electronic supplementary information · 2015-01-13 · s6 table s3: compounds 1, 2 and 3 relative...

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Electronic Supplementary Information

Elucidation of Ac-Gly-NHMe conformational preferences insolution

R. A. Cormanich,a,b R. Rittner*,b and M. Bühl*,a

a EastChem School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST,

UK

b Chemistry Institute, State University of Campinas, P.O. Box 6154, 13083-970, Campinas, SP, Brazil

Electronic Supplementary Material (ESI) for RSC Advances.This journal is © The Royal Society of Chemistry 2015

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(a) (d)

(b) (e)

(c) (f)

Figure S1: Potential energy surface of (a) Ac-Gly-NHMe, (b) CF3-C(O)-Gly-NHMe and (c) Ac-Gly-N(Me)2, built

by scanning its and dihedral angles at the B3LYP/cc-pVDZ level. PES Ramachandran-like and dihedral

angles projection of (d) Ac-Gly-NHMe, (e) CF3-C(O)-Gly-NHMe and (f) Ac-Gly-N(Me)2.

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Ac-Gly-NHMe

1a 1b 1c 1d 1e

1f 1g 1h 1i 1j

1k

CF3-C(O)-Gly-NHMe

2a 2b 2c 2d 2e

2f 2g 2h 2i

Ac-Gly-N(Me)2

3a 3b 3c 3d 3e

3f 3gFigure S2: Compounds 1, 2 and 3 conformer geometrical representations.

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Table S1: Relative energies and mean absolute deviation (MAD) from the CCSD(T)-F12a/VDZ-F12//B3LYP/aug-cc-pVDZ in kcal mol-1 for compound 1conformers optimised geometries at different levels. DFT and DFT-D3 (showed in parenthesis) functionals used the aug-cc-pVDZ basis set. MP2/aug-cc-pVDZlevel was the only ab initio optimisation. Ab initio single point calculations were calculated on B3LYP/aug-cc-pVDZ optimised geometries.

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k MAD

AM1 0.00 1.88 2.04 --- 2.99 2.21 5.29 --- 4.87 4.98 3.56 3.13

Semiepirical PM3 2.61 0.63 2.59 2.92 3.90 0.00 2.68 --- 3.37 2.19 2.03 3.97

PM6 0.00 2.05 2.22 --- 3.12 1.08 5.64 3.12 5.82 3.73 3.73 3.19

B3LYP 0.00 (0.00) 0.28 (1.27) 1.90 (2.53) 2.21 (2.77) 3.84 (3.52) 4.50 (4.33) 4.89 (5.48) 6.43 (6.38) 6.63 (6.83) 8.78 (8.26) 9.40 (8.29) 1.38 (1.30)

BLYP 0.00 (0.00) 1.59 (1.74) 2.08 (2.81) 2.17 (1.54) 3.80 (3.41) 4.35 (4.13) 4.85 (5.53) 6.33 (6.38) 6.49 (6.71) 8.69 (8.08) 9.15 (7.75) 1.38 (1.54)

DFT (DFT-D3) BP86 0.00 (0.00) 0.50 (1.89) 2.09 (2.87) 2.06 (---) 3.62 (3.24) 4.59 (4.42) 4.93 (5.67) 6.50 (6.51) 6.42 (6.72) 8.85 (8.30) 9.40 (8.00) 1.37 (1.37)

B97-D 0.00 (0.00) 1.84 (1.48) 2.57 (2.46) --- (---) 2.86 (2.96) 3.77 (4.15) 5.34 (5.22) 5.90 (6.14) 6.13 (6.30) 7.32 (7.76) 6.96 (7.59) 2.04 (1.85)

M06 0.00 (0.00) 0.25 (0.40) 1.40 (1.50) --- (---) 3.12 (2.99) 4.02 (3.93) 4.35 (4.47) 5.66 (5.64) 5.60 (5.64) 7.50 (7.44) 7.71 (7.41) 2.22 (2.23)

MP2/aug-cc-pVDZ* 0.00 (0.00) 1.75 (1.37) 3.18 (2.99) --- 3.46 (3.70) 4.33 (4.79) 6.12 (5.93) 6.38 (6.72) 7.64 (7.66) 8.45 (8.94) 8.28 (9.11) 1.40 (0.92)

RHF 0.73 0.00 2.09 2.40 4.64 4.90 5.35 6.53 7.86 9.12 10.41 1.04

DF-MP2 0.00 1.51 3.05 2.67 3.99 4.89 5.88 6.78 7.69 9.06 9.43 0.87

Ab initio DF-MP2-F12 0.00 1.24 2.84 2.61 3.97 4.88 5.82 6.82 7.61 9.19 9.66 0.85

SCS-DF-MP2 0.00 1.29 2.89 2.59 4.02 4.67 5.59 6.54 7.54 8.79 9.21 0.99

SCS-DF-MP2-F12/3C(FIX) 0.00 1.02 2.68 2.52 3.99 4.64 5.54 6.59 7.47 8.93 9.44 1.02

CCSD-F12a 0.00 0.72 2.42 2.50 4.07 4.61 5.41 6.42 7.34 8.81 9.51 1.11

CCSD(T)-F12a 0.00 1.26 3.89 3.76 5.26 5.75 6.88 7.74 8.68 10.15 10.65 ---

* MP2/aug-cc-pVTZ//MP2/aug-cc-pVDZ energy and MAD values are showed in parenthesis.

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Table S2: Compounds 1, 2 and 3 relative energies (ΔE) in kcal mol-1 and corresponding populations (%P) obtained at the B3LYP-D3/aug-cc-pVDZ level for theisolated compounds and by using the IEF-PCM implicit solvent model with dichloromethane, acetone, acetonitrile, DMSO, methanol and water dielectricconstants.

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k

ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P ΔE %P

Isolated 0.00 87.4 1.27 10.3 2.53 1.2 2.77 0.8 3.52 0.2 4.33 0.1 5.48 0.0 6.38 0.0 6.83 0.0 8.26 0.0 8.29 0.0

CH2Cl2 0.00 56.2 0.65 18.9 1.77 2.8 0.64 19.2 1.88 2.4 4.19 0.0 3.12 0.3 3.48 0.2 4.22 0.0 5.03 0.0 6.26 0.0

Acetone 0.00 44.7 0.57 17.1 1.72 2.4 0.20 31.9 1.66 2.7 2.96 0.3 2.74 0.4 3.00 0.3 3.88 0.1 4.56 0.0 6.03 0.0

1 Acetonitrile 0.00 39.9 0.54 16.0 1.71 2.2 0.03 37.9 1.59 2.7 2.85 0.3 2.61 0.5 2.82 0.3 3.77 0.1 4.39 0.0 5.95 0.0

DMSO 0.03 38.3 0.56 15.6 1.73 2.1 0.00 40.0 1.59 2.7 2.83 0.3 2.59 0.5 2.79 0.4 3.75 0.1 4.37 0.0 5.95 0.0

Methanol 0.00 40.5 0.54 16.2 1.71 2.3 0.05 37.1 1.60 2.7 2.86 0.3 2.63 0.5 2.85 0.3 3.78 0.1 4.42 0.0 5.96 0.0

Water 0.10 36.1 0.62 15.0 1.80 2.0 0.00 42.8 1.63 2.7 2.85 0.3 2.61 0.5 2.79 0.4 3.78 0.1 4.37 0.0 5.99 0.0

2a 2b 2c 2d 2e 2f 2g 2h 2i

Isolated 0.00 47.7 0.01 47.3 1.35 4.9 --- --- 4.10 0.0 4.04 0.1 5.13 0.0 5.37 0.0 7.84 0.0 --- --- --- ---

CH2Cl2 0.95 13.7 0.00 68.0 1.24 8.4 1.16 9.6 3.92 0.1 4.07 0.1 4.40 0.0 5.04 0.0 5.42 0.0 --- --- --- ---

Acetone 1.06 11.1 0.00 66.2 1.29 7.5 0.88 14.9 3.88 0.1 4.05 0.1 4.26 0.1 5.03 0.0 4.94 0.0 --- --- --- ---

2 Acetonitrile 1.10 10.2 0.00 64.7 1.31 7.1 0.76 17.8 3.87 0.1 4.04 0.1 4.20 0.1 5.03 0.0 4.75 0.0 --- --- --- ---

DMSO 1.11 9.8 0.00 64.1 1.31 7.0 0.72 18.8 3.86 0.1 4.04 0.1 4.18 0.1 5.03 0.0 4.68 0.0 --- --- --- ---

Methanol 1.09 10.3 0.00 64.9 1.30 7.2 0.78 17.4 3.87 0.1 4.04 0.1 4.21 0.1 5.03 0.0 4.77 0.0 --- --- --- ---

Water 1.13 9.4 0.00 63.2 1.32 6.8 0.67 20.4 3.86 0.1 4.04 0.1 4.15 0.1 5.03 0.0 4.59 0.0 --- --- --- ---

3a 3b 3c 3d 3e 3f 3g

Isolated 1.86 4.2 0.00 95.8 4.42 0.1 5.78 0.0 5.60 0.0 6.66 0.0 6.85 0.0 --- --- --- --- --- --- --- ---

CH2Cl2 1.83 4.3 0.00 93.9 2.58 1.2 3.34 0.3 4.27 0.1 5.27 0.0 3.57 0.2 --- --- --- --- --- --- --- ---

Acetone 1.74 4.8 0.00 91.8 2.29 1.9 2.92 0.7 4.07 0.1 5.07 0.0 2.89 0.7 --- --- --- --- --- --- --- ---

3 Acetonitrile 1.71 5.1 0.00 90.6 2.18 2.3 2.76 0.9 3.99 0.1 4.99 0.0 2.63 1.1 --- --- --- --- --- --- --- ---

DMSO 1.69 5.2 0.00 90.1 2.14 2.4 2.71 0.9 3.97 0.1 4.96 0.0 2.54 1.2 --- --- --- --- --- --- --- ---

Methanol 1.71 5.0 0.00 90.8 2.19 2.2 2.78 0.8 4.00 0.1 5.00 0.0 2.66 1.0 --- --- --- --- --- --- --- ---

Water 1.68 5.3 0.00 89.5 2.10 2.6 2.64 1.0 3.94 0.1 4.93 0.0 2.43 1.5 --- --- --- --- --- --- --- ---

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Table S3: Compounds 1, 2 and 3 relative enthalpy energies (ΔH) in kcal mol-1 and corresponding populations (%P) obtained at the B3LYP-D3/aug-cc-pVDZ levelfor the isolated compounds and by using the IEF-PCM implicit solvent model with dichloromethane, acetone, acetonitrile, DMSO, methanol and water dielectricconstants.

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k

ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P ΔH %P

Isolated 0.00 61.1 0.31 36.4 2.21 1.5 2.57 0.8 3.45 0.2 4.39 0.0 4.47 0.0 6.19 0.0 6.39 0.0 8.03 0.0 8.22 0.0

CH2Cl2 0.00 46.1 0.31 27.3 1.52 3.6 0.51 19.6 1.81 2.2 4.27 0.0 2.25 1.0 3.38 0.2 3.90 0.1 4.93 0.0 6.35 0.0

Acetone 0.00 36.5 0.23 24.8 1.46 3.1 0.08 31.9 1.59 2.5 2.88 0.3 2.49 0.5 2.92 0.3 3.58 0.1 4.47 0.0 6.11 0.0

1 Acetonitrile 0.09 32.4 0.29 23.1 1.53 2.9 0.00 37.7 1.60 2.5 2.86 0.3 2.45 0.6 2.84 0.3 3.56 0.1 4.39 0.0 6.11 0.0

DMSO 0.14 31.2 0.33 22.6 1.57 2.8 0.00 39.5 1.64 2.5 2.87 0.3 2.45 0.6 2.83 0.3 3.57 0.1 4.39 0.0 6.13 0.0

Methanol 0.07 33.0 0.27 23.4 1.51 2.9 0.00 36.9 1.59 2.5 2.85 0.3 2.44 0.6 2.84 0.3 3.55 0.1 4.39 0.0 6.10 0.0

Water 0.23 29.2 0.41 21.5 1.65 2.6 0.00 42.7 1.68 2.5 2.90 0.3 2.48 0.6 2.84 0.4 3.61 0.1 4.40 0.0 6.18 0.0

2a 2b 2c 2d 2e 2f 2g 2h 2i

Isolated 0.97 15.8 0.00 81.1 1.95 3.03 --- --- 4.10 0.1 5.02 0.0 5.94 0.0 5.98 0.0 8.58 0.0 --- --- --- ---

CH2Cl2 1.29 8.4 0.00 74.5 1.23 9.3 1.35 7.6 3.87 0.1 4.45 0.0 4.62 0.0 4.45 0.0 5.69 0.0 --- --- --- ---

Acetone 1.40 6.8 0.00 72.2 1.28 8.3 1.04 12.5 3.84 0.1 4.46 0.0 4.48 0.0 5.06 0.0 5.21 0.0 --- --- --- ---

2 Acetonitrile 1.43 6.4 0.00 70.7 1.29 8.0 0.93 14.8 3.82 0.1 4.45 0.0 4.44 0.0 5.06 0.0 5.02 0.0 --- --- --- ---

DMSO 1.43 6.2 0.00 70.2 1.29 7.9 0.89 15.5 3.81 0.1 4.45 0.0 4.43 0.0 5.06 0.0 4.97 0.0 --- --- --- ---

Methanol 1.42 6.4 0.00 70.9 1.29 8.0 0.94 14.5 3.82 0.1 4.46 0.0 4.45 0.0 5.06 0.0 5.04 0.0 --- --- --- ---

Water 1.45 6.0 0.00 69.4 1.30 7.8 0.85 16.5 3.80 0.1 4.44 0.0 4.41 0.0 5.06 0.0 4.91 0.0 --- --- --- ---

3a 3b 3c 3d 3e 3f 3g

Isolated 2.26 2.1 0.00 97.7 3.73 0.2 5.86 0.0 5.88 0.0 6.90 0.0 6.79 0.0 --- --- --- --- --- --- --- ---

CH2Cl2 2.12 2.6 0.00 93.6 1.99 3.2 3.47 0.3 4.57 0.0 5.52 0.0 3.66 0.2 --- --- --- --- --- --- --- ---

Acetone 2.03 3.0 0.00 91.0 1.72 5.0 3.07 0.5 4.38 0.1 5.39 0.0 3.08 0.5 --- --- --- --- --- --- --- ---

3 Acetonitrile 1.98 3.1 0.00 89.6 1.62 5.8 2.92 0.6 4.31 0.1 5.32 0.0 2.85 0.7 --- --- --- --- --- --- --- ---

DMSO 1.97 3.2 0.00 89.1 1.58 6.1 2.87 0.7 4.29 0.1 5.30 0.0 2.76 0.8 --- --- --- --- --- --- --- ---

Methanol 1.99 3.1 0.00 89.8 1.63 5.7 2.94 0.6 4.32 0.1 5.33 0.0 2.88 0.7 --- --- --- --- --- --- --- ---

Water 1.95 3.3 0.00 88.3 1.54 6.6 2.81 0.8 4.25 0.1 5.27 0.0 2.66 1.0 --- --- --- --- --- --- --- ---

S7

Table S4: Compounds 1, 2 and 3 relative Gibbs free energies (ΔG) in kcal mol-1 and corresponding populations (%P) obtained at the B3LYP-D3/aug-cc-pVDZlevel for the isolated compounds and by using the IEF-PCM implicit solvent model with dichloromethane, acetone, acetonitrile, DMSO, methanol and waterdielectric constants.

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k

ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P ΔG %P

Isolated 0.51 24.0 0.77 15.4 1.64 3.5 0.00 56.5 2.97 0.4 5.32 0.0 4.05 0.1 4.26 0.0 4.91 0.0 6.51 0.0 7.76 0.0

CH2Cl2 1.08 11.0 0.00 68.8 2.30 1.4 0.79 18.0 2.88 0.5 5.04 0.0 3.63 0.1 4.17 0.1 4.58 0.0 6.41 0.0 8.14 0.0

Acetone 1.11 8.9 0.00 58.1 2.14 1.6 0.41 29.0 2.57 0.8 3.34 0.2 2.25 1.3 3.75 0.1 4.32 0.0 5.86 0.0 7.77 0.0

1 Acetonitrile 1.13 7.3 0.00 49.4 2.06 1.5 0.13 39.9 2.46 0.8 3.32 0.2 2.51 0.7 3.56 0.1 4.23 0.0 5.65 0.0 7.61 0.0

DMSO 1.16 7.2 0.00 51.5 2.07 1.6 0.18 37.9 2.46 0.8 3.35 0.2 2.58 0.7 3.52 0.1 4.22 0.0 5.60 0.0 7.59 0.0

Methanol 1.13 7.6 0.00 50.9 2.07 1.5 0.17 38.1 2.48 0.8 3.34 0.2 2.49 0.8 3.58 0.1 4.24 0.0 5.68 0.0 7.64 0.0

Water 1.35 5.6 0.22 37.6 2.20 1.3 0.00 54.1 2.62 0.6 3.49 0.1 2.80 0.5 3.60 0.1 4.35 0.0 5.68 0.0 7.68 0.0

2a 2b 2c 2d 2e 2f 2g 2h 2i

Isolated 0.46 27.0 0.00 58.9 0.85 14.0 --- --- 4.64 0.0 4.97 0.0 5.52 0.0 3.92 0.1 8.04 0.0 --- --- --- ---

CH2Cl2 2.03 2.7 0.00 82.4 1.72 4.5 1.23 10.3 3.58 0.2 5.50 0.0 5.37 0.0 6.52 0.0 6.89 0.0 --- --- --- ---

Acetone 2.28 1.7 0.00 80.8 1.96 2.9 1.02 14.4 3.79 0.1 5.92 0.0 5.54 0.0 5.08 0.0 6.52 0.0 --- --- --- ---

2 Acetonitrile 2.43 1.4 0.00 84.6 2.00 2.9 1.21 11.0 3.92 0.1 6.03 0.0 5.62 0.0 5.33 0.0 5.74 0.0 --- --- --- ---

DMSO 2.44 1.4 0.00 84.8 1.97 3.0 1.23 10.7 3.92 0.1 6.01 0.0 5.63 0.0 5.35 0.0 6.05 0.0 --- --- --- ---

Methanol 2.43 1.4 0.00 84.5 2.02 2.8 1.20 11.2 3.92 0.1 6.04 0.0 5.62 0.0 5.32 0.0 5.44 0.0 --- --- --- ---

Water 2.44 1.4 0.00 84.7 1.91 3.3 1.24 10.5 3.92 0.1 6.00 0.0 5.62 0.0 5.38 0.0 6.24 0.0 --- --- --- ---

3a 3b 3c 3d 3e 3f 3g

Isolated 2.92 0.7 0.00 99.3 5.80 0.0 6.94 0.0 7.35 0.0 7.72 0.0 7.12 0.0 --- --- --- --- --- --- --- ---

CH2Cl2 2.93 0.7 0.00 98.9 3.72 0.2 4.15 0.1 5.52 0.0 4.71 0.0 4.25 0.1 --- --- --- --- --- --- --- ---

Acetone 2.90 0.7 0.00 98.7 3.54 0.2 3.69 0.2 5.42 0.0 6.33 0.0 4.07 0.1 --- --- --- --- --- --- --- ---

3 Acetonitrile 2.85 0.8 0.00 98.5 3.48 0.3 3.59 0.2 5.30 0.0 6.31 0.0 3.88 0.1 --- --- --- --- --- --- --- ---

DMSO 2.82 0.8 0.00 98.4 3.44 0.3 3.55 0.2 5.24 0.0 6.30 0.0 3.81 0.2 --- --- --- --- --- --- --- ---

Methanol 2.86 0.8 0.00 98.6 3.49 0.3 3.61 0.2 5.33 0.0 6.31 0.0 3.92 0.1 --- --- --- --- --- --- --- ---

Water 2.76 0.9 0.00 98.3 3.39 0.3 3.47 0.3 5.18 0.0 6.27 0.0 3.69 0.2 --- --- --- --- --- --- --- ---

S8

a)

1a 1b 1d0

50

100

Inte

nsit

y(k

mm

ol-1

)

Conformer

Amide A (CH2Cl

2)

Amide A (CH3CN)

b)

2a 2b 2d0

50

100

150

Amide A (CH2Cl

2)

Amide A (CH3CN)

Inte

ns

ity

(km

mo

l-1)

Conformer

c)

0

20

40

60

80

100

120

140

160

180

Conformer3d3c3b

Inte

nsit

y(k

mm

ol-1

)

3a

Amide A (CH2Cl2)

Amide A (CH3CN)

Figure S3: Ac-Gly-NHMe calculated (B3LYP-D3/aug-cc-pVDZ) IR intensities for a) Amide A and Amide B absorptions for conformers 1a, 1b and 1d inCH2Cl2 and acetonitrile. b) Amide A and Amide B absorptions for conformers 2a, 2b and 2d in CH2Cl2 and acetonitrile and c). Amide A and Amide Babsorptions for conformers 3a, 3b and 3d in CH2Cl2 and acetonitrile

S9

Ac-Gly-NHMe1a 1b 1d

ρ = 0.022 au2ρ = +0.066 auε = 0.034 au

CF3-C(O)-Gly-NHMe2a 2b 2c 2d

ρ = 0.0172ρ = +0.052ε = 0.029 au

Figure S4: QTAIM molecular graphs of compounds 1 and 2 most stable conformers obtained from B3LYP-D3/aug-cc-pVDZ optimisations. Electron density (ρ), Laplacian of the electron density (2ρ) and ellipticity values (ε, au) in the intramolecular hydrogen bond bond critical point (BCP) are indicated for each case.Green points represent BCPs and red points represent ring critical points (RCPs).

S10

Ac-Gly-NHMe1a 1b 1d

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

-0.075

C(O)V(N, H)

V(O)

C(N)

EL

F

N-H...O bond path

+0.087

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0C(O)V(N, H)

V(O)

C(N)

EL

FN-H...O bond path

-0.054+0.0860 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0C(O)V(N, H)

V(O)

C(N)

EL

F

N-H...N bond path

-0.042+0.085

CVBI = +0.012 CVBI = +0.032 CVBI = +0.042CF3-C(O)-Gly-NHMe

2a 2b 2c 2d

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

-0.058

C(O)V(N, H)

V(O)

C(N)

ELF

N-H...O bond path

+0.086

0 1 2 3 4 5 6

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

C(O)

V(O)

V(N, H)C(N)

+0.088 -0.058

N-H...O bond path

EL

F

0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0C(O)V(N, H)

V(O)

C(N)

EL

FN-H...N bond path

+0.060+0.0850 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0 C(O)V(N, H)

V(O)

C(N)

EL

F

N-H...N bond path

+0.041+0.086

CVBI = +0.027 CVBI = +0.030 CVBI = +0.030 CVBI = +0.045Figure S5: ELF localization domains (0.8 au isodensity value) of compounds 1 and 2 main conformers obtained from B3LYP-D3/aug-cc-pVDZ optimisations.Graphs of ELF value along the bond path of the IHB are given for each case. Core valence bifurcation index (CVBI) values (au) for each case obtained fromthose graphs are also indicated.

S11

Ac-Gly-NHMe1a 1b 1d

sign(2) = -0.022 sign(2) = -0.019 sign(2) = -0.016CF3-C(O)-Gly-NHMe

2a 2b 2c 2d

sign(2) = -0.017 sign(2) = -0.020 sign(2) = -0.020 sign(2) = -0.015Figure S6: NCI isosurface plots of compounds 1 and 2 main conformers obtained from B3LYP-D3/aug-cc-pVDZ optimisations. The figures were obtainedwith a reduced density gradient (RDG) value of 0.6 and the blue-green-red values ranging from -0.02 to 0.02 au. Graph of the RDG vs sign(2) are given foreach case. Values of sign(2) (au) corresponding to IHBs peaks in the (RDG) vs sign(2) graphs are given for each case.

S12

Ac-Gly-NHMe1a 1b 1d

sign(2) = -0.022 sign(2) = -0.019 sign(2) = -0.015CF3-C(O)-Gly-NHMe

2a 2b 2c 2d

sign(2) = sign(2) = -0.020 sign(2) = -0.020 sign(2) = -0.015Figure S7: DORI isosurface plots of compounds 1 and 2 main conformers obtained from B3LYP-D3/aug-cc-pVDZ optimisations. The figures were obtainedwith a DORI value of 0.9 au and the blue-green-red values ranging from -0.02 to 0.02 au. Values of sign(2) (au) corresponding to IHBs peaks in the DORI vssign(2) graphs are given for each case.

S13

Ac-Gly-NHMe1a 1b 1d

nO(1) *NH = 2.57 nO(1) *NH = 0.67 nN *NH = 1.24

nO(2) *NH = 3.76 nO(2) *NH = 2.04CF3-C(O)-Gly-NHMe

2a 2b 2c 2d

nO(1) *NH = 1.69 nO(1) *NH = 0.79 nO(1) *NH = 0.83 nN *NH = 1.24

nO(2) *NH = 2.65 nO(2) *NH = 2.49 nO(2) *NH = 2.59 nF(2) *NH = 1.10

nF(2) *NH = 1.10 nF(2) *NH = 0.94 nF(2) *NH = 0.94Figure S8: NBO plots of n *NH interactions for main conformers of 1 and 2. Figures were obtained at the B3LYP-D3/aug-cc-pVDZ level with an isovalue of 0.04 au. n *NH energy values are given in kcal mol-1.

S14

Table S5: Compounds 1, 2 and 3 3JHH calculated SSCCs (in Hz) at the BHandH/EPR-III and SOPPA(CCSD)/EPR-III on B3LYP-D3/aug-cc-pVDZ optimisedgeometries for the isolated compounds.

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k

3JH10H13 (BHand/EPR-III) 7.01 2.76 3.07 9.73 7.82 3.81 3.12 11.35 3.54 10.56 8.37

3JH11H13 (BHand/EPR-III) 6.47 2.79 2.71 4.61 7.71 10.23 3.12 5.22 3.00 5.72 8.17

1 (3JH10H11 + 3JH11H13)/2 6.74 2.78 2.89 7.17 7.77 7.02 3.12 8.29 3.27 8.14 8.27

3JH10H13 [SOPPA(CCSD)/EPR-III] 6.01 1.76 2.04 8.33 6.64 3.22 2.16 10.04 2.55 9.42 7.63

3JH11H13 [SOPPA(CCSD)/EPR-III] 5.66 1.78 1.72 4.00 7.02 8.73 2.16 4.53 2.04 5.10 6.95

(3JH10H11 + 3JH11H13)/2 5.84 1.77 1.88 6.17 6.83 5.98 2.16 7.29 2.30 7.26 7.29

2a 2b 2c 2d 2e 2f 2g 2h 2i

3JH14H15 (BHand/EPR-III) 8.15 3.01 2.57 6.65 2.60 2.30 5.40 2.80 8.45 --- ---

3JH15H16 (BHand/EPR-III) 6.62 2.57 3.24 8.07 2.59 12.08 9.74 2.75 3.90 --- ---

2 (3JH14H15 + 3JH15H16)/2 7.39 2.79 2.91 7.36 2.60 7.19 7.57 2.78 6.18 --- ---

3JH14H15 [SOPPA(CCSD)/EPR-III] 6.65 2.43 2.00 5.86 2.62 1.95 5.38 2.76 7.58 --- ---

3JH15H16 [SOPPA(CCSD)/EPR-III] 5.83 1.99 2.64 6.58 2.60 10.07 9.97 2.72 3.11 --- ---

(3JH14H15 + 3JH15H16)/2 6.24 2.21 2.32 6.22 2.61 6.01 7.68 2.74 5.35

3a 3b 3c 3d 3e 3f 3g

3JH3H6 (BHand/EPR-III) 3.28 2.57 2.98 10.29 8.96 0.03 1.39 --- --- ---

3JH4H6 (BHand/EPR-III) 10.25 2.66 2.98 5.77 7.69 11.80 7.87 --- --- ---

3 (3JH3H6 + 3JH4H6)/2 6.77 2.62 2.98 8.03 8.33 5.92 4.63 --- --- ---

3JH3H6 [SOPPA(CCSD)/EPR-III] 2.70 1.84 2.28 9.40 7.92 -0.41 0.81 --- --- ---

3JH4H6 [SOPPA(CCSD)/EPR-III] 8.98 1.92 2.28 5.09 6.88 10.61 7.13 --- --- ---

(3JH3H6 + 3JH4H6)/2 5.84 1.88 2.28 7.25 7.40 5.10 3.97 --- --- ---

S15

a)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

E(

i

) x

(3J

H1

0H

11

+3

JH

11

H13)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2

ExperimentalBHandHSOPPA(CCSD)

b)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

H(

i

) x

(3J

H1

0H

11

+3J

H11H

13)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


c)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

G(

i

) x

(3J

H1

0H

11

+3J

H11

H1

3)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


d)

0

1

2

3

4

5

6

I

R(

i

) x

(3J

Ha

Hb)/

2]

IR(CH

2Cl

2)

IR Corr.(CH

2Cl

2)

ExperimentalIR (BHandH)

Figure S9: Sum of all Ac-Gly-NHMe conformers contributions [( � i/ � T) x J] for the 3JH10H11 and 3JH11H13 SSCCs average values (3JH10H11 + 3JH11H13/2) obtainedin different solvents (B3LYP-D3/aug-cc-pVDZ level) by using the IEF-PCM model. Conformer contributions ( � i/ � T) values to 3JHH from a) ΔE; b) ΔH; c)ΔG; d) Experimental IR (using BHandH calculated 3JHH) uncorrected and corrected (IR Corr.) by conformers calculated infrared intensities.

S16

a)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

E(

i

) x

(3J

H1

4H

15

+3

JH

15

H1

6)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


b)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

H(

i

) x

(3J

H14H

15

+3J

H1

5H

16)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


c)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

G(

i

) x

(3J

H14H

15

+3J

H1

5H

16)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


d)

0

1

2

3

4

5

I

R(

i

) x

(3J

HaH

b)/

2]

IR(CH

3CN)

IR(CH

2Cl

2)

IR Corr.(CH

2Cl

2)

IR Corr.(CH

3CN)

ExperimentalIR (BHandH)

Figure S10: Sum of all CF3-C(O)-Gly-NHMe conformers contributions [( � i/ � T) x J] for the 3JH14H15 and 3JH15H16 SSCCs average values (3JH14H15 + 3JH15H16)/2obtained in different solvents (B3LYP-D3/aug-cc-pVDZ level) by using the IEF-PCM model. Conformer contributions ( � i/ � T) values to 3JHH from a) ΔE; b)ΔH; c) ΔG; d) Experimental IR (using BHandH calculated 3JHH) and corrected IR (IR Corr.) with calculated infrared intensities.

S17

a)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

E(

i

) x

(3J

H3

H6

+3

JH

4H

6)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


b)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

H(

i

) x

(3J

H3

H6

+3

JH

4H

6)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


c)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

6.5

G(

i

) x

(3J

H3H

6+

3J

H4H

6)/

2]

H2OCH

3OHDMSOCH

3CNAcetoneCH

2Cl

2


Figure S11: Sum of all Ac-Gly-N(Me)2 conformers contributions [( � i/ � T) x J] for the 3JH3H6 and 3JH4H6 SSCCs average values (3JH3H6 + 3JH4H6)/2 obtained indifferent solvents (B3LYP-D3/aug-cc-pVDZ level) by using the IEF-PCM model. Conformer contributions ( � i/ � T) values to 3JHH from a) ΔE; b) ΔH and c)ΔG

S18

1H NMR Spectra (Bruker avance III 600 MHz)1. Ac-Gly-NHMe

Spectrum S1: Ac-Gly-NHMe 1H NMR Spectrum in CD2Cl2.

10 9 8 7 6 5 4 3 2 1 0 ppm

3.0

8

3.0

0

2.0

7

0.8

9

0.9

0

NAME Ac-gly-nhmeEXPNO 1PROCNO 1Date_ 20140729Time 10.41INSTRUM spectPROBHD 5 mm PATXI 1H/PULPROG zg30TD 65536SOLVENT CD2Cl2NS 64DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 32DW 75.733 usecDE 6.50 usecTE -0.2 KD1 1.00000000 secTD0 1

======== CHANNEL f1 ========SFO1 600.1727043 MHzNUC1 1HP1 7.50 usecSI 131072SF 600.1700242 MHzWDW EMSSB 0LB 0.00 HzGB 0PC 1.00

3.84 ppm

3.825

3.834

2.78 ppm

2.777

2.785

6.0 ppm

5.923

6.184

1.995 ppm

1.993

S19

Spectrum S2: Ac-Gly-NHMe 1H NMR Spectrum in acetone-d6.

10 9 8 7 6 5 4 3 2 1 0 ppm

3.0

0

3.2

6

2.1

1

0.8

90

.95

NAME gly-dip-acetonaEXPNO 1PROCNO 1Date_ 20120124Time 11.34INSTRUM spectPROBHD 5 mm PATBO BB-PULPROG zg30TD 32768SOLVENT AcetoneNS 4DS 0SWH 12335.526 HzFIDRES 0.376450 HzAQ 1.3282462 secRG 203DW 40.533 usecDE 6.50 usecTE 298.1 KD1 1.00000000 secTD0 1

======== CHANNEL f1 ========NUC1 1HP1 15.00 usecSI 131072SF 600.1700080 MHzWDW EMSSB 0LB 0.00 HzGB 0PC 1.00

7.27.4 ppm

7.153

7.343

3.77 ppm

3.762

3.772

2.69 ppm

2.684

2.692

1.925 ppm

1.925

S20

Spectrum S3: Ac-Gly-NHMe 1H NMR Spectrum in CD3CN.

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

3.0

3

3.0

2

2.0

3

0.9

6

1.0

0

NAME gli-dip-CN-nhEXPNO 2PROCNO 1Date_ 20120404Time 16.48INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT CD3CNNS 4DS 0SWH 6009.615 HzFIDRES 0.091699 HzAQ 5.4526453 secRG 144DW 83.200 usecDE 6.50 usecTE 298.1 KD1 1.00000000 secTD0 1


3.68 ppm

3.675

3.685

2.66 ppm

2.657

2.665

6.66.8 ppm

6.526

6.715

1.92 ppm

1.917

S21

Spectrum S4: Ac-Gly-NHMe 1H NMR Spectrum in DMSO-d6.

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

2.7

6

2.9

5

2.0

0

0.9

5

0.9

7

NAME gly-dip-dmsoEXPNO 1PROCNO 1Date_ 20120201Time 17.19INSTRUM spectPROBHD 5 mm PATBO BB-PULPROG zg30TD 65536SOLVENT DMSONS 8DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 203DW 75.733 usecDE 6.50 usecTE 297.7 KD1 1.00000000 secTD0 1


8.10 ppm

8.081

7.75 ppm

7.737

7.741

ppm3.601

3.611

ppm

1.847

ppm

2.569

2.577

S22

Spectrum S5: Ac-Gly-NHMe 1H NMR Spectrum in CD3OH.

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

2.6

1

2.6

6

1.8

0

0.8

4

0.8

5

NAME gli-dip-cd3oh-nhEXPNO 1PROCNO 1Date_ 20120701Time 10.06INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT MeODNS 8DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 5.6DW 75.733 usecDE 6.50 usecTE 298.2 KD1 1.00000000 secTD0 1


3.793.80 ppm

3.791

3.801

2.74 ppm

2.732

2.740

8.0 ppm

7.894

8.249

2.00 ppm

2.002

S23

Spectrum S6: Ac-Gly-NHMe 1H NMR Spectrum in H2O. WATERGATE solvent suppression was used.

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

2.8

7

3.0

0

2.2

3

0.6

3

0.7

6

NAME glidip_h2o_d2oEXPNO 4PROCNO 1Date_ 20121113Time 21.25INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG p3919gpTD 65536SOLVENT H2O+D2ONS 256DS 0SWH 6613.757 HzFIDRES 0.100918 HzAQ 4.9545717 secRG 203DW 75.600 usecDE 6.50 usecTE 298.8 KD1 1.00000000 secD16 0.00020000 secD19 0.00016667 secTD0 1

======== CHANNEL f1 ========NUC1 1HP0 7.15 usecP1 7.15 usecP27 7.15 usecSI 32768SF 600.1698238 MHzWDW EMSSB 0LB 0.00 HzGB 0PC 1.00

2.052.06 ppm

2.051

2.74 ppm

2.733

2.741

3.85 ppm

3.849

3.859

8.0 ppm

7.855

8.297

S24

2. CF3-C(O)-Gly-NHMe

Spectrum S7: CF3-C(O)-Gly-NHMe 1H NMR Spectrum in CD2Cl2.

9 8 7 6 5 4 3 2 1 0 ppm

3.0

0

2.0

1

1.0

7

0.9

2

NAME CF3-gly-nhmeEXPNO 1PROCNO 1Date_ 20140729Time 10.56INSTRUM spectPROBHD 5 mm PATXI 1H/PULPROG zg30TD 65536SOLVENT CD2Cl2NS 64DS 0SWH 6613.757 HzFIDRES 0.100918 HzAQ 4.9545717 secRG 203DW 75.600 usecDE 6.50 usecTE -0.2 KD1 1.00000000 secTD0 1

======== CHANNEL f1 ========SFO1 600.1726892 MHzNUC1 1HP1 7.50 usecSI 131072SF 600.1700255 MHzWDW EMSSB 0LB 0.00 HzGB 0PC 1.00

5.65.7 ppm

5.618

3.96 ppm

3.955

3.963

7.2 ppm

7.194

2.86 ppm

2.842

2.850

S25

Spectrum S8: CF3-C(O)-Gly-NHMe 1H NMR Spectrum in acetone-d6.

9 8 7 6 5 4 3 2 1 0 ppm

3.1

2

2.2

0

0.9

1

0.8

2

NAME cf3gli_dip_nh_acetonaEXPNO 1PROCNO 1Date_ 20120731Time 10.42INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT AcetoneNS 8DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 101DW 75.733 usecDE 6.50 usecTE 298.1 KD1 1.00000000 secTD0 1


3.963.97 ppm

3.962

3.971

2.74 ppm

2.726

2.734

8 ppm

7.306

8.528

S26

Spectrum S9: CF3-C(O)-Gly-NHMe 1H NMR Spectrum in CD3CN.

9 8 7 6 5 4 3 2 1 0 ppm

3.0

0

2.0

2

0.8

9

0.8

4

NAME CF3-gli-CD3CNEXPNO 1PROCNO 1Date_ 20121106Time 19.24INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT CD3CNNS 32DS 0SWH 6613.757 HzFIDRES 0.100918 HzAQ 4.9545717 secRG 203DW 75.600 usecDE 10.00 usecTE 298.4 KD1 1.00000000 secTD0 1


3.84 ppm

3.836

3.844

2.70 ppm

2.690

2.698

7.07.58.0 ppm

6.503

7.757

S27

Spectrum S10: CF3-C(O)-Gly-NHMe 1H NMR Spectrum in DMSO-d6.

11 10 9 8 7 6 5 4 3 2 1 0 ppm

2.8

8

2.0

0

0.9

9

1.0

0

NAME CF3-gli-DMSOEXPNO 1PROCNO 1Date_ 20121106Time 15.56INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT DMSONS 128DS 0SWH 7911.393 HzFIDRES 0.120718 HzAQ 4.1419253 secRG 161DW 63.200 usecDE 10.00 usecTE 298.4 KD1 1.00000000 secTD0 1


3.763.78 ppm

3.757

3.767

2.60 ppm

2.597

2.605

9 ppm

7.976

7.980

9.625

S28

Spectrum S11: CF3-C(O)-Gly-NHMe 1H NMR Spectrum in CD3OH. Solvent presaturation experiment was used.

10 9 8 7 6 5 4 3 2 1 ppm

2.8

4

2.0

0

0.5

9

NAME CF3-gli-CD3OHEXPNO 2PROCNO 1Date_ 20121106Time 10.09INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zgprTD 32768SOLVENT MeODNS 64DS 0SWH 7183.908 HzFIDRES 0.219235 HzAQ 2.2807028 secRG 80.6DW 69.600 usecDE 10.00 usecTE 298.4 KD1 1.00000000 secD12 0.00002000 secTD0 1


3.92 ppm3.908

2.75 ppm

2.746

2.754

8.1 ppm

8.035

S29

Spectrum S12: CF3-C(O)-Gly-NHMe 1H NMR Spectrum in H2O. Solvent presaturation experiment was used.

10 9 8 7 6 5 4 3 2 1 0 ppm

2.8

4

2.0

0

0.5

9

NAME CF3-gli-CD3OHEXPNO 2PROCNO 1Date_ 20121106Time 10.09INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zgprTD 32768SOLVENT MeODNS 64DS 0SWH 7183.908 HzFIDRES 0.219235 HzAQ 2.2807028 secRG 80.6DW 69.600 usecDE 10.00 usecTE 298.4 KD1 1.00000000 secD12 0.00002000 secTD0 1


3.92 ppm3.908

2.75 ppm

2.746

2.754

8.1 ppm

8.035

S30

O

N

N

OH

3. Ac-Gly-N(Me)2

Spectrum S13: Ac-Gly-N(Me)21H NMR Spectrum in CD2Cl2.

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

3.0

0

2.9

52.9

7

2.0

5

0.9

1

NAME N-dir_metil_GLI_CD2Cl2EXPNO 1PROCNO 1Date_ 20121219Time 9.59INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT CD2Cl2NS 32DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 32DW 75.733 usecDE 6.50 usecTE 298.8 KD1 1.00000000 secTD0 1


4.00 ppm3.999

4.007

2.95 ppm

2.943

2.964

6.8 ppm

6.813

1.99 ppm

1.987

S31

O

N

N

OH

Spectrum S14: Ac-Gly-N(Me)21H NMR Spectrum in acetone-d6.

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

2.7

3

3.0

03.0

4

2.0

4

0.8

0

NAME N-dir_metil_GLI_acetonaEXPNO 1PROCNO 1Date_ 20121218Time 18.24INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT AcetoneNS 32DS 0SWH 6613.757 HzFIDRES 0.100918 HzAQ 4.9545717 secRG 22.6DW 75.600 usecDE 6.50 usecTE 298.8 KD1 1.00000000 secTD0 1


3.98 ppm3.973

3.981

3.0 ppm

2.895

3.007

7.2 ppm

7.187

1.94 ppm

1.935

S32

O

N

N

OH

Spectrum S15: Ac-Gly-N(Me)21H NMR Spectrum in CD3CN.

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

3.0

0

3.1

73

.20

2.1

3

0.9

1

NAME N-dir_metil_GLI_CD3CNEXPNO 1PROCNO 1Date_ 20121218Time 17.15INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT CD3CNNS 32DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 50.8DW 75.733 usecDE 6.50 usecTE 298.8 KD1 1.00000000 secTD0 1


3.93 ppm3.924

3.932

2.9 ppm

2.878

2.928

6.76.8 ppm

6.747

1.92 ppm

1.917

S33

O

N

N

OH

Spectrum S16: Ac-Gly-N(Me)21H NMR Spectrum in DMSO-d6.

10 9 8 7 6 5 4 3 2 1 0 ppm

2.8

8

3.0

03.0

9

1.9

3

0.8

3

NAME N-dir_metil_GLI_DMSOEXPNO 1PROCNO 1Date_ 20121218Time 15.50INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT DMSONS 32DS 0SWH 6602.113 HzFIDRES 0.100740 HzAQ 4.9633098 secRG 32DW 75.733 usecDE 6.50 usecTE 298.8 KD1 1.00000000 secTD0 1


3.90 ppm3.883

3.892

2.9 ppm

2.823

2.937

7.90 ppm

7.912

1.86 ppm

1.859

S34

O

N

N

OH

Spectrum S17: Ac-Gly-N(Me)21H NMR Spectrum in CD3OH.

9 8 7 6 5 4 3 2 1 0 ppm

5.6

2

5.6

35

.63

3.6

0

1.4

5

NAME N-dir_metil_GLI_CD3OHEXPNO 1PROCNO 1Date_ 20121218Time 19.55INSTRUM spectPROBHD 5 mm TBI 1H/13PULPROG zg30TD 65536SOLVENT MeODNS 256DS 0SWH 6578.947 HzFIDRES 0.100387 HzAQ 4.9807858 secRG 4DW 76.000 usecDE 6.50 usecTE 298.8 KD1 1.00000000 secTD0 1


4.06 ppm4.050

4.058

3.0 ppm

2.961

3.049

8.1 ppm

8.075

2.03 ppm

2.025

S35

Spectrum S18: Ac-Gly-N(Me)21H NMR Spectrum in H2O. WATERGATE solvent suppression was used.

10 9 8 7 6 5 4 3 2 1 0 ppm

2.6

0

3.0

03.1

2

1.9

3

NAME ac-gly-nme2-h2o_insercaoEXPNO 3PROCNO 1Date_ 20140807Time 12.57INSTRUM spectPROBHD 5 mm PATXI 1H/PULPROG p3919gpTD 65536SOLVENT H2O+D2ONS 256DS 2SWH 6631.300 HzFIDRES 0.101186 HzAQ 4.9414644 secRG 203DW 75.400 usecDE 6.50 usecTE -0.2 KD1 1.00000000 secD16 0.00020000 secD19 0.00025000 secTD0 1

======== CHANNEL f1 ========SFO1 600.1728310 MHzNUC1 1HP0 7.50 usecP1 7.50 usecP27 7.50 usecSI 32768SF 600.1699628 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00

ppm

3.032

ppm

2.931

ppm

4.068

2.06 ppm

2.053

S36

Infrared spectra

Ac-Gly-NHMe N-H in CH2Cl2

a)

3500 3480 3460 3440 3420 3400 3380 3360

0.00

0.02

0.04

0.06

0.08

0.10

Ab

so

rba

nce

Wavenumber (cm-1)

b)

3500 3480 3460 3440 3420 3400

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

P(1b) = 31.9%

1b

Experimental SpectrumSum of deconvolded bandsDeconvolved 1aDeconvolved 1b

Ab

sorb

an

ce

Wavenumber (cm-1)

P(1a) = 68.1%

1a

c)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

0

100

200

300

400

500

600

Ep

isilo

n

Wavenumber (cm-1)

Conformer 1aConformer 1bConformer 1d

P(1a) = 56.2%

P(1b) = 18.9%

P(1d) = 19.2%

d)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

0

100

200

300

400

500

Ep

isilo

n

Wavenumber (cm-1)


P(1a) = 46.1%

P(1b) = 27.3%P(1d) = 19.6%

e)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

0

50

100

150

200

250

300

350

400

Epis

ilon

Wavenumber (cm-1)

P(1a) = 11.0%

P(1b) = 68.8%

P(1d) = 18.0%


f)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

0

100

200

300

400

500

600

700

Ep

isilo

n

Wavenumber (cm-1)

Conformer 1aConformer 1b

P(1a) = 68.1%

P(1b) = 31.9%

Figure S12: Ac-Gly-NHMe N-H stretchings region in CH2Cl2 of: a) IR experimental spectrum b)

Deconvolved experimental Spectrum. Each conformer N-H stretchings were weighted by its

B3LYP-D3/aug-cc-pVDZ populations for c) ΔE populations; d) ΔH populations and e) ΔG

populations. f) Theoretical spectrum using B3LYP-D3/aug-cc-pVDZ geometries and populations

obtained from the deconvolved experimental spectrum.

S37

a)

1750 1700 1650 1600 1550 1500 1450

0.00

0.05

0.10

0.15

0.20

0.25

0.30

b)

1720 1700 1680 1660 1640 1620 1600 1580 1560 1540 1520

0

200

400

600

800

1000

1200Conformer 1aConformer 1bConformer 1d

Ab

sorb

an

ce

Wavenumber (cm-1)

P(1a) = 56.2%

P(1d) = 19.2%

P(1b) = 18.9%

c)

1720 1700 1680 1660 1640 1620 1600 1580 1560 1540 1520

0

200

400

600

800

1000

1200

Epis

ilon


Wavenumber (cm-1)

P(1a) = 46.1%

P(1b) = 27.3%

P(1d) = 19.6%

d)

1720 1700 1680 1660 1640 1620 1600 1580 1560 1540 1520

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Ep

isilo

n


Wavenumber (cm-1)

P(1a) = 11.0%

P(1d) = 18.0%

P(1b) = 68.8%

e)

1700 1680 1660 1640 1620 1600 1580 1560 1540

0

200

400

600

800

1000

1200

1400

1600

1800

Ep

isilo

n


P(1a) = 61.1%

P(1b) = 31.9%

Wavenumber (cm-1)

Figure S13: Ac-Gly-NHMe C=O stretchings region (~1700 cm-1; Amide I bands) and mix of

C(O)-N-H bond angle deformation/C-N bond stretching (~1550 cm-1; Amide II) in CH2Cl2 of: a)

IR experimental spectrum. Each conformer C=O bond stretchings/angular bending weighted by

its B3LYP-D3/aug-cc-pVDZ populations for b) ΔE populations; c) ΔH populations and d) ΔG

populations. e) Theoretical spectrum using B3LYP-D3/aug-cc-pVDZ geometries and populations


S38

Ac-Gly-NHMe in Acetonitrile

a)

3480 3460 3440 3420 3400 3380 3360 3340 3320 3300

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14 Experimental Spectrum

Ab

sorb

an

ce

Wavenumber (cm-1)

b)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

0

100

200

300

400

500

Ep

isilo

n


Wavenumber (cm-1)

P(1a) = 39.9%

P(1d) = 37.9%

P(1b) = 16.0%

c)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

-50

0

50

100

150

200

250

300

350

400

Epis

ilon


Wavenumber (cm-1)

P(1a) = 32.4%

P(1b) = 23.1%

P(1d) = 37.7%

d)

3640 3620 3600 3580 3560 3540 3520 3500 3480 3460

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

Ep

isilo

n


Wavenumber (cm-1)

P(1a) = 7.3%

P(1b) = 49.4%

P(1d) = 39.9%

Figure S14: Ac-Gly-NHMe N-H stretchings region (Amide A and B bands) in acetonitrile of: a)

IR experimental spectrum b) ΔE populations; c) ΔH populations and d) ΔG populations.

S39

a)

1720 1700 1680 1660 1640

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Abso

rban

ce

Wavenumber (cm-1)

b)

1710 1680 1650 1620 1590 1560 1530 1500

0

200

400

600

800

1000

1200


Ab

sorb

an

ce

Wavenumber (cm-1)

P(1a) = 39.9%

P(1b) = 16.0%

P(1d) = 37.9%

c)

1710 1680 1650 1620 1590 1560 1530 1500

0

200

400

600

800

1000

Epis

ilon


Wavenumber (cm-1)

P(1b) = 23.1%

P(1d) = 37.7%

P(1a) = 32.4%

d)

1710 1680 1650 1620 1590 1560 1530 1500

0

200

400

600

800

1000

1200

1400

1600

Ep

isilo

n


Wavenumber (cm-1)

P(1b) = 49.4%

P(1d) = 39.9%

P(1a) = 7.3%

Figure S15: Ac-Gly-NHMe C=O stretchings region (~1700 cm-1; Amide I bands) and mix of

C(O)-N-H bond angle deformation/C-N bond stretching (~1550 cm-1; Amide II) in acetonitrile of:

a) IR experimental spectrum. Each conformer bond stretchings/angular bendings were weighted

by its B3LYP-D3/aug-cc-pVDZ populations for b) ΔE populations; c) ΔH populations and d) ΔG

populations.

S40

CF3-C(O)-Gly-NHMe in CH2Cl2

a)

3500 3480 3460 3440 3420 3400 3380 3360 3340 3320 3300

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

0.11

0.12

0.13

Experimental Spectrum

Absorb

ance

Wavenumber (cm-1)

b)

3500 3480 3460 3440 3420 3400 3380 3360 3340 3320 3300

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

0.11

0.12

0.13

2b

2a

P(2b) = 59.6%

Experimental SpectrumSum of deconvolded bandsDeconvolved 2aDeconvolved 2b

P(2a) = 40.4%Ab

sorb

an

ce

Wavenumber (cm-1)

c)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

Ep

isilo

n

P(2c) = 8.4%

Conformer 2aConformer 2bConformer 2cConformer 2d

Wavenumber (cm-1)

P(2b) = 68.0%

P(2a) = 13.7%

P(2d) = 9.6%

d)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600E

pis

ilon


Wavenumber (cm-1)

P(2a) = 8.4%P(2c) = 9.3%

P(2d) = 7.6%

P(2b) = 74.5%

e)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

700

Ep

isilo

n


Wavenumber (cm-1)

P(2a) = 2.7% P(2c) = 4.5%P(2d) = 10.3%

P(2b) = 82.4%

f)

3640 3620 3600 3580 3560 3540 3520 3500

-100

0

100

200

300

400

500

600

700

800

Ep

isilo

n


P(2b) = 59.6%

P(2a) = 40.4%

Wavenumber (cm-1)

Figure S16: CF3-C(O)-Gly-NHMe N-H stretchings region (Amide A and B bands) in CH2Cl2 of:

a) IR experimental spectrum b) Deconvolved experimental Spectrum. Each conformer N-H

stretchings were weighted by its B3LYP-D3/aug-cc-pVDZ populations for c) ΔE populations; d)

ΔH populations and e) ΔG populations. f) Theoretical spectrum using B3LYP-D3/aug-cc-pVDZ

geometries and populations obtained from the deconvolved experimental spectrum.

S41

a)

1800 1750 1700 1650 1600 1550 1500

0.0

0.1

0.2

0.3

0.4

0.5

Ab

sorb

an

ce

Wavenumber (cm-1)

b)

1770 1740 1710 1680 1650 1620 1590 1560 1530

0

200

400

600

800

1000

1200

1400Conformer 2aConformer 2bConformer 2cConformer 2d

Abso

rba

nce

Wavenumber (cm-1)

P(2b) = 68.0%

P(2c) = 8.4%

P(2d) = 9.6%

P(2a) = 13.7%

c)

1770 1740 1710 1680 1650 1620 1590 1560 1530

-200

0

200

400

600

800

1000

1200

1400

1600

Ep

isilo

n


Wavenumber (cm-1)

P(2b) = 74.5%

P(2c) = 9.3%

P(2d) = 7.6% P(2a) = 8.4%

d)

1770 1740 1710 1680 1650 1620 1590 1560 1530

0

200

400

600

800

1000

1200

1400

1600

1800

Ep

isilo

n


Wavenumber (cm-1)

P(2b) = 82.4%

P(2c) = 4.5%

P(2a) = 2.7%

P(2d) = 10.3%

e)

1770 1740 1710 1680 1650 1620 1590 1560 1530 1500

0

200

400

600

800

1000

1200

1400

Ep

isilo

n


P(2b) = 56.6%

P(2a) = 43.4%

Wavenumber (cm-1)

Figure S17: CF3-C(O)-Gly-NHMe C=O stretchings region (~1700 cm-1; Amide I bands) and mix

of C(O)-N-H bond angle deformation/C-N bond stretching (~1550 cm-1; Amide II) in CH2Cl2 of:





S42

CF3-C(O)-Gly-NHMe in Acetonitrile

a)

3480 3450 3420 3390 3360 3330 3300 3270 3240

0.00

0.02

0.04

0.06

0.08

0.10

0.12


Ab

sorb

an

ce

Wavenumber (cm-1)

b)

3480 3450 3420 3390 3360 3330 3300 3270 3240

0.00

0.02

0.04

0.06

0.08

0.10

0.12

2d

2b

P(2d) = 56.3%

Original SpectrumSum of deconvolved bandsDeconvolved 2bDeconvolved 2d

Ab

sorb

an

ce

Wavenumber (cm-1)

P(2b) = 43.7%

c)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

Ep

isilo

n

Deconvolved 2bDeconvolved 2d

Wavenumber (cm-1)

P(2b) = 64.7%

P(2d) = 17.8%

d)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

Ep

isilo

nDeconvolved 2bDeconvolved 2d

Wavenumber (cm-1)

P(2b) = 70.7%

P(2d) = 14.8%

e)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

700

800

Ep

isilo

n

Wavenumber (cm-1)

Conformer 2bConformer 2d

P(2b) = 84.6%

P(2d) = 11.0%

f)

3640 3620 3600 3580 3560 3540 3520

0

100

200

300

400

Ep

isilo

n

Wavenumber (cm-1)

P(2b) = 43.7%


P(2d) = 56.3%

Figure S18: CF3-C(O)-Gly-NHMe N-H stretchings region (Amide A and B bands) in acetonitrile

of: a) IR experimental spectrum b) Deconvolved experimental Spectrum. Each conformer N-H

stretchings were weighted by its B3LYP-D3/aug-cc-pVDZ populations for c) ΔE populations; d)

ΔH populations and e) ΔG populations. f) Theoretical spectrum using B3LYP-D3/aug-cc-pVDZ

geometries and populations obtained from the deconvolved experimental spectrum..

S43

a)

1760 1740 1720 1700 1680 1660

0.0

0.1

0.2

0.3

0.4A

bso

rba

nce

Wavenumber (cm-1)

b)

1750 1700 1650 1600 1550

0

200

400

600

800

1000

1200

1400

1600


P(2b) = 64.7%

Ab

so

rba

nce

Wavenumber (cm-1)

P(2d) = 17.8%

c)

1750 1700 1650 1600 1550

0

200

400

600

800

1000

1200

1400

1600

Epis

ilon

Wavenumber (cm-1)


P(2b) = 70.7%

P(2d) = 14.8%

d)

1750 1700 1650 1600 1550

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Ep

isilo

nConformer 2bConformer 2d

P(2b) = 84.6%

Wavenumber (cm-1)

P(2d) = 11.0%

e)

1750 1700 1650 1600 1550 1500

0

200

400

600

800

1000

1200

Ep

isilo

n


P(2b) = 43.7%

Wavenumber (cm-1)

P(2d) = 56.3%

Figure S19: CF3-C(O)-Gly-NHMe C=O stretchings region (~1700 cm-1; Amide I bands) and mix

of C(O)-N-H bond angle deformation/C-N bond stretching (~1550 cm-1; Amide II) in acetonitrile

of: a) IR experimental spectrum. Each conformer bond stretchings/angular bendings were

weighted by its B3LYP-D3/aug-cc-pVDZ populations for b) ΔE populations; c) ΔH populations

and d) ΔG populations. e) Theoretical spectrum using B3LYP-D3/aug-cc-pVDZ geometries and

populations obtained from the deconvolved experimental spectrum.

S44

Ac-Gly-N(Me)2 in CH2Cl2

a)

3500 3480 3460 3440 3420 3400 3380 3360 3340

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

0.20


Ab

so

rban

ce

Wavenumber (cm-1)

b)

3500 3480 3460 3440 3420 3400 3380 3360 3340

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

0.20

3d

3b

P(3d) = 6.6%

Experimental SpectrumSum of deconvolded bandsDeconvolved 3aDeconvolved 3d

P(3b) = 93.4%

Abso

rba

nce

Wavenumber (cm-1)

c)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

Ep

isilo

n

Wavenumber (cm-1)


P(3a) = 93.9%

P(3b) = 4.3%

P(3c) = 1.2%P(3d) = 0.3%

d)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600E

pis

ilon

Wavenumber (cm-1)


P(3a) = 93.6%

P(3b) = 2.6%

P(3c) = 3.2%

P(3d) = 0.3%

e)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

Ep

isilo

n

Wavenumber (cm-1)


P(3a) = 98.9%

P(3b) = 0.7%

P(3c) = 0.2%P(3d) = 0.1%

f)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

Ep

isilo

n

Wavenumber (cm-1)

Conformer 3aConformer 3d

P(3a) = 93.4%

P(3d) = 6.6%

Figure S20: Ac-Gly-(NMe)2 N-H stretchings region (Amide A and B bands) in CH2Cl2 of: a) IR

experimental spectrum b) Deconvolved experimental Spectrum. Each conformer N-H stretchings

were weighted by its B3LYP-D3/aug-cc-pVDZ populations for c) ΔE populations; d) ΔH

populations and e) ΔG populations. f) Theoretical spectrum using B3LYP-D3/aug-cc-pVDZ

geometries and populations obtained from the deconvolved experimental spectrum

S45

a)

1720 1680 1640 1600 1560 1520 1480

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8


Ab

sorb

an

ce

Wavenumber (cm-1)

b)

1700 1680 1660 1640 1620 1600 1580 1560 1540 1520

0

500

1000

1500

2000

2500

3000

3500

Conformer 3a

P(1a) = 93.9%

Ab

sorb

ance

Wavenumber (cm-1)

c)

1700 1680 1660 1640 1620 1600 1580 1560 1540 1520

0

500

1000

1500

2000

2500

3000

3500

Ep

isilo

n

Conformer 3a

P(3a) = 93.6%

Wavenumber (cm-1)

d)

1700 1680 1660 1640 1620 1600 1580 1560 1540 1520

0

500

1000

1500

2000

2500

3000

3500

Epis

ilon

Conformer 3a

P(3a) = 98.9%

Wavenumber (cm-1)

e)

1700 1680 1660 1640 1620 1600 1580 1560 1540 1520 1500

0

500

1000

1500

2000

2500

3000

Ep

isilo

n

Conformer 3aConformer 3d

P(3a) = 93.4%

Wavenumber (cm-1)

P(3d) = 6.6%

Figure S21: Ac-Gly-(NMe)2 C=O stretchings region (~1700 cm-1; Amide I bands) and mix of

C(O)-N-H bond angle deformation/C-N bond stretching (~1550 cm-1; Amide II) in CH2Cl2 of: a)

IR experimental spectrum. Each conformer bond stretchings/angular bendings were weighted by

its B3LYP-D3/aug-cc-pVDZ populations for b) ΔE populations; c) ΔH populations and d) ΔG



S46

Ac-Gly-N(Me)2 in Acetonitrile

a)

3480 3460 3440 3420 3400 3380 3360 3340 3320 3300

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Ab

sorb

an

ce

Wavenumber (cm-1)

b)

3620 3600 3580 3560 3540

0

100

200

300

400

500

600

Epis

ilon

Wavenumber (cm-1)


P(3a) = 90.6%

P(3b) = 5.1%

P(3d) = 0.9%P(3c) = 2.3%

c)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

Ep

isilo

n

Wavenumber (cm-1)


P(3a) = 89.6%

P(3b) = 3.1%

P(3c) = 5.8%P(3d) = 0.6%

d)

3640 3620 3600 3580 3560 3540 3520 3500

0

100

200

300

400

500

600

700

Ep

isilo

n

Wavenumber (cm-1)


P(3a) = 98.5%

P(3b) = 0.8%

P(3c) = 0.3%P(3d) = 0.2%

Figure S22: Ac-Gly-(NMe)2 N-H stretchings region in acetonitrile of: a) IR experimental

spectrum b) ΔE populations; c) ΔH populations and d) ΔG populations.

S47

a)

1720 1700 1680 1660 1640 1620 1600 1580

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50Experimental Spectrum

Ab

sorb

an

ce

Wavenumber (cm-1)

b)

1680 1660 1640 1620 1600 1580 1560 1540 1520

0

500

1000

1500

2000

2500

3000

3500

Ab

sorb

an

ce

Wavenumber (cm-1)


P(3a) = 90.6%

P(3b) = 5.1%

P(3c) = 2.3%P(3d) = 0.9%

c)

1680 1660 1640 1620 1600 1580 1560 1540 1520

0

500

1000

1500

2000

2500

3000

3500

Ep

isilo

n

Wavenumber (cm-1)


P(3a) = 89.6%

P(3b) = 3.1%

P(3c) = 5.8%P(3d) = 0.6%

d)

1700 1680 1660 1640 1620 1600 1580 1560 1540 1520 1500

0

500

1000

1500

2000

2500

3000

3500

4000

Ep

isilo

n

Wavenumber (cm-1)


P(3a) = 89.6%

P(3b) = 3.1%

P(3c) = 5.8%P(3d) = 0.6%

Figure S23: Ac-Gly-(NMe)2 C=O stretchings region (~1700 cm-1; Amide I bands) and mix of

C(O)-N-H bond angle deformation/C-N bond stretching (~1550 cm-1; Amide II) in acetonitrile of:



populations.

electronic supplementary information · 2015-01-13 · s6 table s3: compounds 1, 2 and 3 relative...

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