*2.1. HN Chemical Shifts*

Primary amines may pose a problem in those cases in which rotation around the C-N bond occurs. This leads to averaged NH chemical shifts or as seen later, to averaged onebond NH coupling constants. In some cases rotation can be stopped at low temperature, as seen e.g., in bis(6-amino-1,3-dimethyluracil-5-yl)-methane derivatives (Figure 3). The

chemical shifts of the hydrogen bonded NH protons in these compounds are in the 8–9 ppm range [11].

**Figure 3.** Bis(6-amino-1,3-dimethyluracil-5-yl)-methane derivatives. R being ethyl, pyridine or *p*-dimethylaminopyridine. Taken from [11].

In compounds with aromatic rings close to the NH proton, the NH chemical shift has to be corrected for ring-current effects (for an example of ring current effects see Figure 4) in order to use this to characterize the NH ... X hydrogen bond. In A ring a current is present, whereas it is absent in B.

**Figure 4.** (**a**). Demonstration of possible ring current effects. In A the ring is twisted 34◦ out to the double bond plane, whereas in B the twist angle is 89◦. Data from [12]. (**b**) Plot of 1H chemical shifts of CH3-5 vs. NH chemical shifts for enaminones with following substituent at nitrogen phenyl substituent, *o*-methyl, *O*,*O*-dimethyl and 4-isopropyl. Data from [13–15].

The plot of Figure 4b demonstrates the low frequency shift of both the NH and the CH3-5 chemical shift as the phenyl group in the ortho-substituted phenyl ring is twisted.

In β-enaminones (Figure 1A), a hydroxyl group at the phenyl ring next to the carbonyl group clearly competes with the NH group and the NH chemical shift drops to 11.89 ppm [12], whereas an OH group in the ortho-position of a phenyl group at the nitrogen also leads to drop [16], but in this case it is a combination of a twist of the phenyl ring and a field effect caused by the OH group. In case of the *o*-hydroxyphenyl derivative, Rodríguez et al. [17] also report the finding of the keto-form at low concentration in the 1H-NMR spectrum but not in the 13C-NMR spectrum. *o*-Hydroxyaromatic Schiff bases T are usually either on the OH-form or being tautomeric [18]. However, recently a large number of Schiff bases based on salicylaldehyde and TRIS have been shown to be on the enamine form in the solid state. This is true for the following salicylaldehydes with substituents as follows: 5-nitro, 5-methylcarboxylate, 4-fluor, 4-choro, 4-bromo, 4-methoxy, 4-amino and 5-phenylazo [1]. A few other examples of compounds entirely on the NH form are Schiff bases of 1,3,5-triacyl-2,4,6-trihydroxybenzene [19–21], 1,3,5-triformyl-2,4-6- trihydroxybenzene [19], of gossypol [22,23] or more recently of primarily on the NH form (2-(anilinemethylidenen)cyclohexane-1,3-dione) [24].

A classic comparison is that of hydrogen bonding involving a ketone or an ester is seen in Figure 5A,B. Another comparison can be found in Ref. [25].

**Figure 5.** Comparison of different acceptors ( **A**,**B**) and demonstration of steric compression ( **C**,**D**). The numbers are NH chemical shifts in ppm. A and B from [15,26]. For the corresponding N-methyl derivatives, the chemical shifts are 10.90 ppm and 8.55 ppm. ( **C**) is from [12] and ( **D**) from [27].

It is obvious that substitution at nitrogen plays a role. Furthermore, steric compression is also an important feature as seen by comparing the 3-methyl derivative C with the corresponding non-substituted compound D. The introduction of the nitro groups leads to a slightly more acid NH group and to a stronger hydrogen bond (A vs. C). By comparison of the following compounds Figure 6, it is also clear that ring-size plays a role.

**Figure 6.** Illustration of the importance of ring size. Taken from [28]. C shows the effect of a six-membered ring. Taken from [29]. The numbers are the NH chemical shifts in ppm.

Another comparison is made in Figure 7, in which the NH is hydrogen bonded to a carbonyl group or to an amide group. The acceptor amide as acceptor clearly leads to the weaker hydrogen bond.

**Figure 7.** Comparison of ketone and amide groups as acceptors. Data from [30]. The numbers are the NH chemical shifts in ppm.

Amides and thioamides as donors are compared in Figure 8 [31].

**Figure 8.** Comparison of amides and thioamides as donors. The numbers are the NH chemical shifts in ppm. For the amide and thioamide the methyl derivatives have chemical shifts of 9.69 and 12.20 ppm. Taken from [31]. The amine is from [24].

It is seen from Figure 6 that the thioamide is the strongest donor followed by the amine and in third place the amide. Hydrogen bonding to a S=O acceptor is demonstrated in Figure 9.

g

**Figure 9.** Hydrogen bonding with different motifs. The numbers are NH chemical shifts in ppm. The sulfoxide is from [32]. The indole derivative is from [33]. Other similar motifs is seen in this reference. The benzo[d]thiazol is from [28].

The low chemical shift of the benzo[d]thiazol is due to the lack of conjugation between the donor and the acceptor. In Figure 10 are comparisons again done between different acceptors. NH chemical shifts may for hydrogen bonded hydrazo compounds reach values as high as 15.8 ppm when the NH is hydrogen-bonded to a pyridine nitrogen. In the minor isomer, in which the NH is hydrogen bonded to an ethyl ester group, the chemical shift is 12.8 ppm [34]. In the other pair it is obvious that the stronger hydrogen bond is to a CH3C=O rather than to a PhC=O. The ability of aromatic nitrogens to form hydrogen bonds is also demonstrated in ( *Z*)-5-((phenylamino)methylene)quinoxaline-6-(5 *H*)-one, 13.15 ppm in DMSO-d6. This value drops to 11.15 ppm in in (*Z*)-4-((phenylamino)methylene)thiadiazol-5- (4*H*)-one, which has a sulphur instead of a CH2=CH2 unit and hydrogen bonding nitrogen is now part of a five-membered ring [35]. This isomer is with hydrogen bonding to nitrogen is the minor form. The authors discuss hydrogen bonding in terms of quasi-aromaticity.

**Figure 10.** Comparison of rotamers. The numbers are NH chemical shifts in ppm. The chemical shifts are from [36]. The NH chemical shifts for the corresponding benzene derivative (benzene instead of naphthalene) are 14.6 ppm instead of 15.8 ppm. [34] If the ring is a 8-benzoquinoline the chemical shift is 15.36 ppm [37].

Pyrroles can also be hydrogen bond donors as seen in a series of compounds (Figure 11). The NH chemical shifts vary from 10.16 to 13.07 ppm [38]. In a similar case but with an OH group as the acceptor, and two pyrroles present, one hydrogen bonded the other not, the chemical shift drops to 9.39 ppm [39].

**Figure 11.** Bifurcated hydrogen bonds. Taken from [40]. The numbers are the NH chemical shifts in ppm.

Bifurcated intramolecular hydrogen bonds were found in azoylmethylidene derivatives of 2-indanone (Figure 11) [40]. Similar kind of molecules have been used to establish a correlation between NH chemical shifts and hydrogen bond energy (see Section 3). It can be seen how the nature of the donor influences the chemical shifts slightly. In case of C the corresponding compound with only one intramolecular hydrogen bond has a chemical shift of 13.73 ppm illustrating the effect of bifurcation. The benzene ring seems to have little effects as the compound corresponding to A simply with the cyclopentanone unit also has a chemical shift of 13.20 ppm. However, by inserting a cyclohexanone ring the chemical shift drops slightly [38]. A different kind of bifurcation can be found in 5-(4-substituted phenylazo)-1-carboxymethyl-3-cyano-6-hydroxy-4-methyl-2-pyridones [41].

Not so common motifs are seen in Figure 12. The question is if the rather high chemical shifts in the N-oxide are caused by a strong hydrogen bond or an electric field effect from the N+-O− bond. A fact is that the deuterium isotope effects on C=O and CH3 carbon chemical are rather small [42] (for a general discussion of isotope effects see Section 2.4.1). The thio-Schiff base in Figure 12 is drawn as a neutral molecule and as a zwitterionic structure. The latter contributes quite considerably. The NH chemical shifts vary from 18.06 ppm for R and R = CH3 to 19.26 ppm for R= PhN(CH3)2 and R=CH3 [43] or 17.33 ppm for CH3=PhCH3, R=CH3 or 18.2 ppm for R=PhOCH3 and R=CH3 [44]. Similar values were also obtained for derivatives in which R is H [45].

**Figure 12.** The amino N-oxide demonstrates hydrogen bonding to a charged acceptor. Taken from [42] For the thio-Schiff base resonance forms are demonstrated. Taken from [43]. The number is the NH chemical shift in ppm.

In Figure 13 is seen a comparison of an aldehyde or an imine as acceptor and a donor being either an amide or a sulfamide. The imine is the best acceptor and as the amide is a better donor than the sulfamide.

**Figure 13.** Comparison of different amides as acceptors. In A Y=O the NH chemical shift is 10.97 ppm, whereas when Y=N-butyl it is 18.83 ppm. In B the NH chemical shift is 10.50 vs. 12.74 ppm. Taken from [46].

Hydrogen bonding is clearly weaker when the hydrogen bonding is to a sp<sup>3</sup> hybridized oxygen and the hydrogen system is a five membered ring as demonstrated in the benzoxazine in Figure 14. Although the hydrogen bond is not so strong it is concentration independent [47].

**Figure 14.** Hydrogen bonding to single bonded oxygen. (**a**). Benzoxazine with intramolecular hydrogen bonding from [47]. (**b**). N'-benzylidenbenzohydrazide from [48]. (**c**). Protonated enamine molecular switch from [49]. (**d**). 1,4-dihydropyridine derivatives from [50]. The numbers are the NH chemical shifts in ppm.

In the case of N-benzylidenbenzohydrazide, as seen in Figure 14b, a weak hydrogen bond to the methoxy group is formed. This is clearly stronger than when a classic amide is the hydrogen bond donor. In Figure 14c an amine is hydrogen bonded to an ester oxygen [49].

Charged species show large NH chemical shifts. The protonated DMAN's are tautomeric, but as long as they are symmetric this will not influence the NH chemical shifts. For a review of these see [51]. Very recently an amide type has been investigated. The R substituent has a small effect [8]. Recently motifs A and C have been combined [52].

It is obvious from the chemical shifts seen in Figure 15 and in Figure 2, that the charged systems have high NH chemical shifts. These systems are typically tautomeric and show strong intramolecular hydrogen bonds.

**Figure 15.** Hydrogen bonding of DMAN types (**A**–**C**). Counter ions are left out, but the numbers vary slightly with the counter ion. (**C**,**D**) are hydrogen bonding to a negative acceptor. Numbers are NH chemical shifts. (**A**) from [53], (**B**,**C**) from [54]. (**D**) from [55]. (**E**) from [56].

Motifs involving urea can be found in a review by Osmialowski [57]. Urea is versatile, as it can act both as an amide type donor and acceptor. The intramolecular nature of the hydrogen bonds were among other things established by measuring the temperature dependence. Temperature dependence was also used to distinguish between NH and OH hydrogen bonds [16]. However, this technique is by no means a reliable tool [58]. Oxamides and thioamides NH temperature coefficients have also been investigated to distinguish intra from inter molecular hydrogen bonding [59].

A number of non-RAHB cases are seen in Figure 14. In addition, proteins often offer many intramolecular hydrogen bonds (for use of coupling constants see Section 2.2). To use NH chemical shifts these should be corrected. This subject has been treated in dipeptides by Scheiner [60].

The results of Figures 4–14 can be summarized in the following way: thioamides seem to be better than hydrazo groups as donors. They are slightly better than aromatic amines, which again are better than aliphatic amines, amides and sulfamides in that order. The pyrroles are not so easy to fit into this scheme. Even when the hydrogen bond is part of a seven membered ring, they are clearly forming strong hydrogen bonds. As acceptors thiones are better than pyridines and other nitrogen containing rings, imines are better

than ketones, which are better than amides and esters. Sulfoxides are rather poor. Single bonded oxygens are even poorer. For charged systems the number of cases is limited, but seems to follow the neutral ones. However, the chemical shifts are much higher both in cases with the donor being positive charged or the acceptor being negatively charged as compared to the neutral cases.
