Unpicking the determinants of amide NH?OC hydrogen bond strength with diphenylacetylene molecular balances

Article abstract of DOI:10.1039/c7ob02026k

Hydrogen bonding plays an essential part in dictating the properties of natural and synthetic materials. Secondary amides are well suited to cross-strand interactions through the display of both hydrogen bond donors and acceptors and are prevalent in poly

Full text of DOI:10.1039/c7ob02026k

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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Unpicking the determinants of amide NH••O=C hydrogen bond
strength with diphenylacetylene molecular balances
James Luccarelli,a Ian M. Jones,ab Sam Thompson*ac and Andrew D. Hamilton*abd
Received 00th January 2017,
Accepted 00th January 2017
Hydrogen bonding plays an essential part in dictating the properties of natural and synthetic materials. Secondary amides
are well suited to cross–strand interactions through the display of both hydrogen bond donors and acceptors and are
prevalent in polymers such as proteins, nylon, and Kevlar™. In attempting to measure hydrogen bond strength and to
delineate the stereoelectronic components of the interaction, context frequently becomes vitally important. This makes
molecular balances – systems in which direct comparison of two groups is possible – an appealing bottom up approach
that allows the complexity of larger systems to be stripped away. We have previously reported a family of single molecule
conformational switches that are responsive to diverse stimuli including Brønsted and Lewis acids, anions, and redox
gradients. In this work we assess the ability of the scaffold, based on a 2,6-disubstituted diphenylacetylene, to measure
accurately the difference in hydrogen bond strength between variously functionalised amides. In all of the examples
investigated hydrogen bond strength closely correlate to measures of Brønstead acidity suggesting that the scaffold is
well-suited as a platform for the accurate determination of bond strength in variously substituted systems.
DOI: 10.1039/x0xx00000x
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Introduction
Hydrogen bonding is a critical determinant of structure, and
thus function, in biological1 and synthetic systems,2 playing
significant roles in properties such as solvation3 and
membrane permeability.4 The nature of H–bonding has been
debated in the literature since at least the 1930s.5 IUPAC
currently defines an H-bond broadly,6 listing various forms of
structural, spectroscopic, and computational evidence that
may suggest that the interaction is present (Eq. 1).7
A ꢀ H ꢁ B ⇌ A ꢀ H ∙∙∙ B
(Eq. 1)
However, recognizing the presence of an H–bond (HB) is of
limited use in predicting how the relative strengths among
multiple H–bond donors can affect conformational dynamism
in natural and synthetic systems.8,9 To answer this question a
precise understanding of the factors underlying HB strength is
required. Large–scale database searches, as well as numerous
experimental and theoretical scales, have attempted to
elucidate relative energies of hydrogen bonds and determine
their effect on conformation.10–12
Fig. 1 Cross-strand hydrogen bonds between amides. Importance in medicine,
technology and industry: (a) Aß plaques (pdb: 3ow9),13 (b)
nanopore
A
(pdb: 3m2l),14 (c) Nylon 6,6 (ccdc: 1176016, H-bonds as dashed black lines);15
(d) A molecular balance to measure H–bonding strength: two donors compete
for a single acceptor. The equilibrium conformational ratio is determined by the
relative H bond donor ability of the two benzamide NHs. Varying groups R1 and
R2 allows probing of subtle steric and electronic effects.
Some of the earliest work in quantitative description of
molecular properties was by Hammett, who described the
aqueous ionization equilibria of substituted benzoic acids.16
This work was expanded specifically for measuring H–bonding
by Gurka and Taft, who developed the pKHB scale of H-bond
basicity using 19F NMR studies of the complexation of bases
with p–fluorophenol in carbon tetrachloride.17 This H–bond
basicity was found to be independent of aqueous pKa,
although the two scales are linearly correlated for a given
functional group differing only in the electronic character of
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substituents.18 An expanded scale was developed by Abraham of the p–methoxybenzamide of
1 when the equilibrium ratio is
and colleagues to describe 1:1 complexation of a variety of 1:1 (50 % control). The second control compound
solutes in carbon tetrachloride.19,20 Using this system, H–bond p–chloro– and p–methoxy–benzamide, similarly to
9
1
balances
however
donors are described by a log KAH scale (alternatively described the HB acceptor is now para to the alkyne linkage. Because the
H
as α2H) and bases by a log KB (or β2H) scale. These were intramolecular HB has been removed, the p–methoxy amide
subsequently expanded to include other stoichiometries, 1H resonance of
9
estimates the chemical shift of the same
if the H–bond equilibrium were biased
molecules indicate that these H–bond scales are likewise completely toward the other side (0 % control).47 The p–MeO–
distinct from Brønsted acidity. More recently, theoretical benzamide resonance of ) is downfield of the analogous
descriptions of H–bonding have been developed using a resonance in ), but upfield of that for ). This suggests
variety of computational methods,22–25 with varying degrees of that the p–MeO NH experiences more than 0 % but less than
success. 50 % of the total H–bond interaction. Thus the position of the
H
H
leading to Σα2 and Σβ2 scales.21 Studies on hundreds of resonance in
1
1 (ꢀ
9
(
ꢀ
8 (
Of particular use would be a system in which two or more conformational equilibrium must be biased toward the p–Cl
H–bond donors could be compared directly, giving internally NH. Using the chemical shifts of these resonances the
consistent experimental evidence of the relative H–bond equilibrium ratio is estimated to be 1.43:1 toward the chloride
strengths. We recently reported the synthesis of molecular substitution (Fig. 2, Eq. 2). The equilibrium ratio is related to
switches based on a diphenylacetylene (DPA), or tolan(e), the free energy difference of the two states by Eq. 3, in this
scaffold26 in which the relative HB strength of two amide NHs case indicating
a
free energy difference for the two
mol-1.
is the key determinant of conformation (Fig. 1d).27–31 conformations of 0.21 kcal
Experimental32,33 and computational34–40 methods are
⋅
Δꢂ = ꢀꢃꢄ ꢅꢆ(ꢇꢈꢆꢉꢈꢊꢋꢌꢍꢎꢈꢆꢌꢅ ꢊꢌꢍꢎꢈ)
(Eq. 3)
consistent with a small barrier for the relative rotation of two
phenyl rings about an acetylene ( 0.6 – 0.8 kcal
mol-1 at room Free energy differences for compounds
temperature), and single crystal X-ray diffraction indicate a using this method (Table 1, column 7).†
≈
⋅
2
–
7
were estimated
Fig. 2 Molecular balance 1, with 50 % 8, and 0 % 9
, control compounds. Inset: 1H
separation of 3.0 – 3.2 Å between nitrogen and oxygen for the
N-H••O=C HB arrangement of a 2,6–difunctionalised scaffold.
Whilst our previous work focussed on the use of external
stimuli to moderate HB donor ability, and thus elicit large
changes in conformational ratio, the system also has potential
as a molecular balance for the direct measurement of relative
HB strength. Through comparison of variously functionalised
amides (Fig. 1d, R1/R2) there is scope to unravel structural and
conformational determinants. Following Wilcox’ seminal
development of a molecular torsion balance,41 Diederich,42,43
Cockroft,44,45 and others,46 have shown that single molecule
systems offer fundamental insights into various non–covalent
interactions in molecular recognition events.
• 50 % Control
O
O
O
O
N
H
N
H
O
•
1H NMR of N-H
MeO
OMe
OMe
OMe
8
OMe
8
1
• Balance
O
N
H
N
H
O
Cl
1
OMe
In order to test this hypothesis we set out to derive free
energy differences from the conformational ratios of: (i) our
previously published molecular switches; and (ii) expand the
data set by synthesising and evaluating a library of novel
compounds.
9
• 0 % Control
O
N
H
N
H
Cl
δ 50%
δ 50%
- δ
% H-bond preference =
(Eq. 2)
-
δ 0%
9
Results and discussion
O
OMe
A
series of DPAs incorporating
withdrawing and electron–donating groups in positions R1 and
R2 (balances
), along with 0 % and 50 % control
a variety of electron–
NMR conformational analysis. Unambiguous assignment of NH 1H signals was
performed by interpretation of nOe correlations with aryl ortho–hydrogens
relative to the carbonyl group of the benzamide.27
1
– 7
compounds, were synthesised according to previously
described methods (Table 1, columns 1–3).27,28,† Taking
In addition to the experimentally derived free energies, the
molecules can also be described using various series of
tabulated values of acidity or HB strength. For example, Δσp
gives the difference between the Hammett descriptor values
of R1 and R2 (Fig. 1, and Eq. 4).
balance 1
(R1 = Cl, R2 = OMe) as an example, the solution phase
conformational ratio is estimated by comparing the 1H NMR
amide NH resonances with those of two control compounds
(Fig. 2). Control compound
8 juxtaposes the two p–methoxy–
benzamides, and due to the symmetry of the system, the H–
bond acceptor partitions equally between the two NH donors.
Thus the amide resonance should estimate the chemical shift
ꢒ
ꢓ
Δꢏꢐ = ꢏꢑ ꢀ ꢏꢑ
(Eq. 4)
2 | Org. Biomol. Chem., 2017, 00, 1-3
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PAPER
Table 1 Calculated values for variously substituted diphenylacetylene molecular balances: Δ σp (pKa), Δ σp
(
19F), Δ log KAH; and Δ G values based on 50 % and 100 % controls.
H
ꢀ σp (19F)
– 0.42
– 0.40
0.00
ꢀ log KA
ꢀ G (50 %)
– 0.17
– 0.03
0.00
ꢀ G (100 %)
– 0.16
– 0.10
0.00
Balance
R1
NMe2
OMe
H
R2
H
ꢀ σp (pKa)
– 0.83
– 0.27
0.00
2
3
4
5
1
6
7
Not reported
– 0.11
H
H
0.00
H
Cl
+ 0.23
+ 0.50
+ 0.78
+ 1.05
+ 0.21
+ 0.61
+ 0.75
+ 1.15
+ 0.34
+ 0.17
+ 0.21
+ 0.37
+ 0.44
+ 0.24
+ 0.22
+ 0.45
+ 0.59
OMe
H
Cl
+ 0.45
NO2
NO2
+ 1.05
OMe
+ 1.16
Table 1 gives the calculated Δσp values using benzoic acid
Hammett parameters, Hammett parameters calculated using
19F chemical shifts of substituted 1–fluorobenzene,48 and
H
log KA values from p–substituted phenols (columns
4 – 6
).19
The experimentally derived equilibrium ratios are strongly
correlated to the aqueous Hammett Δσp values (r2 = 0.97), 19F–
derived values measured in organic solvent (r2 = 0.93), and for
H
Δ log KA measurements (r2 = 0.99, Figs. 3a–c).§ This indicates
that in this system, HB strength among the homologous series
of donors is highly correlated with metrics of Brønsted acidity.
R1
• 100 % Control
HN
O
O
δ
-
δ 0%
N
H
O
% H-bond preference =
(Eq. 5)
δ 100% δ 0%
-
R2
OMe
Fig. 4 Conformational analysis using a 100 % control compound.
Whilst the 0 % and 50 % control compounds appear to
perform well, in order to exclude the possibility that the close
correlation exhibited with Hammett parameters (Fig. 3) was
due to fortuitous error cancellation, or unforeseen
interference with our NMR assay, an alternative 100 % control
molecule was designed and synthesized (Fig. 4). This molecule,
which replaces the 50 % control, has similar electronic
characteristics, but a markedly different conformation.
The R1
benzamide group is positioned para to the alkyne linkage,
leaving only the benzamide R2–functionalised donor available
for HB formation. Using this control, the conformational ratio
can then be determined by observing the amount a given NH
resonance has shifted downfield of the 0 % control toward the
100 % control (Fig. 4, Eq. 5). The corresponding 100 % controls
Fig. 3 Correlation between experimentally observed conformational free energy
differences of variously substituted molecular balances with descriptors from: (a)
aqueous Hammett ionization ratios; (b) 19F NMR shifts; (c) 1:1 H–bond complex
formation in carbon tetrachloride.
for compounds 2, 3, 5 – 7 were used to determine new free
energy differences (Table 1, column 8. See supplementary
information Chapter 4 for spectra and tabulated data of
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conformational ratios).† While the 50 % and 100 % data are state.27,28,30 In keeping with these values newly acquired
similar for and , 100 % controls give slightly larger values for diffraction data for and have dihedrals of 34 ˚ and 36 ˚
and . Despite this increase these new values produce a respectively (Fig. 6). Balance , in which p–H competes with
1
2
3
4
3
5
–
7
3
similar correlation with the reported descriptors (Fig. 5).
p-OMe, is a particularly interesting case in that the solid–state
conformation adopted is opposite that of the solution–phase.
Table 2 Inductive and mesomeric components of Hammett parameters for para–
substituted benzoic acids.48
para–Substituent R
H
Cl
NO2
NMe2
+ 0.17
– 0.56
OMe
+ 0.30
– 0.43
σI
0.00
0.00
+ 0.43
– 0.16
+ 0.64
+ 0.16
σπ
A plausible hypothesis is that attenuation of the mesomeric
contribution (σπ) for p–OMe due to sterics leads to a superior
H–bond donor relative to p–H through the operation of
inductive effects (σI), albeit by a small margin. This is
consistent with the comparable magnitudes, and opposite in
sign, of the mesomeric and inductive components for p–OMe
(Table 2).48
O
O
O
O
N
H
N
H
O
N
H
N
H
O
OMe
OMe
OMe
3
4
34°
36°
2.3
2.4
Fig.
6
The solid–state structures of balances
3
and
4
(CCDC 871789 and
871790).† The measured carbonyl–aryl dihedral angles are illustrated in blue on
the structural formulae and the values are shown in red next to the diffraction
images. The black dashed lines and black labels give H–bond lengths in Å.
To gain insights into the contrasting behaviour between
solid– and solution–state data we sought a method to
determine the effect of dihedral angle on H–bond strength in
the solution phase. The ionization energies of para–
substituted benzoic acids were determined using the high–
level composite CBS–QB3 quantum chemical method.49,† The
deprotonation energies for p–substituents H, Cl, NO2, NMe2,
and OMe were calculated as a function of the dihedral angle
between the carboxyl group and the aryl ring (Fig. 7, Table 3).
The results do not appear to fit a simple function, but instead
show very little variation in deprotonation energy until 40˚ is
reached, at which point the energy difference becomes more
pronounced. For example, the electron donating
Fig. 5 Correlation between the observed conformational free energy difference
of molecular balances using the 100 % control molecules with descriptors from:
(a) aqueous Hammett ionization ratios; (b) 19F NMR shifts; (c) 1:1 H–bond
complex formation in carbon tetrachloride.
The level of correlation between free energies derived
from conformational ratios and thermodynamic parameters is
noteworthy given the steric clash inherent in H–bonding
between the methyl benzoate and the benzamide ring
(Fig. 1d). This rotation might be expected to reduce the π–
overlap (σπ) between the para–substituent and the amide
carbonyl, and thus impact HB donor ability. However, the data
fit very well to the unscaled, planar Hammett descriptors.
Previously reported dihedral angles between the carbonyl
and aryl groups range between 36 ˚ and 52 ˚ in the solid–
dimethylamino substituent of
difference of – 3.23 kcal
mol–1 at 70˚ between the neutral and
deprotonated forms. The methoxy substituted molecule has a
+ 0.52 kcal
mol–1 energy difference relative to benzoic acid at
2 experiences a maximal energy
⋅
⋅
90˚, but intriguingly only a + 0.08 kcal⋅
mol–1 difference at the
maximum crystallographically observed 50˚ dihedral.†
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O
O
comes from solid–state data obtained for mono–substituted
benzamide 10, in which hydrogen bonding to the aniline is
preferred over the potentially superior benzamide donor
(Fig. 8).
- H
OH
O
+ H
R
R
Fig. 7 Calculation of deprotonation energy for para–substituted benzoic acids as
a function of dihedral angle (indicated in blue). See also Table 3.
Conclusions
Table 3 Calculated deprotonation energies for para–substituted benzoic acids as
Computation, solid–, and solution–phase conformational
analysis demonstrate that a simple molecular balance based
on a 2,6–disubstituted DPA allows direct comparison of HB
strength in aryl amides. An operationally quick and
a function of dihedral angle relative to the planar conformation.
ꢀE / kcal•mol-1, para–substituent R
Dihedral
angle
0
H
Cl
NO2
NMe2
OMe
0.00
1
0.00
0.00
0.00
0.00
straightforward H NMR assay in organic solvent, using one of
10
20
30
40
50
60
70
80
90
– 0.01
– 0.03
– 0.08
– 0.18
– 0.97
– 0.59
– 0.96
– 1.19
– 1.25
– 0.01
– 0.03
– 0.09
– 0.23
– 1.00
– 0.58
– 0.98
– 1.22
– 1.26
+ 0.02
– 0.09
– 0.24
– 0.47
– 1.36
– 1.11
– 1.44
– 1.70
– 1.66
– 0.34
– 0.42
– 0.64
– 0.96
– 1.95
– 1.83
– 3.23
– 2.64
– 1.19
– 0.01
– 0.03
– 0.09
– 0.22
– 1.05
– 0.84
– 1.25
– 1.64
– 1.77
two sets of control compounds, provides data that correlate
closely with tabulated parameters such as Hammett
substituent constants measured in physiologically relevant
aqueous media. An interesting insight gained from ab initio
calculations of p–substituted benzoic acid acidity was the
dependence of π–overlap on dihedral angle. For various
inductive and mesomeric groups the effect was small
(< 1 kcal⋅
mol–1) at angles of less than 40 ˚. The study also
sounds a cautionary note when inferring solution–phase
conformational preferences of H–bond systems from their
solid–state data. Whilst crystal–packing forces are frequently
cited as important determinants of solid–phase conformation
the underlying stereoelectronics are often difficult to unravel.
Future work will explore the extension of the balance to
aqueous solvents with heterocyclic, aliphatic and amino acid
derived amides.
The magnitude of values from the calculations suggests
that all dihedral angles are thermally accessible at room
temperature. Moreover the effect of rotating the benzamide
involved in the hydrogen bond is relatively constant, up to
approximately 40 ˚, despite a range of substituents. Thus this
small effect exists essentially as a constant in the linear free
energy relationships and is not large enough to significantly
bias the equilibrium conformational ratios of these molecules
(Table 1, Figs. 3 and 5). This hypothesis is supported by
previously reported studies on the 13C NMR substituent
chemical shifts (SCS) of 4–substituted–2,6–dimethyl
benzamides.50 Solid–state analysis of these dimethyl
benzamides shows that the aryl ring is rotated out of the
Experimental details
The synthesis and conformational behaviour, relative to 0 %
and 50 % controls, of 2, , 5 and 6 have previously been
4 ‡
reported.27,28 For full experimental details describing: (i) the
amide plane by
of conjugation.†
≈
56 ˚ and is accompanied by only partial loss
synthesis of precursors; (ii) the synthesis of 0 % and 50 %
control molecules for balances
3
and
7; (iii) the synthesis of
100 % control molecules for balances
1
–
3
and 5–7; (iv)
O
N
H
N
conformational analysis; and (v) computation, please refer to
the ESI.†
H
H
MeO
O
2.2
OMe
Synthetic procedures
Methyl 2–((2–(4–chlorobenzamido)–6–(4–methoxybenza–
10
mido)phenyl)ethynyl)benzoate (1). 4–Dimethylaminopyridi
–
ne (0.1 mg) was added to a solution of methyl 2–((2–amino–6–
Fig. 8 The solid–state structure of mono–substituted benzamide 10 (CCDC
1565855).† The black dashed lines and black labels give H–bond lengths in Å.
(4–methoxybenzamido)phenyl)ethynyl)benzoate 10† (100 mg,
0.25 mmol) in dichloromethane (0.05 M). Pyridine (23
The computational analysis (Table 3) is consistent with the mmol, 1.1 eq.) was added and the solution was stirred for 10
goodness of fit between our experimentally determined mins. Freshly prepared 4–chlorobenzoyl chloride S8† (71 L,
ꢁL, 0.28
ꢁ
conformational ratios in the solution–phase and unscaled 0.55 mmol, 2.2 eq.) was added dropwise over 1 min and the
Hammett data. Returning to the reversal of H–bond donor solution stirred for 18 h. The reaction mixture was poured into
preference in the solid–state for balance 3, in the absence of 2 N hydrochloric acid (10 mL), extracted with dichloromethane
aryl–carbonyl free rotation, attenuation of mesomeric (3 x 10 mL), and washed with 2 N sodium hydroxide (10 mL).
donation (σπ) likely leads to a slight preference in favour of The organic layers were dried over sodium sulfate, and
inductive withdrawal (σI) and thus the p–H substituted concentrated in vacuo
. The residue was purified by
benzamide becomes an inferior H–bond donor.51,52 Further recrystallization from refluxing acetonitrile/water to give the
evidence for the importance of sterics in H–bond preference title compound
1
as a white solid (90 mg, 0.27 mmol, 66 %):
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δH (400 MHz, CDCl3) 9.25 (s, 1H), 9.02 (s, 1H), 8.36 (d, J 8.3, (s, 3H); δC (101 MHz, CDCl3) 166.2, 164.8, 164.2, 163.0, 139.8,
1H), 8.32 (d, J 8.3, 1H), 8.10 (d, J 7.8, 1H), 7.96 (d, J 8.8, 2H), 139.2, 138.8, 133.2, 131.5, 131.2, 131.0, 130.2, 129.4, 129.0,
7.93 (d, J 8.5, 2H), 7.60 (d, J 4.0, 2H), 7.49 (m, 2H), 7.44 (d, J 128.5, 126.9, 125.9, 115.4, 115.1, 113.3, 103.4, 101.8, 83.1,
8.4, 2H), 6.98 (d, J 8.7, 2H), 3.89 (s, 3H), 3.52 (s, 3H); δC (126 55.7, 52.7;HRMS (ESI): found 539.1372; C31H23ClN2O5 [M + H]+
MHz, CDCl3) 165.6, 165.5, 165.4, 162.7, 140.3, 140.1, 138.0, requires 539.1368.
133.9, 133.1, 132.6, 131.2, 131.1, 130.3, 129.5, 129.4, 129.0,
128.7, 127.4, 123.1, 115.2, 115.2, 113.9, 102.88, 102.4, 86.0, ethynyl)benzoate (10).‡ N–(3–amino–2–iodophenyl)–4–met
77.4, 77.2, 76.9, 55.6, 52.1; HRMS (ESI): found 539.1359; hoxybenzamide S5† (541 mg, 1.47 mmol) was added to a
C31H23ClN2O5 [M + H]+ requires: 539.1368.
stirred solution of methyl 2–ethynylbenzoate S6† (260 mg,
Methyl 2–((2–benzamido–6–(4–methoxybenzamido)ph– 1.62 mmol, 1.1 eq.) in anhydrous triethylamine (0.15 M) and
Methyl 2–((2–amino–6–(4–methoxybenzamido)phenyl)–
–
enyl)ethynyl)benzoate (3).‡ Based on the procedure for
1
,
N,N–dimethylformamide (0.15 M). The solution was degassed
by sparging with nitrogen for 10 mins after which copper(
methyl 2–((2–amino–6–(4–methoxybenzamido) phenyl)ethyn
–
I)
yl)benzoate 10† and benzoyl chloride S9† gave the title iodide (25 mg, 0.13 mmol, 10 mol%) and palladium(II) chloride
compound as a white solid (95 mg, 0.18 mmol, 70 %): H (500 bis(triphenylphosphine) (63 mg, 0.09 mmol, 6 mol%) were
3
δ
MHz, CDCl3) 9.21 (s, 1H), 9.06 (s, 1H), 8.32 (dd, J 4.9, 8.3, 2H), each added as a single portion. Following 2 h at 60 ˚C the
8.05 (d, J 7.9, 1H), 7.95 (dd, J 8.6, 9.8, 4H), 7.54 (m, 3H), 7.44 solution was allowed to cool, filtered over Celite™ and
(dd, J 7.4, 15.1, 4H), 6.94 (d, J 7.9, 2H), 3.86 (d, J 0.9, 3H), 3.44 concentrated in vacuo. The residue was purified by flash
(d, J 1.0, 3H); δC (126 MHz, CDCl3) 166.4, 165.7, 165.3, 162.7, column chromatography on silica gel (9:1 CHCl3/EtOAc) to give
140.4, 140.3, 135.4, 133.1, 132.5, 132.3, 131.9, 131.1, 131.0, the title compound 10 (472 mg, 1.18 mmol, 80 %) as a yellow
130.3, 129.6, 128.9, 128.6, 127.8, 127.5, 123.2, 115.2, 115.1, solid:
102.9, 102.4, 86.1, 55.5, 52.2; HRMS (ESI): found 527.1568; (d, J 8.7, 2H), 7.92 (d, J 8.3, 1H), 7.58 (d, J 7.6, 1H), 7.53 (t, J
C31H24N2O5 [M + Na]+ requires 527.1577.
7.5, 1H), 7.39 (t, J 7.6, 1H), 7.19 (t, J 8.2, 1H), 6.97 (d, J 8.7, 2H),
Methyl 2–((2–(4–methoxybenzamido)–6–(4–nitroben– 6.49 (d, J 8.1, 1H), 4.86 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H); C (126
zamido)phenyl)ethynyl)benzoate (7). Based on the procedure MHz, CDCl3) 165.9, 165.4, 162.5, 149.7, 140.2, 133.1, 132.4,
for , methyl 2–((2–amino–6–(4–methoxybenzamido)phenyl) 131.2, 131.0, 130.0, 129.4, 128.0, 127.9, 124.1, 113.9, 109.5,
ethynyl)benzoate 10† and 4–nitrobenzoyl chloride gave the 108.6, 101.4, 97.5, 87.9, 55.6, 52.4; HRMS (ESI): found
title compound
as a pale yellow solid (64 mg, 0.12 mmol, 47 401.1488; C24H20N2O4 [M + H]+ requires 401.1496.
%) after precipitation from refluxing acetonitrile/water:
H (400 MHz, CDCl3) 9.44 (s, 1H), 8.95 (s, 1H), 8.40 (d, J 8.4,
1H), 8.32 (dd, J 4.9, 11.7, 3H), 8.17 (m, 2H), 8.10 (d, J 7.8, 1H), The position of the conformational equilibrium exhibited by
7.96 (m, 2H), 7.60 (m, 2H), 7.51 (m, 2H), 7.00 (d, J 8.9, 2H), balances was examined by comparison of the position of
3.90 (s, 3H), 3.49 (s, 3H);
c (126 MHz, CDCl3) 165.6, 165.3, the 1H NMR signal corresponding to the R1 or R2 benzamide NH
δH (500 MHz, CDCl3) 8.96 (s, 1H), 8.06 (d, J 7.9, 1H), 7.95
δ
1
–
7
Conformational analysis
δ
1
– 7
δ
164.9, 162.8, 149.7, 141.2, 140.3, 139.9, 133.0, 132.8, 131.3, with its position in the corresponding 0 % and 50 % control
131.2, 130.4, 129.4, 129.2, 127.3, 123.6, 123.0, 115.6, 115.4, molecules (Eq. 2), or by comparison with the 0 % and 100 %
114.1, 103.0, 102.6, 85.8, 55.6, 52.2; HRMS (ESI): found control molecules (Eq. 5). See the ESI† for spectra.
550.1605; C31H23N3O7 [M + H]+ requires 550.1609.
CBS–QB3 quantum chemical method
Methyl 2–((2,6–bis(4–methoxybenzamido)phenyl)ethyn–
yl)benzoate (8). Based on the procedure for 1, methyl 2–((2– The protonated and deprotonated form of each carboxylic acid
were built in GaussView53 and analysed using a modredundant
optimization with the carbonyl dihedral angle fixed to the
amino–6–(4–methoxybenzamido)phenyl)ethynyl)benzoate 10
†
and 4–methoxybenzoyl chloride S3† gave the title compound
8
as a white solid (108 mg, 0.20 mmol, 81 %) following specified value relative to the plane of the phenyl ring.
recrystallization from refluxing acetonitrile/water:
MHz, CDCl3) 9.10 (s, 2H), 8.33 (d, J 8.3, 2H), 8.11 (d, J 7.7, 1H), composite CBS–QB3 method49 using the default parameters in
7.97 (d, J 8.8, 4H), 7.65 – 7.56 (m, 2H), 7.49 (t, J 5.4, 2H), 6.97 Gaussian09.54,†
δH (500 Calculations were performed in the gas phase using the
(d, J 8.8, 4H), 3.89 (s, 6H), 3.55 (s, 3H); δC (101 MHz, CDCl3)
165.7, 165.4, 162.6, 140.3, 133.1, 132.6, 131.1, 131.0, 130.3,
129.6, 128.9, 127.5, 123.2, 114.9, 113.8, 102.8, 102.2, 86.1,
55.6, 52.2; HRMS (ESI): found 535.1857; C32H26N2O6 [M + H]+
requires 535.1864.
Acknowledgements
We thank the University of Oxford, the Marshall Aid
Commemoration Commission, and Oriel College for funding.
This research utilized the high–performance computational
capabilities of the Biowulf Linux cluster at the National
Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov).
Dr Mark E. Light (University of Southampton) is gratefully
acknowledged for assistance with x–ray crystallography.
Methyl 4–((2–(4–chlorobenzamido)–6–(4–methoxybenza–
mido)phenyl)ethynyl)benzoate (9). Based on the procedure
for
ethynyl)benzoate S13† and 4–chlorobenzoyl chloride S8† gave
the title compound as a yellow solid (70 mg, 0.13 mmol, 52
%): H (500 MHz, CDCl3) 8.65 (s, 2H), 8.38 (d, J 8.3, 1H), 8.32 (d,
1, methyl 4–((2–amino–6–(4–methoxybenzamido)phenyl)–
9
δ
J 8.3, 1H), 8.13 (d, J 8.0, 2H), 7.91 (dd, J 8.5, 11.5, 4H), 7.60 (d, J
8.0, 2H), 7.50 (d, J 8.6, 3H), 7.00 (d, J 8.4, 2H), 3.98 (s, 3H), 3.91
6 | Org. Biomol. Chem., 2017, 00, 1-3
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‡
The X–ray data for 3, 4, and 10 has been deposited in the Cambridge
Crystallographic Data Centre (CCDC 871789, 871790 & 1565855).
§ The value for NMe2 was not reported and thus the fit is through one fewer
point.19
§§ Chloro was not reported.
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