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For compounds 6-1, 6-2 (section 6.3.1) and 6-3a, 6-3b (section 6.3.2), an intramolecular hydrogen bond is expected to form, on the basis of the 1_{H chemical shifts, between the NHa proton and the aldehyde}

oxygen (6-1, 6-2) and oxime nitrogen (6-3a, 6-3b), respectively. In compound 6-4, in which the oxime is converted into the nitrile (the NHa proton and the nitrile nitrogen do not sit within hydrogen bonding distance, given the expected linear nature of the nitrile functionality), and in 6-5 where the NHa proton is replaced by an amide functional group (in preparation for the ring closure reaction, 6-5 to 6-6), this intramolecular interaction is no longer a possibility. As a result, the observed 1_{H –} 1_{H (600 MHz)}

DQ/SQ MAS spectra of 6-4 and 6-5, presented in Fig. 6.13 and 6.14, respectively, are markedly different when compared to the DQ spectra already presented in this chapter. Specifically, these differences are manifested as changes in the respective 1_{H chemical shifts which are observed at ~8.0}

ppm and below, for 6-4 and 6-5, reflecting the reduced capacity of these molecules to form strong hydrogen bonding interactions.

In the case of both 6-4 and 6-5, assignment of the various 1_{H chemical shifts of the NH protons is only}

possible by means of the respective 14_{N –} 1H HMQC spectra, recorded at a short recoupling time ( RCPL

region of the spectrum, hence making accurate assignment based only upon the 1_{H –} 1_{H DQ spectra}

alone impossible.

Interestingly, for 6-4, the 14_{N shift of the Na nitrogen, i.e., the nitrogen directly bonded to the NHa}

proton (see Fig. 6.13d), is revealing if it is compared to the 14_{N shift of this same nitrogen environment}

in 6-2 (Fig. 6.5d). In 6-2 this nitrogen is observed at approximately 90 ppm, whereas for 6-4 it is observed at 55 ppm. This is a large difference in shift (~ 150 ppm) and is indicative of a significant change in environment for this nitrogen site, i.e., loss of an intramolecular hydrogen bonding interaction in 6-4, when compared to 6-2.

For 6-5, the presence of the amide moiety bonded to this same Na nitrogen complicates analysis for this molecule. By analysing the 1_{H –} 1_{H DQ/SQ MAS (Fig. 6.14c) and} 14_{N –} 1_{H HMQC (Fig. 6.14d) spectra}

together, it can be seen that the two NH2 protons are observed at 1H chemical shifts of SQ = 3.7 and 8.1

ppm. This difference in 1_{H chemical shift between the two NH protons leads to the suggestion of a}

weakly hydrogen bonded dimer interacting via the amide moiety, as presented in Fig. 6.15a. However,

the absence of an NH – NH auto-peak (expected at DQ = 8.1 + 8.1 = 16.2 ppm) seems to speak against

such a dimeric arrangement. Since such an arrangement in the same plane would likely bring the amide oxygen lone pair into close spatial proximity with the nitrile CN triple bond, it is likely that such an arrangement would cause a rotation of the N(a) – C bond (see Fig. 6.15a), thus forcing the amide moiety out of the plane of the molecule. However, an alternative explanation for the observed NH21H chemical

shifts could be an intramolecularly hydrogen bonded species, as presented in Fig. 6.15b. However, it is not clear whether or not the bulky aromatic and nitrile moieties could sit in such close spatial proximity. It would however explain why no cross-peak is observed between the NH proton (3.7 ppm) and a nearby aromatic proton in the 1_{H –} 1_{H DQ/SQ MAS spectra of 6-5 (see Fig. 6.14c). Note that the intramolecular}

species presented in Fig. 6.15b requires that the amide carbonyl C – N bond be rotated, thus explaining

the absence of the aforementioned aromatic CH – HN cross-peak in the 1_{H –} 1_{H DQ/SQ MAS spectrum}

Figure 6.13 For 6-4 (a, c) 1D 1_{H (}_ _{600 MHz) DQ-filtered, i.e., t}

1 = 0, and 2D 1H – 1H ( 600 MHz) spectra, (b, d) 1D

HMQC filtered and 2D 14_{N –} 1_{H (}_ _{600 MHz) HMQC spectra, using R}3 _{recoupling of the} 14_{N –} 1_{H heteronuclear dipolar}

couplings, with a RCPL = 130 s. All experiments were recorded at 60 kHz MAS. For (c), 16 transients were recorded for

each of 128 t1 FIDs. For (d), 16 transients were recorded for each of 32 t1 FIDs. In each case, the recycle delay was 2

Figure 6.14 For 6-5 (a, c) 1D 1_{H (}_ _{600 MHz) DQ-filtered, i.e., t}

1 = 0, and 2D 1H – 1H ( 600 MHz) spectra, (b, d) 1D

HMQC filtered and 2D 14_{N –} 1_{H (}_ _{600 MHz) HMQC spectra, using R}3 _{recoupling of the} 14_{N –} 1_{H heteronuclear dipolar}

couplings, with a RCPL = 130 s. All experiments were recorded at 60 kHz MAS. For (c), 16 transients were recorded for

each of 128 t1 FIDs. For (d), 16 transients were recorded for each of 32 t1 FIDs. In each case, the recycle delay was 2

seconds. The 1D spectra correspond to the first row of the respective 2D spectra. The base contour level is at (c) 5, and (d) 80% of the maximum peak height.

Figure 6.15 Schematic representation of: (a) a hypothesised weak hydrogen bonded dimer for 6-5 interacting via the amide and (b) a potential intramolecularly bonded species. The wiggly lines in (a) indicate a potential CN bond rotation. Note that

in (b) the other aryl moiety may also rotate to avoid unfavourable steric interference.

Table 6.5 DQ correlations extracted from the 1_{H –} 1_{H DQ/SQ MAS spectrum of 6-4 in Fig. 6.13c.}

6-4 # Correlation SQ(1) + SQ(2) / ppm DQ / ppm 1 CH3 – CH3   2 CH3 – CH3 0.7 + 0.7 1.4 3 CH3 – CH (aro) 0.4 + 6.8 7.2 4 CH3 – CH (aro) 0.7 + 7.3 8.0 5 CH2 – CH2 4.0 + 5.0 9.0 6 CH2 – CH (aro) 4.0 + 6.8 10.8 7 CH2 – CH (aro) 5.0 + 6.1 11.1 8 CH (aro) – CH (aro) 6.8 + 6.8 13.6 9 CH(aro) – NHa 7.3 + 8.0 15.2

Table 6.6 DQ correlations extracted from the 1_{H –} 1_{H DQ/SQ MAS spectrum of 6-5 in Fig. 6.14c.}

6-5 # Correlation SQ(1) + SQ(2) / ppm DQ / ppm 1 CH3 – CH3   2 CH3 – CH2 0.9 + 4.8 5.7 3 CH3 – CH (aro) 0.9 + 7.0 7.9 4 CH2 – CH2 4.3 + 4.8 9.1 5 CH2 – CH (aro) 4.8 + 6.5 11.3 6 NH – NH 3.7 + 8.1 11.8

6.3.4 1_{H –} 1_{H DQ/SQ MAS spectrum of 6-6}

The ring closure reaction (6-5 to 6-6) yields a cytosine-like hydrogen bond motif (AAD), as presented in Fig. 6.16. Due to a lack of alternative donor/acceptor groups in 6-6, a dimeric arrangement is expected with two molecules of 6-6 interacting through this AAD interface (see Fig. 6.16). The observed cross-

peaks in the 1_{H –} 1_{H (600 MHz) DQ/SQ MAS (55 kHz) spectrum of 6-6, presented in Fig. 6.17, are}

consistent with such a self-assembled structure.

Figure 6.16 Schematic representation of the proposed hydrogen bonded dimer for 6-6. The cytosine-like moiety is highlighted in red. The wiggly lines represent a possible CN bond rotation.

The high abundance of methyl group protons in 6-6 leads to the appearance of three distinct auto-peaks in the 1H DQ MAS spectrum (Fig. 6.17), at 

DQ = 0.7 + 0.7 = 1.4, 1.3 + 1.3 = 2.6, and 1.8 + 1.8 = 3.6

ppm, respectively. The appearance of these peaks is consistent with a rotation about the CN bond highlighted in Fig. 6.16 (wiggly lines), in which the bulky aromatic groups are rotated away from one another to reduce steric tension in 6-6 (as shown in Fig. 6.16). Indeed, this is a common feature in all BOC protected compounds reported thus far in this chapter. It is perhaps possible that such a rotation

allows for a weak C=O ⋯ H – C interaction to occur, between the carbonyl oxygen on the BOC group

and the adjacent aromatic moiety, in addition to a N ⋯ H – C interaction (see Fig. 6.16), which may act to stabilise such a conformation, in addition to moving the carbonyl oxygen on the BOC group away from the electron lone pair on the nearby heterocyclic nitrogen. Such a conformation is consistent with

three distinct methyl environments observed in the 1_{H MAS NMR data.}

Such a high abundance of methyl groups in 6-6 leads to cross-peaks with the nearby aromatic protons, with cross-peaks being observed at DQ = 0.7 + 6.4 = 7.1, 1.3 + 7.1 = 8.4, and 1.8 + 7.5 = 9.3 ppm.

These interactions are expected based upon the molecular structure, since these environments are locked in close spatial proximity via covalent bonds. Interestingly, a proximity between methyl protons and

Figure 6.17 1_{H –} 1_{H (}_ _{600 MHz) DQ/SQ MAS (55 kHz) spectrum of 6-6, alongside skyline projections and a schematic}

representation of the proposed hydrogen bonded dimer. One rotor period of BABA recoupling was used for the excitation and reconversion of DQ coherence. For each of 256 t1 FIDs, 64 transients were coadded with a recycle delay of 3 seconds.

benzylic CH2 protons is also apparent, as evidenced by an observed cross-peak at DQ = 0.7 + 4.4 = 5.1

ppm. Such a proximity between these proton environments is not possible within an individual molecule of 6-6 and so must indicate an intermolecular interaction, that is consistent with a packing arrangement of dimers in the solid state. However, based on the data presented in Fig. 6.17, it is impossible to speculate further on the form this packing takes.

The presence of an NH2 moiety in 6-6 leads to a strong cross-peak at DQ = 6.3 + 10.8 = 17.1 ppm, with

such interactions leading to intense peaks due to the close spatial proximity (typically ~ 1.5 Å). The NHb proton (10.8 ppm) interacts with itself, as evidenced by a weak auto-peak observed at DQ = 10.8

+ 10.8 = 21.6 ppm. This is consistent with an intermolecular dipolar coupling across the dimeric hydrogen bonding interface (see the hydrogen bonding structure in Fig. 6.17). As was observed in previous chapters, the dipolar coupling associated with this intermolecular interaction is truncated by the strong NH2 intramolecular interaction. Based upon the structure of 6-6, NHa (6.3 ppm) is expected

to form an intramolecular hydrogen bonding arrangement with the benzylic oxygen. However, this interaction is expected to be weak (as expected from the low observed 1_{H chemical shift of NHa) since}

aryl ethers are typically poor hydrogen bond acceptors.(259)

Table 6.7 DQ correlations extracted from the 1_{H –} 1_{H DQ/SQ MAS spectrum of 6-6 in Fig. 6.17.}

6-6 # Correlation SQ(1) + SQ(2) / ppm DQ / ppm 1 CH3 – CH3   2 CH3 – CH3 1.3 + 1.3 2.6 3 CH3 – CH3 1.8 + 1.8 3.6 4 CH3 – CH2 0.7 + 4.4 5.1 5 CH3 – CH (aro) 0.7 + 6.5 7.2 6 CH3 – CH (aro) 1.3 + 7.1 8.4 7 CH2 – CH2 4.4 + 4.4 8.8 8 CH3 – CH (aro) 1.8 + 7.6 9.4 9 CH2 – CH (aro) 4.4 + 6.7 11.1 10 CH (aro) – CH (aro) 6.5 + 6.7 13.2 11 CH (aro) – CH (aro) 7.5 + 7.5 15.0 12 NHa – NHb 6.4 + 10.8 17.2 13 NHb – NHb 10.8 + 10.8 21.6