Aldehyde containing compounds: 6-1 and 6-2

In solution-state NMR, aldehyde protons are typically observed in the 9.0 – 10.0 ppm range. In the absence of substantive literature precedence for such moieties in the solid state, 1_{H –} 13_{C INEPT based}

methods can be exploited to ascertain the chemical shift of the CHO proton. The CP MAS data for 6-1

(Fig. 6.2) reveals that the 13_{C aldehyde environment is observed at 186.7 ppm, analysis of which is}

made easier by the absence of any other carbonyl groups in this molecule. However, in terms of 1_H

chemical shifts, the situation is complicated for 6-1 in that the NHa and NHb protons, which are postulated to form hydrogen bonding interactions, are observed in the same chemical shift region as the

aldehyde, thereby complicating analysis. This is indeed observed in the 1_{H –} 1_{H (600 MHz) DQ/SQ}

MAS (60 kHz) spectrum of 6-1 presented in Fig. 6.3d (DQ correlations are listed in Table 6.1), which exhibits broad spectral features due to two simultaneous effects: the presence of typically strong aromatic dipolar coupling interactions and the overlapping aldehyde and amine resonances. Fig. 6.3e presents a 14_{N –} 1_{H (600 MHz) HMQC spectrum of 6-1, recorded at a short recoupling duration of 130}

s, in which only one-bond NH proximities are expected to be observed. Despite the high abundance of nitrogens in this molecule sitting in close spatial proximity to several aromatic sites (accounting for the correlations observed between 6.0 and 9.0 ppm in the 1_{H dimension), two clear, strong correlations}

are observed at overlapping 14N chemical shifts of ~ 30 ppm and 1_{H chemical shifts of 11.0 and 9.7}

ppm. The 1_{H –} 13_{C INEPT spectrum presented in Fig. 6.3f, confirms that the resonance at a} 1_{H chemical}

shift of 9.9 ppm does indeed correspond to the aldehyde proton, since this environment experiences a clear correlation with the aforementioned aldehyde C=O 13_{C chemical shift at 186.7 ppm.}

These data allow for a description of the solid-state packing arrangement for 6-1. In the 1_{H DQ MAS}

data, in Fig. 6.3d, the auto-peak observed at DQ = 9.7 + 9.7 = 19.4 ppm is, in light of the HMQC data

presented in Fig. 6.3e, assigned as an NHb – NHb contact across the hydrogen bonding face (presented in Fig. 6.4). The resonance observed at 11.0 ppm is therefore assigned as the NHa environment which undergoes an intramolecular hydrogen bonding interaction with the aldehyde carbonyl oxygen (see Fig. 6.4). Interestingly, a cross-peak is observed at DQ = 9.9 + 11.0 = 20.9 ppm, assigned herein as a close

spatial proximity between the aldehyde proton and the intramolecularly hydrogen bonded NHa proton environments. This interaction may be explained as a close approach of individual dimers or some form of weakly associated linear assembly: putative structural arrangements are presented in Fig. 6.4. From a self-assembly standpoint, both of the structures presented in Fig. 6.4 are feasible. With the linear arrangement, a cross-peak between the nearby aromatic proton and the aldehyde proton would be expected given their proximity. Unfortunately due to the close NHa and aldehyde chemical shifts, it is not possible to distinguish such a cross-peak at DQ = 7.1 + 9.9 = 17.0 ppm in the 1H DQ MAS spectrum

(Fig. 6.3d). The number of aromatic moieties in 6-1 mean that a  stacking of individual linear ‘tapes’ would be expected.

Figure 6.2 1_{H (}_ _{500 MHz) –} 13_{C CP MAS (12.5 kHz spinning) spectrum of 6-1, recorded with 1024 transients and a}

Figure 6.3 For 6-1, (a, d) 1D 1_{H ( 600 MHz) DQ-filtered, i.e., t}

1 = 0, and 2D 1H – 1H ( 600 MHz) DQ/SQ MAS

spectra, (b, e) 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 (c, f) 1H ( 500 MHz) – 13C INEPT filtered INEPT spectra,

recorded at (a, b, d, e) 60 and (c, f) 12.5 kHz MAS. For (d), 16 transients were recorded for each of 128 t1 FIDs. For (e), 32

transients were recorded for each of 64 t1 FIDs. For (f), 256 transients were recorded for each of 32 t1 FIDs. The recycle

delay was 3 (a, b, d, e) and 2 seconds (c, f). The 1D spectra correspond to the first row of the respective 2D spectra. The base contour level is at (d) 1, (e) 41, and (f) 3% of the maximum peak height.

Figure 6.4 Schematic representation of expected hydrogen bonding exhibited by 6-1. The weak NH – HCO cross-peak, observed in Fig. 6.3d (straight arrows) can be explained by a stacked dimer or linear arrangement. With the linear arrangement, a cross-peak between aromatic and aldehyde protons, as indicated by the curved arrow, is expected.

A 1_{H –} 1_{H (600 MHz) DQ/SQ MAS (60 kHz) spectrum of 6-2, presented in Fig. 6.5c (DQ correlations}

are presented in Table 6.2), is easier to interpret compared to the corresponding spectrum of 6-1. This is due to the absence of the NHb proton, which in 6-1 was postulated to form a dimeric hydrogen bonded structure (see Fig. 6.4), but which in 6-2 has been protected at this position with a t-butyloxycarbonyl

(BOC) group. The resulting hydrogen bonding capacity of 6-2 is subsequently reduced, although the

intramolecular NHa ⋯ O=C hydrogen bond is retained. This therefore leaves a weakly associated dimer

as the only viable structural possibility, as shown in Fig 6.6. The appearance of a cross-peak in the 1_H

– 1_{H DQ/SQ MAS spectrum of 6-2} at 

DQ = 7.2 + 9.5 = 16.7 ppm, is consistent with an aldehyde proton

– aromatic proton spatial proximity. However, given that the NH amine group forms a cross-peak at DQ = 6.6 + 10.3 = 16.9 ppm, with what is likely an aromatic proton in the nearby aryl moiety, it is

perhaps more likely that the former cross-peak is explained by some spatial arrangement whereby the benzyl aromatic functionality is close in space with the aldehyde proton environment (intermolecular). A short recoupling time (RCPL = 130 s) 14N – 1H (600 MHz) HMQC spectrum of 6-2 is presented in

Fig. 6.5d. Analysis of the observed correlations reveals a strong peak at ~ 140 ppm and 10.2 ppm in the 14_{N and} 1_{H dimension, respectively. Weaker correlations due to close spatial proximities of this}

Figure 6.5 (a, c) 1D 1_{H (}_ _{600 MHz) DQ-filtered, i.e., t}

1 = 0, and 2D 1H – 1H ( 600 MHz) DQ/SQ MAS 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 of 6-2, recorded in all cases 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 3

seconds. The 1D spectra correspond to the first row of the respective 2D spectra. The base contour level is at (c) 2, and (d) 17% of the maximum peak height.

Figure 6.6 Schematic representation of a possible weakly associated dimer for 6-2.

Three distinct resonances corresponding to three different methyl group environments are clearly observed in the 1_{H DQ MAS spectrum in Fig. 6.5c which result in three auto-peaks at} 

DQ =

, 1.4 + 1.4 = 2.8, and 1.8 + 1.8 = 3.6 ppm, respectively. These three peaks correspond to the three methyl group environments in 6-2: the two t-butyl groups directly bonded to the aromatic moieties and the t-butyl group contained within the BOC protecting group. Given that in precursor 6-1

(no BOC group) the two former t-butyl groups resulted in one broad resonance at SQ = 0.8 ppm, this

observed splitting of the methyl signal is perhaps consistent with a rotation of a CN bond as presented in Fig. 6.7. This potential bond rotation would relieve the steric tension between the two aromatic rings. In 6-1, this rotation is not expected to occur due to the hydrogen bonding capacity offered by the unprotected NHb proton (see Fig. 6.4). This hypothesis is consistent with the observed cross-peaks in the DQ spectrum of 6-1, presented in Fig. 6.3d, specifically the auto-peak at DQ = 9.7 + 9.7 = 19.4

ppm, which is consistent with an intermolecular dipolar coupling of this NH proton with itself across a hydrogen bonding interface (see Fig. 6.4).

Table 6.1 DQ correlations extracted from the 1_{H –} 1_{H DQ/SQ MAS spectrum of 6-1 in Fig. 6.3d.} 6-1 # Correlation SQ(1) + SQ(2) / ppm DQ / ppm 1 CH3 – CH3   2 CH3 – CH2 0.7 + 4.0 4.7 3 CH3 – CH (aro) 0.7 + 6.6 7.3 4 CH2 – CH2 3.5 + 4.0 7.5 5 CH3 – NHb 0.7 + 9.7 10.4 6 CH3 – CHO 0.7 + 9.9 10.6 7 CH3 – NHa 0.7 + 11.1 11.8 8 CH (aro) – CH (aro) 6.8 + 6.8 13.6 9 CH (aro) – NHb 6.8 + 9.7 16.5 10 CH (aro) – NHa 7.5 + 11.1 18.6 11 NHb – NHb 9.7 + 9.7 19.4 12 CHO – NHa 9.9 + 11.1 21.0

Table 6.2 DQ correlations extracted from the 1_{H –} 1_{H DQ/SQ MAS spectrum of 6-2 in Fig. 6.5c.}

6-2 # Correlation SQ(1) + SQ(2) / ppm DQ / ppm 1 CH3 – CH3   2 CH3 – CH3  1.1 3 CH3 – CH3 1.3 + 1.3 2.6 4 CH3 – CH3 1.8 + 1.8 3.6 5 CH3 – CH (aro)  5.8 6 CH3 – CH2 1.8 + 4.6 6.4 7 CH3 – CH2 1.8 + 5.0 6.8 8 CH3 – CH (aro) 1.3 + 7.5 8.8 9 CH2 – CH2 4.6 + 5.0 9.6 10 CH2 – CH (aro) 5.0 + 6.7 11.7 11 CH (aro) – CH (aro) 6.7 + 6.7 13.4 12 CH (aro) – CH (aro) 7.1 + 7.1 14.2

13 CH (aro) – CHO 7.1 + 9.5 16.6

14 CH (aro) – NHa 6.7 + 10.3 17.0

15 CHO – NHa 9.5 + 10.3 19.8