generated using the external (d_e) and internal (d_i) distances from the specific atoms to the Hirshfeld surface [30].

4. Conclusions

In conclusion, 2-iodopyridin-3-yl acetate was synthesized and crystallized with the aim of investigating its supramolecular crystalline structure. The importance of I···O contacts and weak non-classical hydrogen bonds was highlighted together with other secondary interactions. A comparison with the parent 2-iodo-3-hydroxypyridine was made to confirm the propensity of the iodine atom for halogen bond formation.

The halogen bond implying iodine is present in six of the eight 2-iodine derivatives, which might suggest interesting applications for the class of 2-iodo-3-ORpyridines.