Chapter Snynthesis and Structure Investigation of Molecular Crescent Aromatic Oligoamides 2.1 Introduction Oligomers that adopt stable, compact conformations have been coined as “foldamers”1a that are largely inspired by naturally occurring folding biomolecules including proteins and DNAs. An effective strategy in the designs of foldamers1,2 involves biasing the preferred conformations of synthetic oligomers by incorporating a multitude of non-covalent interactions such as hydrogen-bonding (H-bonding), solvophobic, π-π stacking and metal coordination bonds. Helical structures3,4 appear to occupy a privileged position among the folding patterns observed in reported foldamers. The progress made so far in designing helical foldamers has allowed a number of functionalities to be incorporated into various structural designs. As such, folding helices endowed with diverse properties have been extensively investigated in recent years that can 1) bind either neutral (saccharides,4g,4h,5a-d water3f,5e-g and other small molecules5h,5i) or protein-membrane7i-l interactions, and 8) kill bacterial.7m-q A recently emerged concept in designing sophisticated helical foldamers explores the proper use of multiply centered intramolecular H-bonds of varying types to constrain the backbones of aromatic oligoamides and their analogs such as aromatic oligohydrazides and oligoureas. Manipulating the folding of these aromatic oligomers 17 based on this strategy has allowed the creation of foldamers with a helically wrapped interior cavity of as small as 1.4 Å8 and as large as 30 Å in radius.3d This concept can be traced back to the pioneering work on pyridine amide oligomers by Hamilton,3a,3b,9a aromatic oligoamides/ureas/hydrazides/arylene ethynylenes by Gong,3d,10 aromatic oligoureas by Zimmerman,9b pyridine amide oligomers and quinoline carboxamide oligomers by Lehn,3c,11a-d and Huc,3c,3e,3f,3m,5e-g,6i,6k,11a,11b,11e-r followed by the active explorations on aromatic amides/hydrazides by Li,4g,5b,5d,5m,5n,6a,6b,12a-c Chen,6f,12d-g and others.3g,12h-j By including novel building blocks and H-bonding patterns, we8,13 and others5n,10k,12a,12b,12i have been interested in further developing the corresponding field. In this Chapter, we focus on shedding additional insights into the largely unexplored structural features (backbone bending, columnar packing, and potential channel formation) and on revealing the location-dependent strength of multiply centered intramolecular H-bonds, which play a critical role in the folding of these oligomers. Firstly, 1H NMR and X-ray diffraction were used to establish the folding of these conformationally rigid aromatic oligomers. Secondly, amide hydrogen-deuterium (H-D) exchange studies were used to infer the strengths of various intramolecular H-bonds placed at different locations along a backbone, results from which has allowed us to pinpoint the local conformational weakness along the oligoamide backbone. The conclusion from H-D exchange was confirmed by the crystal structures of a series of oligomers, which allows a qualitative correlation between the conformational stability of the H-bond enforced backbones and the 18 strength of individual H-bonds that are sensitive to local structural environments.10e,13 The correlation derived from H-D studies and solid state investigations was substantiated by results from ab initio calculations at the level of B3LYP/6-31G*. Examining the assembly of the oligomers in the solid state revealed a columnar packing shared by all the oligomers ranging from dimer to hexamer. The interplay of π-π stacking and van der Waals’ interactions provide the driving forces for the observed formation of columns. With their persistent shapes, tunable sizes and tendency to aggregate into column- and channel-like structures, these folding oligomers may serve as novel building blocks for constructing higher-order supramolecular structures with non-collapsible pores and channels capable of conducting ions and small molecules.10m 2.2 Result and Discussion 2.2.1 Synthesis of Oligoamides OC 8H 17 R2 O N H O 8R O N O H O O O N O 11 H 10 O R2 O 15 16 N H 20 O N O O O R3 NH R1 N H 10 10 O 2f O O R3 N H O 11 O 15 3d: R = R = O CH 3, R = OC 8H 17 NO2 10 25 13 12 15 16 N H O 17 18 N 19 O 22 N R3 O O N H O O H H21 O 2N 23 R O O 20 O 24 e: R = O CH 3, R = OC 8H 17, R = O CH(CH 3)2 3f: R = OCH 3, R2 = OCH(CH3)2, R = O C8H 17 O R2 14 O O 3b: R = R = O CH 3, R = H c: R = R = R = OCH 4a: R = R = R = H O N O 11 H O O2N H O O R1 H O 2g: R = OCH 3, R = OCH(CH3)2 O NO2 N 2e: R1 = OCH 3, R = OC 8H 17 O O 2d: R = R2 = OCH3 10 O O NO2 2c: R = H, R = O C H 17 O a: R = R = R 3= H O 2b: R = OCH 3, R = H R1 R2 2a: R = R = H R1 5a: R = R = R 3= H 24 26 N b: R = OC 8H17, R = R = OCH(CH3)2, R = CH O H 30 O O2N 4b: R = OC8H 17, R = OCH(CH 3)2, R = CH3 5c : R = OC 8H 17, R = OCH(CH 3)2, R3 = R4 = CH 27 28 29 R2 5d: R = R = R = H, R = OCH(CH3)2 a: R = R = H 6b: R1 = OCH(CH 3)2, R2 = OC 8H17 6c: R1 = OCH(CH 3)2, R2 = CH 19 All the aromatic oligoamides in Schemes 2-4 were synthesized from commercially available salicylic acid, 2,5-dihydroxybenzoic acid and 2-hydroxy-5-methylbenzoic acid in up to 18 steps. Monomeric building blocks 1k, 1l, 1m, 1q and 1t were prepared according to Scheme 2.1. These five building blocks differ from each other only by the remote alkoxyl substituents meta to nitro group. prove Introducing of these side chains critically important in conformational characterization in solution by 2D NOESY study and in the solid state by X-ray diffraction method. Scheme 2.1. Synthesis of Monomeric Building Blocksa OH OH OR c b a COOH COOCH3 OH COOCH3 OH 1a COOCH3 OH 1e, 1f , 1g OR d 1b, 1e, 1h, 1k: R = CH3 e O2N COOCH3 OCH3 1h, 1i, 1j O2N 1c, 1f, 1i, 1l: R = C8H17 COOH OCH3 1k, 1l, 1m 1d, 1g, 1j, 1m: R = CH(CH3) R1 R1 R1 f, a COOH O2N OH 1b,1c,1d OR OH OR e d O2N COOCH3 OH 1o, 1r R1 O2N COOCH3 OCH3 1p, 1s O2N COOH OCH3 1q, 1t 1o, 1p, 1q: R1 = CH3 1r, 1s, 1t: R1 = H a a) conc. H2SO4, MeOH, reflux, 97%; b) K2CO3/RBr (or RI), anhydrous acetone, reflux, 51~65%; c) Bi(NO3)3, MMT K10, THF, 58~67%; d) K2CO3/CH3I, DMF, 72~91%; e) NaOH, MeOH/H2O, reflux, 53~85%; f) conc. HNO3, Conc. H2SO4, 80%. Among the above five building blocks, 1k, 1l and 1m were prepared after five steps starting form 2,5-dihydroxybenzoic acid. As shown in Scheme 2.1, esterification in methanol provided methyl ester 1a in a high yield of ~90%. The second step 20 involving chemoselective alkylation turned out to be quite sensitive to the solvents used. While the use of dimethylformamide (DMF) produced dialkylated product in both hydroxyl groups, a desirable shifting to the monoalkylation occurred almost exclusively at the hydroxyl group meta to ester group with the use of alkyl iodides/bromides under refluxing conditions in the presence of potassium carbonate (K2CO3) in acetone. Since 1a has two hydroxyl groups on the same benzene ring, no more than 1.1 equiv of the alkyl iodine (or bromide) was used. This led to a long reaction time and moderate chemical yields (~ 60%) for 1b-1d. Nevertheless, simple flash column chromatography allows the easy purification of the products and recycling of the starting material. This chemoselective alkylation was unambiguously confirmed by the determined crystal structure of 1c (Figure 2.3). Attempted nitrations of 1b-1d by varying the ratio of conc. nitric acid and conc. sulfuric acid in dichloromethane (CH2Cl2) at varying temperatures from -40 oC to 45 o C invariably led to a mixture of at least three products detectable by Thin Layer Chromatography (TLC), from which the desired products 1e-1g were obtained in a unacceptable low yield of less than 30%. After testing a few more other conditions (i.e., conc. nitric acid (HNO3) in acetic acid (AcOH), or slow addition of conc. sulfuric acid (H2SO4) into conc. nitric acid containing compounds to be nitrated), the nitration method using montmorillonite (MMT) impregnated with bismuth nitrate (Bi(NO3)3) was finally singled out. The condition was very mild, simply involving mixing the compounds to be nitrated (1b-1d) with Montmorillonite K10 impregnated with bismuth nitrate in Tetrahydrofuran (THF) at room temperature and stirring the 21 solution for 12 hrs. Under this condition, a clean reaction producing only 1e-1g was obtained. The chemical yield was around 65%. It was later found out that a considerable amount of nitrated products was absorbed into solid support Montmorillonite K10, which can not be efficiently extracted out using CH2Cl2. This issue was solved by adding a small amount of acid (1M hydrochloric acid (HCl)) to the filtered Montmorillonite K10, followed by extraction with CH2Cl2 to maximize the chemical yield. The subsequent straightforward methylation of the second OH group using iodomethane or dimethyl sulfate in DMF at 60 ˚C, following by the NaOH-mediated saponification led to the production of monomeric acidic building blocks 1k-1m. During the synthesis of 1q from 2-hydroxy-5-methylbenzoic acid, bismuth nitrate-mediated nitration at room temperature tends to give inconsistent low chemical yields from time to time. It was finally realized that such nitration is highly sensitive toward both reaction temperature and reaction time. By controlling reaction temperature at -20 ˚C for 20 minutes, followed by immediate quenching with water, desired product can be obtained in a yield of as good as 80%. This bismuth nitrate-mediated nitration, surprisingly, did not work for 1r. Its mono-nitration, however, can be accomplished using conc. HNO3 and conc. H2SO4 in CH2Cl2, under which conditions, ironically the nitration of 1b-1d did not proceed at all. To facilitate the separation of mono-nitrated acid product 1r from its isomer that contains a nitro group ortho to hydroxyl group and minor product containing two nitro groups, the reaction mixtures were converted to ester compounds. It is interesting to note that 22 saturated (Sodium hydrogen carbonate (NaHCO3) can dissolve dinitro compound, but not mononitro compounds, into the aqueous layer. The two mono-nitrated isomers thus can be efficiently separated by flash column chromatography using hexane/CH2Cl2 (v:v 4:1) as the eluent to give pure product 1r as a bright yellow solid. Scheme 2.2. Synthesis of Trimersa H3COOC COOCH3 O O a, b O 2N R1 OCH OCH3 O O 1h N H R1 H3CO N O 2b, 2d, 2e H O N H R2 O NO O NO O 2b: R1 = H 2d: R1 = OCH3 2e: R1 = OC8H17 a O a, c 3b, 3c, 3d O 3b: R1= H, R2 = OCH3 3c: R1 = R2 = OCH3 3d: R1 = OCH3, R2 = OC8H17 a) H2, Pd/C, THF, 40 ˚C, 94%; b) ethyl chloroformate, 4-methylmorpholine, CH2Cl2, 1t (for 2b) or 1k (for 2d) or 1l (for 2e), RT, 72~77%; c) ethyl chloroformate, 4-methylmorpholine, CH2Cl2, 1k, RT 67~83%. Scheme 2.3. Synthesis of Hexamer 6aa O a, b repeat O2N COOCH3 H3COOC O O N H O d n HOOC O O 2h 2a: n = 1; 3a: n = O 3a a, c repeat H3COOC O N H O 4a n a, e H3COOC O O NO2 4a: n = 3; 5a: n = a O NO2 NO2 1s N H N H 6a O NO2 a) H2, Pd/C, THF, 40 ˚C, 96%; b) ethyl chloroformate, 4-methylmorpholine, CH2Cl2, 1t, RT, 71%, c) (COCl)2, DMF, CH2Cl2, 1t, then TEA/CH2Cl2,71~82%; d) KOH, KCl, MeOH/H2O, 2a, reflux, 83%; e) ethyl chloroformate, 4-methylmorpholine, CH2Cl2, 2h, RT, 19%. Following the elaboration of the synthetic routes for the efficient preparation of various monomeric building blocks (Scheme 1: 1h-1m, 1p, 1s, 1q and 1t), a series of oligoamides was prepared according to schemes 2-4. A convergent route was seldom 23 used here because it either did not give the expected product or gave a low coupling yield (19% for 6a by coupling tetramer 4a with dimer 2h and 6% for 6b by coupling trimer 3a with trimer 3g). Instead, backbone construction (C-to-N) of the oligoamides 1-6 in a unidirectional stepwise fashion proved to be a more efficient, time-saving strategy by reacting monomeric active ester or acid chloride with amino-terminated oligoamides. This stepwise construction can be exemplified by the preparation of tetramer 4a (Scheme 2.4). The synthesis of 4a started from monomers 1s and 1t. Reduction of 1s by Palladium on carbon (Pd/C)-mediated hydrogenation at 40 oC in THF converted 1s into amine intermediate that coupled with in situ generated active ester produced from 1t (conditions: ethyl chloroformate, 4-methylmorpholine (NMM), CH2Cl2, room temperature) to give nitro-terminated dimer 2a with a chemical yield of 71%. Hydrogenation of 2a under the typical conditions (Pd/C, Hydrogen (H2), THF, 40 oC) produced amino-terminated intermediate that was subjected to the next coupling reaction with the above in situ generated active ester from 1t to afford trimer 3a with a chemical yield of 82%. Trimer 3a was further hydrogenated (Pd/C, H2, THF, 40 oC) to yield the corresponding amine intermediate that reacted with the acid chloride, which was generated from 1t under the conditions involving oxalyl chloride (COCl2) and a few drops of DMF in CH2Cl2 at room temperature, to produce 4a with a chemical yield of 61%. Unfortunately, despite our numerous attempts, neither convergent nor stepwise synthesis was able to produce oligoamides of higher than heptamer, a reason why 24 only the oligoamides of up to hexamers were presented and studied in the furture work. Scheme 2.4. Synthesis of Oligomers from Dimers to Hexamersa a O2N OCH3 OCH3 OCH3 COOH O O 1k 1u O b, c H N O2N C8H17O O H N N H O O O 2f NO2 O O O O2N COOCH3 b, d H3COOC N H O O N O 2g 1t O O b, c NO2 H O OC8H17 O NO2 3f O O N H O OC8H17 O O O2N COOCH3 b, c H3COOC N H O O 1s O OC8 H17 b, d N H N H O O O O 2c O NO2 O NO2 3e O OC8H17 O OC8H17 O O O N b, e H O O O N H O N b, f O H O 4b O N O O O H O N H O O H O 5b, 5c O O H O 5b: R1 = OCH(CH3)2 5c: R1 = CH3 N O2N O2N N O R1 O O O O O g 3f N O O H N H O OC8H17 h, i O NO2 3g N H O O a O 4a O H O N O O2N OC8H17 O O O N H N b, d O NO2 O O 6b O OH N H O H O O O O N N H H O O N b, e O NO2 O O O O O O 5d H O N H O O H O O 6c N O O2N a) EDC, HOBT, Propan-2-amine, CH2Cl2, 95%; b) H2, Pd/C, THF, 40 oC, 64%; c) ethyl chloroformate, 4-methylmorpholine, CH2Cl2, 1l, 64%; d) ethyl chloroformate, 4-methylmorpholine, CH2Cl2, 1m, 71%; e) (COCl)2, DMF, CH2Cl2, 1q, 83%; f) (COCl)2, DMF, CH2Cl2, 1m (for 5b) or 1q (for 5c), 46~49%; g) KOH, KCl, MeOH/H2O, reflux, 93%; h) (COCl)2, DMF, CH2Cl2, 7%; i) H2, o Pd/C, THF, 40 C, 3a, then TEA/CH2Cl2, 90%. 25 2.2.2 One-Dimensional 1H NMR Studies of Folding Oligoamides The oligoamides 2-6 studied here contain three important sets of proton signals, i.e., amide protons, aromatic protons and interior methoxy protons. Among them, the chemical shift values of the amide protons are the simplest diagnostic of the existence of intramolecular H-bonds when compared to other more advanced analytical techniques (i.e., 2D NOESY and X-ray diffraction). In chloroform, upon forming intramolecular H-bonds, amide protons typically exhibit a substantial downfield shift due to the deshielding of amide protons by the adjacent electron-negative elements. The degree of downfield shifting thus provides a good indication as to the occurrence and strength of hydrogen bonds found in H-bond enforced aromatic foldamers. For example, amide protons involved in two-center H-bonds have a typical chemical shift of less than 9.6 ppm4f while those involved in three-center H-bonds most often downfield shift to much larger than 10 ppm,3d,4f,8,10a,10b,10e,13 suggesting that three-center H-bonds have a higher stability than two-center H-bonds of similar types.10e The representative 1H NMR spectra containing the amide and aromatic signals (Figure 2.1) for some selected oligomers were presented in Figure 2.1 with the chemical shifts for all the amide protons of oligoamides 4-6 tabulated in Table 2.1. The majority of these amide protons resonant at >10 ppm at mM in CHCl3, a more than ppm downfield shift than the amide proton (8.70 ppm) in 2f and others10b that are involved in the formation of two-center H-bonds. This experimental observation is consistent with the expectation that these amide protons be engaged in a continuous intramolecular H-bonding network as originally conceived. The formed H-bonding 26 Compound 4b: 3e (0.84 g, 1.20 mmol) was reduced by catalytic hydrogenation in THF (20 mL) at 40 C, using Pd-C (0.17 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 1q (0.30 g, 1.42 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. Freshly-prepared dry CH2Cl2 (8 mL) and DMF (64 μL) were added to the acid, followed by dropwise addition of oxalyl chloride (0.16 mL, 1.26 mmol). The reaction mixture was allowed to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.80 g, 1.20 mmol) was dissolved in 15 mL dry CH2Cl2 and triethylamine (0.60 mL, 4.2 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 0C for hrs and then was washed with aq NaHCO3 (50 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was recrystallised from methanol and further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (2:1 v/v) as the eluent to give pure 4b as white solid. Yield: 0.59 g, 57%. 1H NMR (300 MHz, CDCl3) δ 10.33 (s, 1H), 10.14 (s, 1H), 10.10 (s, 1H), 8.84 (d, 1H, J = 7.0), 8.46 (d, 1H, J = 2.8), 8.41 (d, 1H, J = 3.2), 8.23 (d, 1H, J = 1.7), 7.83 (d, 1H, J = 1.7), 7.61 (d, 1H, J = 7.0), 7.42 (m, 2H), 7.23 (m, 1H), 4.66 (m, 1H), 4.09 (s, 3H), 4.05 (m, 2H), 3.96 (s, 3H), 3.94 (s, 6H), 3.91 (s, 3H), 2.48 (s, 3H), 1.84 (m, 2H), 1.48 (s, 6H), 1.39 (m, 8H), 1.22 (m, 2H), 0.87 (m, 3H). 13 C NMR (75 MHz, CDCl3) δ 165.92, 162.79, 162.74, 161.64, 156.33, 155.17, 73 149.26, 149.03, 143.98, 140.85, 136.83, 135.67, 133.08, 132.93, 132.66, 129.13, 128.63, 126.74, 126.60, 126.18, 126.04, 124.68, 124.40, 123.44, 113.06, 112.39, 111.42, 111.08, 110.80, 70.74, 68.62, 64.40, 63.31, 63.24, 62.42, 52.37, 31.80, 29.66, 29.30, 29.22, 29.17, 25.97, 22.64, 21.97, 20.68, 14.09. HRMS-ESI: calculated for [M+Na]+ (C45H54N4O13Na): m/z 881.3580 found: m/z 881.3572. Compound 5b: 4b (0.40 g, 0.47 mmol) was reduced by catalytic hydrogenation in THF (20 mL) at 50 C, using Pd-C (0.08 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 1m (0.24 g, 0.94 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. Freshly-prepared dry CH2Cl2 (8 mL) and DMF (40 μL) were added to the acid, followed by dropwise addition of oxalyl chloride (0.10 mL, 0.78 mmol). The reaction mixture was allowed to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.39 g, 0.47 mmol) was dissolved in 10 mL dry CH2Cl2 and triethylamine (0.40 mL, 2.8 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 0C for hrs and then was washed with aq NaHCO3 (50 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was recrystallised from methanol and further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (2:1 v/v) as the eluent to give pure 5b as 74 yellow solid. Yield: 0.23 g, 46%. 1H NMR (300 MHz, CDCl3) δ 10.35 (s, 1H), 10.22 (s, 1H), 10.10 (s, 1H), 9.86 (s, 1H), 8.82 (d, 1H, J = 8.2), 8.61 (d, 1H, J = 1.7), 8.43 (m, 2H), 7.91 (d, 1H, J = 3.3), 7.68 (d, 1H, J = 4.7), 7.59 (d, 1H, J = 1.7), 7.47 (d, 1H, J = 3.3), 7.39 (m, 2H), 7.20 (m, 1H), 4.64 (m, 1H), 4.05 (s, 3H), 4.04 (m, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.45 (s, 3H), 1.79 (m, 2H), 1.47 (s, 6H), 1.37 (m, 2H), 1.28 (m, 8H), 0.86 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 165.61, 163.24, 162.89, 162.75, 161.41, 156.32, 155.18, 154.18, 149.32, 145.14, 144.67, 144.32, 140.98, 140.80, 135.88, 133.12, 132.94, 131.61, 129.76, 126.83, 126.78, 126.61, 126.24, 126.10, 125.40, 124.72, 124.38, 123.33, 122.27, 119.88, 116.22, 113.02, 112.27, 111.89, 111.61, 110.91, 71.56, 70.74, 68.64, 64.45, 63.14, 62.27, 31.76, 29.62, 29.27, 29.17, 25.95, 22.60, 21.98, 21.70, 21.30, 14.01. HRMS-ESI: calculated for [M+Na]+ (C56H67N5O16Na): m/z 1088.4755 found: m/z 1088.4750. Compound 5c: 4b (0.20 g, 0.24 mmol) was reduced by catalytic hydrogenation in THF (10 mL) at 50 C, using Pd-C (0.040 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 1q (0.10 g, 0.47 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. Freshly-prepared dry CH2Cl2 (5 mL) and DMF (20 μL) were added to the acid, followed by dropwise addition of oxalyl chloride (0.060 mL, 0.50 mmol). The reaction mixture was allowed 75 to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.19 g, 0.24 mmol) was dissolved in mL dry CH2Cl2 and triethylamine (0.20 mL, 1.40 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 0C for hrs and then was washed with aq NaHCO3 (20 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was recrystallised from methanol and further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (2:1 v/v) as the eluent to give pure 5c as yellow solid. Yield: 0.12 g, 49%. 1H NMR (500 MHz, CDCl3) δ 10.28 (s, 1H), 10.21 (s, 1H), 9.95 (s, 1H), 9.84 (s, 1H), 8.83 (d, 1H, J = 8.2), 8.79 (m, 3H), 7.92 (d, 1H, J = 3.1), 7.90 (m, 3H), 7.61 (d, 1H, J = 7.9), 7.49 (d, 1H, J = 3.1), 7.40 (m, 3H), 7.20 (m, 1H), 4.65 (m, 1H), 4.06 (s, 3H), 4.02 (s, 6H), 3.96 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 1.38 (s, 6H). 1H NMR (500 MHz, CDCl3) δ 10.35 (s, 1H), 10.10 (s, 2H), 9.85 (s, 1H), 8.83 (d, 1H, J = 8.2), 8.60 (d, 1H, J = 1.7), 8.43 (m, 2H), 8.22 (d, 1H, J = 3.3), 7.79 (d, 1H, J = 4.7), 7.68 (d, 1H, J = 1.7), 7.60 (d, 1H, J = 3.3), 7.39 (m, 2H), 7.21 (m, 1H), 4.65 (m, 1H), 4.08 (s, 3H), 4.04 (m, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.46 (s, 3H), 2.44 (s, 3H), 1.79 (m, 2H), 1.47 (s, 6H), 1.37 (m, 2H), 1.28 (m, 8H), 0.87 (m, 3H). 13 C NMR (75 MHz, CDCl3) δ 165.60, 163.26, 162.88, 162.74, 161.65, 156.28, 155.12, 149.29, 149.05, 145.10, 143.82, 140.94, 140.78, 136.78, 135.87, 135.52, 133.09, 132.90, 131.58, 129.24, 129.03, 128.91, 128.81, 128.69, 128.51, 128.34, 126.81, 126.69, 126.51, 128.33, 126.81, 126.70, 126.52, 126.12, 125.45, 124.72, 124.40, 123.25, 113.00, 112.20, 111.57, 76 110.83, 70.69, 68.59, 64.33, 63.16, 62.29, 52.11, 31.76, 29.62, 29.27, 29.18, 25.94, 22.60, 21.96, 21.33, 20.64, 14.04. HRMS-ESI: calculated for [M]- (C54H62N52O15): m/z 1020.4242 found: m/z 1020.4203. Compound 2g: 1t (4.00 g, 18.9 mmol) was reduced by catalytic hydrogenation in THF (100 mL) at 50 0C for h. The resulting amine was dissolved in CH2Cl2 (100 mL) was immediately used for the next coupling. Acid 1m (6.00 g, 23.5 mmol) was dissolved in CH2Cl2 (150 mL) to which NMM (3.60 mL, 28.6 mmol) and ethyl chloroformate (3.20 mL, 26.0 mmol) was added at 0C. The reaction mixture was stirred for at least 15 then a solution of the above amine was added. The reaction mixture was allowed to stir continuously overnight at room temperature. The reaction mixture was washed with 1M KHSO4 (200 mL), followed by saturated NaHCO3 (200 mL) and saturated NaCl (200 mL). Drying over Na2SO4 and removal of solvent in vacuo gave the crude product, which was recrystallized from methanol to give the pure product 2g. Yield: 4.91 g, 62%. 1H NMR (300 MHz, CDCl3) δ 10.48 (s, 1H), 8.79 (d, 1H, J = 8.2), 7.93 (d, 1H, J = 3.2), 7.62 (d, 1H, J = 7.8), 7.47 (d, 1H, J = 3.2), 7.24 (m, 1H), 4.65 (m, 1H), 4.60 (s, 3H), 4.02 (s, 3H), 3.94 (s, 3H), 1.37 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 165.80, 161.20, 153.98, 149.41, 144.47, 132.73, 129.59, 126.46, 124.51, 124.20, 123.50, 122.30, 116.13, 71.46, 64.51, 62.51, 52.28, 21.71. HRMS-ESI: calculated for [M+Na]+ (C20H22N2O8Na): m/z 440.1190 found: m/z 440.1194. Compound 3f: 77 2g (2.70 g, 6.45 mmol) was reduced by catalytic hydrogenation in THF (80 mL) at 50 C for h. The resulting amine dissolved in CH2Cl2 (80 mL) was immediately used for the next coupling. Acid 1l (2.50 g, 7.69 mmol) was dissolved in CH2Cl2 (70 mL) to which NMM (1.24 mL, 10.1 mmol) and ethyl chloroformate (1.00 mL, 8.45 mmol) was added at 0C. The reaction mixture was stirred for at least 15 then a solution of the above amine was added. The reaction mixture was allowed to stir continuously overnight at 50 0C. The reaction mixture was washed with 1M KHSO4 (60 mL), followed by saturated NaHCO3 (60 mL) and saturated NaCl (60 mL). Drying over Na2SO4 and removal of solvent in vacuo gave the crude product, which was recrystallized from methanol to give the pure product 3f. Yield: 3.70 g, 83%. 1H NMR (300 MHz, CDCl3) δ 10.65 (s, 1H), 10.42 (s, 1H), 8.84 (d, 1H, J = 3.2), 8.50 (d, 1H, J = 3.2), 8.01 (d, 1H, J = 3.2), 7.61 (d, 1H, J = 8.0), 7.39 (d, 1H, J = 3.2), 7.23 (m, 1H), 7.11 (d, 1H, J = 2.9), 7.24 (m, 1H), 4.65 (m, 1H), 4.06 (s, 3H), 4.61 (m, 2H), 4.04 (m, 2H), 3.94 (s, 6H), 3.91 (s, 3H), 3.89 (s, 3H), 1.85 (m, 2H), 1.56 (s, 6H), 1.43 (m, 8H), 1.27 (m, 2H), 0.85 (m, 3H). 13 C NMR (75 MHz, CDCl3) δ 165.91, 162.64, 161.24, 155.29, 155.02, 149.21, 144.62, 144.45, 140.93, 133.05, 132.64, 129.44, 126.70, 126.13, 124.52, 124.35, 123.43, 121.25, 115.12, 112.28, 112.53, 70.72, 69.29, 64.52, 63.33, 62.45, 52.32, 50.77, 31.73, 29.64, 29.18, 29.14, 28.87, 25.83, 22.59, 21.95, 14.08. HRMS-ESI: calculated for [M+Na]+ (C36H45N3O11Na): m/z 719.2846 found: m/z 719.2980. Compound 3g: 78 3f (0.38 g, 0.54 mmol) was dissolved in hot methanol (10 mL) to which 1M KOH (1.37 mL, 1.37 mmol) and KCl (0.14 g, 1.82 mmol) was added. The mixture was heated under reflux for h and then quenched with water (20 mL). The aqueous layer was neutralized by addition of 1M HCl (2.0 mL) until the pH was at least 1. The precipitated crude product was collected by filtration, which was recrystallized from hot methanol to give a pure white solid 3g. Yield: 0.34 g, 93%. 1H NMR (500 MHz, CDCl3) δ 10.45 (s, 3H), 10.30 (s, 3H), 8.55 (d,1H, J = 7.6), 7.96 (d, 1H, J = 3.2), 7.65 (d, 1H, J = 3.2), 7.57 (d, 1H, J = 3.2), 7.50 (d, 1H, J = 7.6), 7.25 (d, 1H, J = 3.2), 7.22 (m, 1H), 4.61 (m, 1H), 4.08 (s, 3H), 4.07 (m, 2H), 4.01 (s, 3H), 3.85 (s, 6H), 4.03 (s, 3H), 1.73 (s, 6H), 1.41 (m, 2H), 1.31 (m, 8H), 1.28 (m, 2H), 0.84 (m, 3H). 13C NMR (75 MHz, DMSO-d6) δ 166.81, 162.94, 162.52, 154.26, 153.47, 149.22, 144.48, 143.27, 142.76, 132.52, 132.31, 127.38, 125.87, 125.23, 124.32, 123.80, 120.1, 114.36, 112.32, 112.08, 70.15, 68.85, 64.07, 62.86, 62.23, 31.25, 28.67, 28.39, 25.47, 22.10, 21.75, 13.95. HRMS-ESI: calculated for [M+Na]+ (C35H43N3O11Na): m/z 704.2790 found: m/z 704.2801. Compound 6b: Compound 3a (0.20 g, 0.39 mmol) was reduced by catalytic hydrogenation in THF (15 mL) at 50 0C, using Pd-C (0.040 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 3g (0.30 g, 0.44 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. 79 Freshly-prepared dry CH2Cl2 (5 mL) and DMF (27 μL) were added to the acid, followed by dropwise addition of oxalyl chloride (67 μL, 0.53 mmol). The reaction mixture was allowed to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.17 g, 0.36 mmol) was dissolved in 10 mL dry CH2Cl2 and triethylamine (0.10 mL, 0.69 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 0C for hrs and then was washed with aq NaHCO3 (50 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was recrystallised from methanol and further purified by flash column chromatography (silica gel as the stationary phase) using CH2Cl2/CH3CN (20:1 v/v) as the eluent to give pure product 6b as a white solid. Yield: 25 mg, 6%. 1H NMR (500 MHz, CDCl3) δ 10.20 (s, 2H), 10.12 (s, 1H), 10.09 (s, 1H), 10.08 (s, 1H), 9.82 (s, 1H), 8.65 (m, 2H), 8.61 (m, 2H), 8.26 (d, 1H, J = 3.2), 7.74 (m, 2H), 7.68 (d, 1H, J = 7.8), 7.62 (d, 1H, J = 3.2), 7.31 (d, 1H, J = 7.8), 7.21 (m, 3H), 7.16 (d, 1H, J = 3.2), 6.95 (t, 1H), 4.49 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 3.63 (s, 3H), 3.61 (s, 3H), 1.66 (m, 2H), 1.46 (s, 6H), 1.29 (m, 8H), 1.13 (m, 2H), 0.63 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 165.22, 163.26, 162.83, 162.74, 161.11, 155.22, 155.14, 149.00, 147.26, 147.18, 147.02, 144.32, 144.04, 140.80, 133.09, 132.77, 132.41, 132.16, 129.32, 126.68, 126.58, 126.48, 126.38, 126.28, 126.06, 125.90, 125.86, 125.76, 125.26, 124.87, 124.78, 124.58, 124.25, 122.99, 121.34, 114.71, 112.83, 112.51, 70.73, 69.19, 64.45, 63.34, 63.00, 62.91, 62.13, 53.14, 50.70, 31.70, 29.61, 80 29.17, 29.11, 28.87, 25.84, 22.56, 21.91, 14.00. HRMS-ESI: calculated for [M+Na]+ (C41H37N3O13Na): m/z 1165.4377 found: m/z 1165.4356. Compound 5d: 4a (0.50 g, 0.734 mmol) was reduced by catalytic hydrogenation in THF (20 mL) at 50 0C, using Pd-C (0.14 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 1m (0.40 g, 1.56 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. Freshly-prepared dry CH2Cl2 (10 mL) and DMF (0.10 mL) were added to the acid, followed by dropwise addition of oxalyl chloride (0.20 mL, 1.60 mmol). The reaction mixture was allowed to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.48 g, 0.73 mmol) was dissolved in 10 mL dry CH2Cl2 and triethylamine (0.30 mL, 2.10 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 0C for hrs and then was washed with aq NaHCO3 (40 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was recrystallised from methanol and further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (2:1 v/v) as the eluent to give pure 5d as yellow solid. Yield: 0.33 g, 52%. 1H NMR (500 MHz, CDCl3) δ 10.28 (s, 1H), 10.21 (s, 1H), 9.95 (s, 1H), 9.84 (s, 1H), 8.83 (d, 1H, J = 8.2), 8.79 (m, 3H), 7.92 (d, 1H, J = 3.1), 7.90 (m, 3H), 7.61 (d, 1H, J = 7.9), 7.49 (d, 1H, J = 3.1), 7.40 (m, 3H), 7.20 81 (m, 1H), 4.65 (m, 1H), 4.06 (s, 3H), 4.02 (s, 6H), 3.96 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 1.38 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 165.64, 163.17, 163.08, 162.88, 161.45, 154.19, 149.27, 147.29, 147.20, 144.65, 144.28, 133.04, 132.20, 132.02, 126.82, 126.66, 126.52, 126.39, 126.17, 125.87, 125.73, 125.09, 124.93, 124.84, 124.73, 124.44, 123.29, 122.36, 116.23, 71.54, 64.54, 63.21, 63.03, 62.36, 52.16, 29.65, 21.71 HRMS-ESI: calculated for [M+Na]+ (C44H43N5O14Na): m/z 888.2699 found: m/z 888.2723. Compound 6c: 5d (0.10 g, 0.12 mmol) was reduced by catalytic hydrogenation in THF (5 mL) at 40 C, using Pd-C (0.020 g, 20%) as the catalyst for h. The reaction mixture was then filtered and the solvent removed in vacuo to give the pure amine which was immediately used for the next coupling. Acid 1q (0.15 g, 0.71 mmol) was placed in a very dry round bottom flask and saturated with nitrogen gas. Freshly-prepared dry CH2Cl2 (4 mL) and DMF (32 μL) were added to the acid, followed by dropwise addition of oxalyl chloride (0.080 mL, 0.63 mmol). The reaction mixture was allowed to stir for hrs. The solvent was then removed in vacuo and saturated with nitrogen gas before addition of 10 mL dry CH2Cl2. The above amine (0.090 g, 0.12 mmol) was dissolved in mL dry CH2Cl2 and triethylamine (0.060 mL, 0.42 mmol) before addition to the reaction mixture above. The reaction mixture was stirred at 50 0C for hrs and then was washed with aq NaHCO3 (10 mL). Drying over anhydrous Na2SO4 and removal of solvent in vacuo gave the crude product which was recrystallised from 82 methanol and further purified by flash column chromatography (silica gel as the stationary phase) using hexane/ethyl acetate (1.5:1 v/v) as the eluent to give pure 6c as white solid. Yield: 38 mg, 31%. 1H NMR (300 MHz, CDCl3) δ 10.28 (s, 1H), 10.25 (s,1H),10.15 (s, 1H), 10.14 (s, 1H), 9.85 (s, 1H), 8.83 (m, 2H), 8.81 (m, 2H), 8.46 (d, 1H, J = 3.2), 8.15 (d, 1H, J = 1.9), 7.94 (m, 3H), 7.68 (d, 1H, J = 1.9), 7.54 (d, 1H, J = 1.9), 7.52 (d, 1H, J = 1.9), 7.45 (m, 3H), 7.18 (m, 1H), 4.71 (m, 1H), 4.15 (s, 3H), 4,14 (s, 3H), 4.07 (s, 3H), 4.06 (s, 3H), 4.05 (s, 3H), 4.00 (s, 3H), 3.82 (s, 3H), 2.06 (s, 3H), 1.42 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 165.26, 163.29, 162.87, 162.79, 161.40, 155.17, 149.04, 148.73, 147.19, 147.04, 143.69, 140.77, 136.74, 135.61, 133.13, 132.80, 132.42, 132.33, 132.16, 129.01, 128.36, 126.72, 126.62, 126.51, 126.43, 126.31, 126.07, 125.92, 125.81, 125.30, 124.89, 124.82, 124.61, 124.24, 123.06, 112.85, 112.44, 70.72, 64.33, 63.36, 63.04, 62.94, 62.19, 60.33, 52.18, 29.64, 21.94, 20.98, 20.64, 14.14. HRMS-ESI: calculated for [M]- (C53H51N6O16): m/z 1027.3366 found: m/z 1027.3362. 83 Reference: 1. (a) Gellman, S. H. Acc. Chem. 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This differs from the isomers containing two H-bonds (i.e., three center H-bonding system in 2a or a continuous H-bonding network in oligomers 3-6) where two NOEs with comparable intensities should be seen between every amide proton and its two neighbouring methoxy methyl groups. 16. Wu, Z.-Q.; Jiang, X.-K.; Zhu, S.-Z.; Li, Z.-T. Org. Lett. 2004, 6, 229. 88 [...]... for 2b that packs along diagonal axis ac forming an angle of 63º between axis ac and plane of the molecules, all the other three dimers (2a, 2c and 2d) are stacked along axis a with angles of 90º, 53º and 70º, respectively, between axis a and plane of the molecules by virtue of aromatic π-π interactions (Figure 2. 6) These columns further assemble into 2D sheets and 3D structures via van der Waals interactions... highlight the twisted six-membered H-bonds Figure 2. 5 Top and side views of crystal structure of (a) 4a and (b) 6a.8 The calculated structure of 6a is shown in (c) All the interior methoxy methyl groups were removed for clarity of view 34 a) b) c) d) Figure 2. 6 Side and top views of columnar assemblies observed in the solid state structures of (a) 2a along axis a, (b) 2b along axis ac, (c) 2c along... involving the two end interior methoxy groups Table 2. 1 Crystal growth conditions for oligomers 2- 4 Solvent Pair Solvent Pair Solvent Pair (1:1) (1:1) (1:1) 2a CH2Cl2 : MeOH 2d CHCl3 : MeOH 3c C CHCl3 : Hexane 2b CH2Cl2 : Hexane 3a CHCl3 : MeOH 3d DMF : CH3CN 2c CHCl3 : MeOH 3b CH2Cl2 : Hexane 4a CH2Cl2 : MeOH A closer look into the crystal structures of oligoamides 2 & 3 reveals a quite surprising structural... oligomers.c oligomer H6 H11 H16 H21 H26 10.36 2a (0.13) 10.37 2b (0 .20 ) 10.47 2c (0.90) 10 .25 2d (0 .24 ) 10.49 2e (0.56) 10 .24 2f 8.70 (0.30) (0 .21 ) 10.49 2g (0.83) 10 .21 4a 10.35 10.38 (1.34) 10.38 (0.11) (0.65) 10.36 (0.07) (0.90) 10.35 (0.05) (0. 72) 10 .20 3f (0 .24 ) 10.33 3e (0.05) 10.35 3d 10.37 10.36 3c (0 .27 ) (0.08) 3b 10 .23 (0.04) 10 .24 3a 10.10 10.00 (0.63) (0.03) (0.06) 32 10.33 6c a 9.85 10 .25 (0.33)... oligoamides 2- 6 were probed by 2D NOESY studies (Figures 2. 2 and 2. 3) Due to the highly repetitive nature of oligoamides 2- 6, extensive 1 H NMR signal overlaps among aromatic protons were observed for an oligoamide as simple as trimer 3a This prevents the accurate and complete assignment involving the amide protons and adjacent interior methoxy methyl protons and so hampers the elucidation of their folded structures. .. of Oligoamides Crystals of oligomers 2- 4 suitable for X-ray structure determination were obtained by slow evaporation of these oligomers in mixed solvents at room temperature (Table 2. 1) The top and side views of the determined crystal structures for oligoamides 2- 4 are presented in Figure 2. 3 These crystal structures demonstrate that with the stepwise addition of aromatic building blocks the elongated... rectangles in Figures 2. 7b and 2. 7c) Additionally, among the eight oligomers 2a-2d and 3a-3d, only 3d packs in a parallel fashion along the stacking axis The consistent columnar assembly of the above short oligomers 2- 3 in solid states suggests that, with their cavity-containing backbones, oligomers longer than trimer may be capable of stacking on top of one another into channel-like structures This possibility... (m, 2H), 1.76 (m, 2H), 1. 42 (m, 2H), 1 .25 (m, 8H), 0.89 (m, 3H) 13 C NMR (75 MHz, CDCl3) δ 171. 02, 156.63, 1 52. 24, 125 .25 , 119.10, 113.57, 48 1 12. 53, 69.51, 52. 92, 32. 49, 30.03, 29 .97, 29 .91, 26 .71, 23 .33, 14.76 HRMS-EI: calculated for [M]+ (C16H24O4): m/z 28 0.1675 found: m/z 28 0.1677 Compound 1d: 1a (1.34 g, 8.00 mmol) was dissolved in anhydrous acetone (30 mL), to which anhydrous K2CO3 (2. 00 g, 14.5... 20 11 /21 6 11 16 (16 ,20 ) 1 5 15 10 20 8 25 (6,1) & (6,5) (11,10) (16,15) (11,15) & (21 ,20 ) (16 ,20 ) (21 ,25 ) Figure 2. 2 NOE contacts (NOESY, 500 MHZ, 29 8 K, 10 mM, 500 ms, 4 hrs) seen between amide protons and their adjacent interior methoxy protons: (a) dimer 2f in DMSO-d6, (b) trimer 3d in 50% CDCl3/50% DMSO-d6, (c) tetramer 4b in CDCl3 and (d) pentamer 5c in CDCl3 29 2. 2.4 Solid State Structures of. .. solved by deliberately introducing linear and branched alkoxyl side chains as well as a methyl group para to the interior methoxy groups into oligoamides 2- 6 (i.e., 2f, 3d, 4b, 5b, 5c, 6b and 6c) The introduction of these side chains indeed led to the well-resolved amide protons, aromatic protons and internal methoxy groups in oligoamides 2f (Figure 2. 2a), 3d (Figure 2. 2b) and 5b8 that permit us to detect . of varying types to constrain the backbones of aromatic oligoamides and their analogs such as aromatic oligohydrazides and oligoureas. Manipulating the folding of these aromatic oligomers 18. constructing higher-order supramolecular structures with non-collapsible pores and channels capable of conducting ions and small molecules. 10m 2. 2 Result and Discussion 2. 2.1 Synthesis of Oligoamides. O O H O O N H O O 2 N O R 1 R 2 R 3 R 4 5 2 3 4 7 13 12 8 9 14 17 19 24 22 18 23 30 26 27 29 28 6 6 11 6 11 16 6 24 1 5 10 5 10 5 10 15 5 10 15 20 6a:R 1 =R 2 =H 6c: R 1 =OCH(CH 3 ) 2 ,R 2 =CH 3 6b: