**Intramolecular N**−**H···X (X = F, Cl, Br, I, and S) Hydrogen Bonding in Aromatic Amide Derivatives - The X-Ray Crystallographic Investigation**

Dan-Wei Zhang and Zhan-Ting Li *Department of Chemistry, Fudan University, Shanghai China* 

#### **1. Introduction**

94 Current Trends in X-Ray Crystallography

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Hydrogen bonding (H-bonding) has recently been defined by IUPAC as "an attractive interaction between a hydrogen atom from a molecule or a molecular fragment X–H in which X is more electronegative than H, and an atom or a group of atoms in the same or a different molecule, in which there is evidence of bond formation". In most cases, the strength of an H-bond increases with the increase of the electronegativity value of the acceptor atom (Pauling, 1960). This is exactly the case for oxygen and nitrogen atoms. The H-bonds formed between them and the NH and OH groups are usually strong, which play essential roles in studies in supramolecular, crystal engineering, materials, and life sciences (Scheiner, 1997; Jeffrey,1997). As s result of their growing applications in supramolecular chemistry and crystal engineering, in the past two decades, the critical assessment of the weaker H-bonds has also become an important topic (Desiraju & Steiner, 2001). In this context, organic halogen and sulfur atoms, C-X (X = F, Cl, Br, I, S), have all been demonstrated to be weak H-bonding acceptors (Dunitz & Taylor, 1997), although their electronegativities (Pauling scale: 3.98, 3.16, 2.96, 2.66, and 2.58, respectively) are all higher than that of hydrogen (2.20). Indeed, over years it has been accepted that organic fluorine ''hardly ever accepts hydrogen bonds (Dunitz, 2004),'' presumably due to its low polarizability and tightly contracted lone pairs. For other organic heteroatoms, the increased van der Waals radius and decreased electronegativities may also weaken their capacity of forming the intramolecular electrostatic interaction, i.e., H-bonding, with the amide hydrogen and lose the competition with the amide oxygen of another molecule which forms the intermolecular N−H⋅⋅⋅O=C H-bonding. In contrast, the halogen anions are capable of forming strong intermolecular H-bonding with NH, OH or even CH protons (Harrell & McDaniel, 1964; Simonov et al., 1996; Del Bene & Jordan, 2001).

This chapter summarizes recent progresses in the assessment of the weak intramolecular six- and five-membered H-bonding patterns formed by aromatic amides bearing the above five atoms. Theoretical investigations show that similar intermolecular H-bonding patterns can be formed by fluorine in DNA or RNA base analogues (Frey et al., 2006; Koller et al., 2010; Manjunatha et al., 2010), although they are difficult to be confirmed in solution

Intramolecular N−H⋅⋅⋅X (X = F, Cl, Br, I, and S) Hydrogen Bonding

1999).

F H2N N

**2.39 2.23**

O OMe

O Ph Ph Ph

Fig. 1. Compounds 1-3 and their crystal structures.

H

N O

H

**1.94 2.18**

<sup>F</sup> <sup>F</sup>

**1 2 3**

O NH

Ph Ph Ph

in Aromatic Amide Derivatives - The X-Ray Crystallographic Investigation 97

Cambridge Structural Database System (CSDS) and concluded that organic fluorine is at best only a weak H-bonding acceptor (Howard et al., 1996). In 1997, Dunitz and Taylor also executed an intensive search of the CSDS and confirmed that organic fluorine accepts hydrogen bonds only in the absence of a better acceptor (Dunitz & Taylor, 1997). They also examined the evidence for H-bonding to organic fluorine in protein–ligand complexes and found that it is unconvincing. They thus proposed that, due to its low polarizability and tightly contracted lone pairs, organic fluorine does not compete with stronger H-bond acceptors such as oxygen or nitrogen, and only when other better acceptor atoms are sterically hindered that the O–H⋅⋅⋅F or N–H⋅⋅⋅F H-bonding can be formed (Barbarich et al.,

> OMe O

In 1982, Kato et al. reported the crystal structure of 2-fluorobenzamide (Kato & Sakurai, 1982). Although the positions of hydrogen atoms were not determined, the N⋅⋅⋅F distance is 2.80 Å, which corresponded to an N*H*⋅⋅⋅F distance of 2.15 Å by molecular modeling. Clearly, an intramolecular six-membered N–H⋅⋅⋅F hydrogen bond exists in the crystal. In 2003, Li et al. found that 2-fluorobenzamide derivatives might promote the stability of hydrazidebased quadruply hydrogen-bonded heterodimers by forming six-membered intramolecular N−H···F hydrogen bonding (Zhao et al, 2003). A number of model compounds were then designed and prepared (Li et al., 2005). The crystal structures of compounds **1**-**3**, which bear one triphenylmethyl or two nitro groups to increase their cystallinity (Corbin et al, 2003; Yin et al., 2003), were obtained (Figure 1). All the three compounds adopt a well-defined planar conformation rigidified by the intramolecular N−H⋅⋅⋅F H-bonds. The F⋅⋅⋅H (amide) distance of compound **1** is 2.23 Å, and the N−H⋅⋅⋅F angle is 106°. The fluorine atoms of both **2** and **3** are located to the proximity of the amide hydrogen due to the formation of the threecentered H-bonds, which is common for similar alkoxyl-substituted aromatic amide (Gong, 2001). The F⋅⋅⋅H (amide) distance of the six- and five-membered H-bonds is 1.94 and 2.18 Å in **2**, and 1.97 and 2.18 Å in **3**, respectively. The corresponding F⋅⋅⋅H−N angle is 136 and 108° for **2**, and 136 and 111° for **3**. All these values fall into the range of the criterion for the judgment of a F⋅⋅⋅H−N H-bond⎯the F⋅⋅⋅*H*N distance < 2.3 Å and the N−H⋅⋅⋅F angle > 90°

F N O

H H

O2N NO2

N O

**1.97 2.18 2.20**

**1.96**

F

Me

F

experimentally. The crystal structures of many organic halogen or sulfur (ether) compounds exhibit such intermolecular short contacts, which may be mainly driven by the intrinsic preference of these atoms in forming the H-bonding or formed due to the assistance of the intermolecular stacking and van der Waals force (Toth et al., 2007) and other intra- and intermolecular interactions.

Due to the increased conformational flexibility of the backbones and the decreased acidity of the amide proton, the H-bonding in aliphatic amide derivatives is expected to be even weaker. However, five-membered intramolecular N−H⋅⋅⋅F (F: Hughes & Small, 1972; O'Hagan et al., 2006), N−H⋅⋅⋅Cl (de Sousa et al., 2007; Kalyanaraman et al., 1978) and N−H⋅⋅⋅I (Savinkina et al., 2008) H-bonding patterns have been observed in aliphatic amides. To the best of our knowledge, the six-membered one is not available yet in simple organic molecules.

One consideration for exploiting the intramolecular N−H⋅⋅⋅X (X = F, Cl, Br, I, S) H-bonding of the aromatic amides is that the new patterns may find applications in designing new preorganized building blocks for crystal and supramolecular engineering (Biradha, 2003; Desiraju, 2005). Furthermore, new H-bonding motifs may also be useful in building foldamers (Zhu et al., 2011; Zhao & Li, 2010; Saraogi & Hamilton, 2009; Li et al,, 2008; Li et al., 2006; Huc, 2004; Sanford & Gong, 2003), the artificial secondary structures, and for designing biologically or medicinally useful structures (Tew et al., 2010; Li et al., 2008; Bautista et al., 2007). For doing this, the more competitive intermolecular N−H⋅⋅⋅O=C Hbonding of the amide unit has to be suppressed. There are two approaches for realizing this purpose. The first one concerns the introduction of a strong intramolecular H-bond to "lock" the amide proton. The second one is to introduce one or more bulky groups to impede the contact of the amides. In these ways, the very weak intramolecular N−H⋅⋅⋅I hydrogen bonding can be observed. There are several techniques for investigating the formation of the weak intramolecular H-bonding. The NMR spectroscopy is promising for studies in solution (Manjunatha et al., 2010), and the infrared spectroscopy can be used to detect samples in both the solution and solid state (Legon, 1990), while the computational modeling can provide useful information about the effects of discrete factors on the stability of the Hbonds (Dunitz, 2004; Liu et al., 2009), which are particularly valuable when experimental evidences are not available. In view of the feature of this book, we will focus on the investigations by the X-ray crystallography.

The crystal structure of an aromatic amide molecule is affected by many factors, including the stacking pattern, van der Waals force, intra- and intermolecular hydrogen and halogen bonding, and shape matching of the molecule. The entrapped solvent molecules, particularly those containing heteroatoms, may also play an important role because they are able to form hydrogen or halogen bonding with the molecule and thus affect the stacking pattern to suppress or promote the formation of the intramolecular H-bonding. Concerning the criterion for the formation of the weak intramolecular H-bonding, we simply check the distance between the heteroatom and the amide hydrogen in the crystal structure. If it is shorter than the sum of the radius of the two atoms, we consider that an H-bonding is formed (Desiraju & Steiner, 2001). Although in X-ray structures the proton/hydrogen is not located accurately and may bend toward or away from the acceptor, for clarity we simply use the reported distances between the two concerned atoms as the criteria.
