Computational and DNMR Analysis of the Conformational Isomers and Stereodynamics of Secondary 2,2′-Bisanilides

Article abstract of DOI:10.1021/acs.joc.5b02330

The conformational preference of 2,2′-bisanilides was investigated by variable-temperature NMR spectroscopy, NMR titration and diffusion experiments, IR spectroscopy, computational analysis, and X-ray crystallography. The formation of a conformation havin

Full text of DOI:10.1021/acs.joc.5b02330

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Article
Computational and DNMR Analysis of the Conformational
Isomers and Stereodynamics of Secondary 2,2’-Bisanilides
Andrea Mazzanti, Michel Chiarucci, Luca Prati, Keith W Bentley, and Christian Wolf
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02330 • Publication Date (Web): 10 Dec 2015
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Computational and DNMR Analysis of the Conformational Isomers and
Stereodynamics of Secondary 2,2’-Bisanilides
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†
†
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‡
‡
Andrea Mazzanti,* Michel Chiarucci, Luca Prati, Keith W. Bentley, Christian Wolf*
†
Department of Industrial Chemistry “Toso Montanari”. University of Bologna,
Viale Risorgimento 4, I-40136 Bologna, Italy. andrea.mazzanti@unibo.it
‡
Department of Chemistry, Georgetown University,
Washington, DC 20057, USA. cw27@georgetown.edu
Abstract
The conformational preference of 2,2’-bisanilides were investigated by variable temperature
NMR spectroscopy, NMR titration and diffusion experiments, IR spectroscopy, computational analysis
and X-ray crystallography. The formation of a conformation having the two amide moieties linked by
an intramolecular hydrogen bond was detected at low temperatures. The interconversion kinetics of the
two conformational species of bisanilide 2 were determined by NMR lineshape analysis. The formation
of a supramolecule linked by intermolecular hydrogen bonds was ruled out by means of DMSO
titration, DOSY experiments and steric considerations.
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INTRODUCTION
The structural diversity and unique dynamic stereochemistry of amides continues to attract
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widespread attention among medicinal and synthetic chemists. The control of steric interactions and
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stereoelectronic forces that affect the conformational bias of tertiary amide units in peptoids, e.g. non-
natural peptide analogues consisting of N-substituted glycine monomers, is essential for manipulating
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backbone folding and chiral amplification processes of these and other important peptidomimetics.
The E/Z-isomerism and atropisomerism of tertiary benzamides, naphthamides and other structural
analogues showing restricted rotation about the aryl-carbonyl bond have been studied by Clayden,
Walsh and others and are well known to play important roles in asymmetric synthesis, medicinal
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chemistry and chiral amplification processes. For similar reasons, Curran and others have investigated
the relative stability and interconversion of rotational conformers and E/Z -isomers of tertiary anilides
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in great detail. Despite the remarkable utility of secondary anilides as auxiliary groups in asymmetric
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synthesis, the dynamic stereochemistry of this structural motif remains largely unexplored.
Figure 1. Comparison of the structure of 2,2’-binaphthalene-1,1’-diol diisobutyrate, 1, and structural
analogues 2-10 investigated herein.
We recently reported that 2,2’-binaphthalene-1,1’-diol diisobutyrate 1 shows a complex
stereodynamic behavior due to hindered rotation about the central naphthyl-naphthyl axis and the two
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aryl-ester bonds. The latter process results in the formation of three conformational diastereoisomers
when the rotation about the stereogenic aryl-aryl axis is blocked. At the outset of our investigation, we
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speculated that the secondary bisanilide 2 and analogues thereof would have similar stereochemical
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properties (Figure 1).
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RESULTS AND DISCUSSION
When initial NMR analysis of 1,1’-biphenyl-2,2’-diamine diisobutyramide, 2, was performed
2 2
between 25 °C and -99 °C using CD Cl as solvent the expected lineshape evolution for the isopropyl
signals was not observed. Although the two anisochronous doublets corresponding to the diastereotopic
methyls of the isopropyl group clearly indicate that the rotation about the aryl-aryl bond is slow on the
NMR timescale at ambient temperature, we did not detect any conformational diastereoisomer due to
hindered rotation about the N-aryl bond under cryogenic conditions. The multiplicity of the two methyl
signals and of the isopropyl CH septet remains unchanged upon cooling to -78 °C. When the sample
was cooled to -99 °C a series of new signals arose in both the aliphatic and aromatic regions of the
spectrum. In particular, at least 4 new broad peaks emerged between 4 and 10 ppm (Figure S1 in the
Supporting Information). Because it seemed unlikely that this could be attributed to dynamic exchange
of conformational isomers, further investigations were carried out to elucidate the nature of this
unexpected behavior.
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Additional H-NMR spectra of 2 were then recorded at lower temperature using a mixture of
2 2
CDFCl :CDF Cl (5:1 v/v) as solvent (Figure 2). Again, at -107 °C a new set of signals between 4 and
10.5 ppm emerged at once from the baseline without any heavy broadening effect on the other NMR
signals already present. No significant changes were observed when the sample was further cooled to -
1
39 °C. In spite of extensive overlap of the broad signals, a close inspection of the aliphatic region in
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the H NMR spectrum suggested the presence of two species in approximately 4:1 ratio, the major one
displaying four CH
S2 in the SI).
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and two CH signals and the minor showing two CH and one CH signals (Figure
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Figure 2. Temperature dependence of the H NMR spectra of 2 (600 MHz in CDFCl
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/CDF
2
Cl 5/1 v/v
Given the low polarity of the Freon mixture, a new set of spectra was acquired in a 50 mM
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sample of 2 in CDFCl
2
/CDF
2
Cl containing 50 µL of CD
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OD (about 3 eq). When the sample was
cooled, no significant variations were observed in the NMR spectra until -128 °C, and at -139 °C the
same set of new signals appeared between 5 and 10 ppm (Figure S3 in the SI). However, the second set
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of signals emerged at lower temperature with respect to the sample without CD OD. This suggests that
the presence of methanol alters the equilibrium between the distinct species of 2 which ultimately leads
to the appearance of the second set of signals. The VT-NMR experiments were also repeated in a more
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dilute solution (25 mM) with or without addition of CD OD, but appreciable variations were not
observed. When a very diluted sample (2 mM) was cooled to -140°C, the second set of signals was still
present, albeit with a lower intensity (see Figure S4 in the SI). In this case, however, any trace of
moisture present in the solvents can alter the equilibria at a great extent (see titration section below) A
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lineshape simulation of the more concentrated sample was performed in the -97 to -107 °C temperature
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range by considering two identical rate constants that exchange the single signal of the C conformation
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into the two signals of the C
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conformation. (see Figure S5 in the SI). Assuming reversible first-order
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reaction kinetics, we obtained three rate constants (70, 35, and 15 s ) corresponding to an activation
energy of 8.6 ±0.2 kcal/mol. Although the temperature range investigated was small, there is no
≠
evidence of a noticeable ΔS . On the contrary, the relative ratio between the two conformations changes
with the temperature and linear regression analysis was performed to determine ΔH° as -4.1 kcal/mol
2 1
and ΔS° as -25 cal/mol K for the interconversion of the C conformation to the C species (see Figure
1
0
S5 in the SI).
The same experimental NMR results discussed above for 2 were obtained with the secondary
amides bearing the trifluoromethyl, phenyl and methyl groups (3-5, see Figure S6 in SI). On lowering
the temperature, a new set of signals emerged with chemicals shift pattern very similar to that observed
for the isopropyl analogue 2. However, the ratio between the two species varied within the series of 2-5
with the methyl derivative 5 showing the smallest amount of the asymmetric species.
Figure 3. X-ray structures of bisanilides 2 and 5. Distances in Å.
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Single crystals of compound 2 suitable for X-ray diffraction were grown from slow evaporation
of a chloroform solution, and crystals of 5 were obtained from an acetonitrile solution. In both cases,
the solid-state structure shows the presence of an intramolecular hydrogen bond with global C
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symmetry (Figure 3), as well as an intermolecular H-bond with the neighboring molecules forming an
infinite chain (Figure S7 of SI).
Figure 4. X-ray structure of bisanilide 3. The numbers in italics measure the H-N-C2-C1 dihedral
angles of the two different conformations.
In contrast, the X-ray structure of bisanilide 3 (crystals obtained from chloroform, Figure 4)
2
showed the existence of two different C conformations with an intermolecular hydrogen bond
connecting the CO with the NH of the neighbor molecules (see Figure S7 of SI). In the two
conformations the disposition of the amide moiety is largely different. In one conformation the H-N-
C2-C1 dihedral angle is 31.4° while it is -121.7° in the other. This different disposition allows for the
formation of intermolecular hydrogen bonds only. It is evident that the conformational preference in
the solid state is driven by minute energy differences, and crystal packing forces can play a decisive
role.
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Two scenarios should be considered to rationalize the experimental data obtained in solution.
First, the formation of an intramolecular hydrogen bond (as in the X-ray structures of 2 and 5) results in
molecular asymmetry which affords two methine signals and four methyl signals in the case of 2, as
well as eight signals for the aromatic hydrogens. Based on this hypothesis, the predominant set of
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signals observed at low temperature for compounds 2-5 should be assigned to the C
1
conformation
found in the solid state. Second, the appearance of new signals at low temperatures could be a result of
1
1
the formation of a dimeric structure, as previously reported for a series of biphenyl carbinols. The
presence of a dimer of 2 in solution could explain the main set of signals observed at -128 °C (two
isopropyl CH signals with the same intensity) and the co-existence of monomeric 2 could afford the
second set of signals (one CH and two methyls). Compounds 2-5 contain two identical amide moieties
that can act both as hydrogen bond donor and acceptor, and the differentiation between the two
scenarios is not straightforward. As a first consideration, we point out that the X-ray structures of 2, 3
and 5 do not show dimers in the solid state, while in the case of biphenyl carbinols the dimeric
structures observed in solution were experimentally observed also in the solid state. To obtain more
information about the present case we designed a set of theoretical and experimental analyses.
Theoretical analysis
A theoretical investigation of compound 2 using B3LYP/6-31G(d) suggested that in the most
stable conformation, hereafter named C
yielding global C symmetry. The carbonyl groups point towards the aromatic hydrogen adjacent to the
amide unit (H3) and do not undergo hydrogen bonding with the NH belonging to the other ring (Figure
5). A conformation close to that observed in the crystal (hereafter named C -H-bond) was validated as
2
-NH-in, the amide moieties lie in the plane of the phenyl rings,
2
1
a local minimum about 2 kcal/mol higher in energy. The same situation occurs for compound 5, where
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the C
2
-NH-in is calculated to be more stable than C
1
-H-bond by 2.8 kcal/mol, and by 12.0 kcal with
respect to the other C
2
conformation (C
2
-NH-out hereafter).
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Figure 5. The two most stable conformations of compound 2 calculated at the B3LYP/6-31G(d) level.
Distances in Å.
Table 1: Computational data for the two most stable conformations of 2. The same 6-31G(d)
basis set was employed in the calculations.
ΔE
kcal/mol)
ΔH°
(kcal/mol)
Conformation
Method
Energy (a.u.)
H° (a.u.)
(
C
2
-NH-in
B3LYP
B3LYP
-1036.596083
-1036.591816
-1036.185695
-1036.185473
-1036.281224
0.00
2.68
0.00
0.13
0.08
0.00
-1036.164819
-1036.161215
-1035.751855
-1035.752128
-1035.845280
-1035.846213
0.00
2.26
0.17
0.00
0.58
0.00
C
1
-H-bond
C
2
-NH-in
M06-2X
M06-2X
ωB97XD
ωB97XD
C
1
-H-bond
C
2
-NH-in
a
C
1
-H-bond
-1036.281361
_
___________________
a
2
This structure converged to C symmetry with a biphenyl torsion angle of 66°.
However, when a different theoretical level such as M06-2X/6-31G(d,p) was employed for
optimization, the two conformations have essentially the same energy (see Figure S8 in SI), and at the
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ωB97XD/6-31G(d,p) level the C
1
-H-bond conformation is not a minimum of energy (optimization
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starting from the M06-2X optimized geometry reverted to C -NH-in geometry) as summarized in
Table 1. These striking results underscore the complexity of the stereodynamic behavior of 2.
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At this point, X-ray analysis of 2 revealed that the most stable conformation in the solid state features
C
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2
symmetry and an intramolecular hydrogen bond, whereas the conformation C -NH-in emerged as
the most or exclusively populated species according to B3LYP/6-31G(d) and ωB97XD/6-31G(d)
1 2
computations, while M06-2X calculations suggest that the C -H-bond and the C -NH-in
conformations should have similar stabilities.
Figure 6. Optimized structures of the dimers of 2. Distances in Å. Optimization at the B3LYP/6-
3
1G(d) level. Except for the NH, all the hydrogens were removed for clarity.
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If we consider the formation of dimers, two kinds of structures should be discussed. Due to the
stereogenic aryl-aryl axis, the dimer can be built using two molecules with the same axial chirality
(“homodimer”) or from two molecules with opposite chirality (“heterodimer”). In the first case the
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whole symmetry can be C or C , whereas in the second case the symmetry can be C or C
2
1
i
s
.
Two stable dimeric structures (frequency calculation displayed no imaginary values) were obtained for
both cases (Figure 6), with very similar energies. At the B3LYP/6-31G(d) level, the heterodimer is
more stable by 0.5 kcal/mol (as ΔH°) while the M06-2X/6-31G(d) level computation favors the
i 2
heterodimer by 2.7 kcal/mol (as ΔH°). The heterodimer features C symmetry and the homodimer is C
symmetric. Both structures are in agreement with the NMR analysis showing four signals for the
isopropyl methyl groups. Due to the different local environment, there are two different isopropyl
groups for each molecule, each one related to another by the inversion center or by the rotation axis.
Taking into account the intrinsic diastereotopicity of the isopropyl methyls, a total of four signals for
the methyl and two signals for the methine groups is expected, as was observed experimentally.
2
The individual conformation of the two molecules of the heterodimer resembles that of the C -NH-in,
the aryl-aryl torsion angle being 113°. Two NH moieties are nearly coplanar with the aryl rings,
whereas the remaining two are slightly out-of-plane to accommodate a better geometry for the
hydrogen bond (skew angle = 21°). The homodimer is composed of two molecules with similar
conformation and torsion angle (114°). The dimerization energy was evaluated using the counterpoise
1
2
correction suggested by Bernardi and Boys (see Table 2) it was found to be 6.8 kcal/mol for the
heterodimer and 5.0 kcal/mol for the homodimer (21.3 and 18.3 kcal/mol at the counterpoise-corrected
M06-2X/6-31G(d) level). Within the dimeric structure, the two NMR signals at 4.5 and 9.9 ppm could
be correlated to the two pairs of NHs, with the signal at 9.9 ppm corresponding to the pair involved in
1
3
the intermolecular hydrogen bond , and that at 4.5 ppm assigned to the remaining pair of free NH
groups that are shielded by the phenyl ring currents. Although we could not obtain experimental
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3
support for the assignment of these two signals (HSQC is unfeasible at -140°C), the averaged chemical
shift of these signals (7.2 ppm) is in very good agreement with the higher temperature shift of the NH
units (7.0 ppm at -50 °C)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The dimerization energies for 3-5 were also calculated at two different level of theory taking into
account the intrinsic BSSE error by the counterpoise correction (Table 2). The energy gain for
dimerization (EDim in Table 1) favors the formation of the heterodimer in all cases. This is most
probably due to the smaller distortion required to the two monomers to get a favorable interaction
between the NH and C=O in the heterodimer. On the contrary, the trend of the relative energies
calculated for the dimers (as global optimization of the supramolecule) is not constant.
Table 2. Summary of dimers energies and dimerization energies for 2-5. Dimerization energies
E
Dim were calculated with counterpoise correction (all energies are in kcal/mol).
B3LYP/6-31G(d)
Heterodimer Homodimer
M06-2X/6-31G(d)
Heterodimer Homodimer
E
E
Dim.
E
E
Dim.
E
E
Dim.
E
E
Dim.
2
3
4
5
0.00
0.75
5.55
0.00
-6.8
-5.5
-4.3
-8.6
0.50
0.00
0.00
2.03
-5.0
-0.6
-1.6
-6.4
0.00
0.54
0.31
0.00
-21.3
-17.2
-24.0
-18.0
2.67
0.00
0.00
1.16
-18.3
-13.1
-17.7
-17.8
3
The homodimers of compounds 3 and 4 (CF and phenyl) were calculated to be more stable than the
heterodimers at both levels of theory. This effect is probably due to the larger BSSE error evaluated for
the homodimer and to the greater distortion of the two monomers to reach a geometry suitable for the
formation of the dimer.
Albeit the large dimerization energy calculated with M06-2X could suggest that the hypothesis of a
dimerization process should be favored over that of the formation of an intramolecular hydrogen bond,
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the inconsistent trend observed for compounds 2-5 and the huge difference in the dimerization energies
determined by the two methods did not allow for a reliable interpretation.
As an additional way to rationalize the experimental NMR results, we calculated the chemical shifts of
the two monomeric conformations of 2 and of the two dimers (Table 3). Calculations were run at the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
GIAO-B3LYP/6-311++G(2d,p)//B3LYP/6-31G(d) level of theory. In the case of the C
conformation the chemical shift difference between the two NH units is larger than in the case of the
dimers. In absolute terms, the chemical shift of the free NH in the C -H-bond conformation is more
1
-H-bond
1
shielded than that of the free NH in both dimers. If the chemical shift of the hydrogen ortho to the
carbonyl (H-3) is considered, it is worth to note that the conformations of the dimers have all carbonyl
groups arranged almost coplanar to the aryl rings, and the proximity of the carbonyl group should move
the H-3 signal downfield. Calculations support this hypothesis and suggest a chemical shift difference
1
of 0.5 ppm. On the contrary, the calculated chemical shift difference for the C -H-bond conformation
is much larger (1.6 ppm). The observed upfield shift of the H-3 signal on lowering the temperature is
therefore more consistent with the formation of an intramolecular hydrogen bond.
Table 3. Summary of calculated chemical shifts for compound 2. Calculations at the GIAO-
B3LYP/6-311++G(2d,p)//B3LYP/6-31G(d) level. Reported chemical shift are related to that of
TMS calculated at the same level of theory.
NH
8.1
6.7
8.7
8.2
NH’
6.5
6.7
7.5
7.5
H-3
9.0
9.5
9.5
9.0
H-3’
7.4
C
1
-H-bond
-NH-in
C
2
9.5
Heterodimer
Homodimer
9.0
8.5
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IR spectroscopy
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In a different attempt to elucidate the structure of the main species we resorted to IR
spectroscopy. Because of the much faster timescale compared to NMR spectroscopy, a high-resolution
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
IR spectrum of compound 2 dissolved in CDCl
3
was acquired with the aim to detect, either in the NH-
or in the CO-stretching region, separated signals for the two conformations observed by NMR at low-
-
1
temperature (Figure 7). Interestingly, the NH region of the spectrum exhibits a sharp band at 3415 cm
-
1
accompanied by a broad band at lower frequency (3340 cm ). Although the shape of the bands in this
spectral region may be strongly affected by the presence of water or by the concentration of the sample,
similar results have been attributed to an equilibrium between amides not involved in hydrogen
-
1
bonding (sharp band above 3400 cm ) and amides exhibiting hydrogen bonding (broad band at 3300-
-
1 13
3350 cm ).
The IR spectrum of the C
1
-H-Bond conformation of 2 as well of the two dimers was calculated
1
4
at the B3LYP/6-31G(d) level of theory and the calculated frequency were scaled by 0.9614. For the
monomer, two strong IR absorbances were calculated for the NH stretching. The lower frequency
-1
absorption (3384 cm ) was calculated for the stretching of the NH moiety involved in the
-
1
intramolecular hydrogen bonding, whereas a higher frequency (3453 cm ) was obtained for the two
free NH units. This is in agreement with the experimental spectrum. Since the calculations correspond
to isolated molecules in the gas phase, any line-broadening contributions from solvent interactions are
not taken into account. However, the same kind of IR behavior can be rationalized with the presence of
two intermolecular hydrogen bonds (broad band) and of two free NH groups (sharp band) in the
dimeric structures (See Figure S9 in the SI for the simulations).
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Figure 7. Top: IR spectra of 2 in CDCl solution after solvent subtraction. Bottom left: IR Excerpt of
the N-H stretching region of the spectrum. Bottom right: Calculated IR spectrum of 2 for the same
spectral region at the B3LYP/6-31G(d) level.
NMR Titration experiments
To obtain additional data, we monitored changes in the δ-shift occurring when 2 was titrated
6
with DMSO-d . It is known that hydrogen bonding results in proton deshielding, thus the addition of
DMSO or another strong hydrogen bond acceptor should result in a downfield shift for an NH proton
that is available for hydrogen bonding with a polar solute. On the other hand, if a competing
1
5
intramolecular hydrogen bond already exists the downfield shift should be limited. When aliquots of
DMSO-d were added to a CDCl solution of 2 two signals were strongly shifted: the NH proton
6
3
moved downfield by more than 1 ppm and the H3 proton (located adjacent to the amide group in the
phenyl ring) was shifted upfield by 0.4 ppm (Figure 8). All other signals were not affected. These
results could be rationalized by a competition of DMSO with the exchanging hydrogen bonds, yielding
a conformational change. The upfield shift of the aromatic proton in position 3 (H3) suggests that, upon
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solvent complexation, the amide carbonyl moves out of the plane of the aryl ring and thus away from
H3.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Figure 8. Top. H NMR aromatic region of bisanilide 2 in CDCl
3
(600 MHz, 25 °C) obtained by
3
DMSO titration. The sample was prepared by dissolving 7.7 mg (23.8 µmol) of 2 in 0.6 mL of CDCl .
a) control spectrum b) 60 µL of DMSO added. c) 120 µL of DMSO added. The asterisks mark the
1
residual signal of CDCl3. Bottom: changes in the chemical shift of the H NMR signals of 2 during
DMSO titration.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In an attempt to model this behavior, DFT calculations were carried out by considering the
interactions with one and two explicit molecules of the hydrogen bond acceptor DMSO (Figure 9). Full
optimization was performed for the substrate-solute adducts and the stabilization energies due to the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
interactions were determined as the difference between the counterpoise corrected energy of the
complex and the sum of the energies of C
calculations confirmed that the C -H-bond conformation is stabilized by hydrogen bonding with a
solute molecule with respect to the free C -NH-in species, with stabilization energy higher than 8
kcal/mol. When two DMSO molecules were considered during optimization, the conformation of the
bisanilide displays C symmetry with the amides moved out of the plane by 38° and a stabilization
2
-NH-in and one or two isolated solute molecules. All the
1
2
2
energy of 16.4 kcal/mol (as counterpoise corrected value).
The interaction between DMSO and 2 and the modification of the amide disposition can explain
the shifts observed during titration. This seems to support the hypothesis that a strong intramolecular
hydrogen bond is responsible for the set of signals observed at low temperature.
Figure 9. Structures and stabilization energies of 2-solute complexes optimized at the B3LYP/6-
31G(d) level. The reference energy was that of C
2
-NH-in plus one or two isolated molecules of DMSO.
Distances in Å, energies in kcal/mol.
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5
To rationalize the experimental spectroscopic and crystallographic data obtained with 2, we
therefore suggest the model shown in Figure 10.
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 10. Proposed model to explain the dynamic behavior of 2 in solution.
The C
while the C
2
-NH-in conformation is stabilized by conjugation of the amide with the phenyl ring,
1
-H-Bond, found to be the most stable species in the solid state, is stabilized by
intramolecular hydrogen bonding. At room temperature the two species are in fast exchange and
contribute to an averaged NMR spectrum. On lowering the temperature, the exchange rate decreases
and the signals belonging to both conformations can be distinguished, which explains the appearance of
the new signals under cryogenic conditions. The fact that the peaks emerge at once from the baseline
rather than from a dynamic exchange of the existing signals can be explained by a large variation in the
population ratio of the two conformers as a function of temperature. If the two conformations have
similar enthalpies, entropic factors (and therefore temperature) may become important and greatly
affect the relative population. Because hydrogen bonding plays an important role here, the presence of
H-bond acceptors can affect the relative stability of the two conformations, which is evident from the
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
titration experiments with DMSO. When a strong acceptor is added it can interact with the free NH of
the C -H-Bond species or with one of the two free NH groups of the C -NH-in conformer. As the
1
2
amount of the hydrogen bond acceptor is increased, the solute can afford a second hydrogen bond
which ultimately leads to a bis-solute. In this case both carbonyls are displaced out of the phenyl plane,
thus explaining the large upfield shift experienced by H-3.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Within the series of compounds 2-5, the change in the ratio of the two species observed at low
temperature can be rationalized by the different interactions between the carbonyl residues and the
solvent additive. Hydrogen bonding interactions with DMSO may be more sterically hindered with
compound 2 bearing relatively large isopropyl groups, while this interaction with the acetyl derivative
5
is more accessible. With regard to dimerization, similar considerations should play a role. In this
case, the smaller the aliphatic residue next to the carbonyl function the larger should be the dimer
11
proportion, as experimentally observed in the case of biphenyl bis-carbinols. The opposite
experimental trend found with 2-5 could rule out the hypothesis of dimer formation at low temperature,
and supports the prevalence of a strong intramolecular hydrogen bond.
On the other hand, the formation of any hydrogen bond relies on a delicate balance of
conformational geometries that can arrange the amide groups in close proximity without substantially
raising the conformational energy. A close inspection of the X-ray structures of compounds 2 and 5
revealed that the aryl-aryl dihedral angles are 109.9° and 95.4°, respectively. We therefore speculated
that any interference due to other conformational constraints could greatly influence the intramolecular
hydrogen bonding interaction. To explore this matter we acquired variable temperature NMR spectra of
the tetra-ortho-substituted bisanilide 10, i.e. the atropisomeric analogue of compound 2. This secondary
amide can be prepared starting from enantiopure (M)-6,6’-dimethyl-2,2’-diaminobiphenyl, as well as
from the racemic precursor. The considerable steric repulsion between the ortho-substituents forces the
dihedral angle to approximately 90°, and significantly decreases the conformational flexibility
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3
compared to compounds 2-5. The increased rigidity poses more constraints to any interaction requiring
a modification of the aryl-aryl bite angle. Moreover, enantiopure 10 can be used to rule out the
feasibility of formation of a heterodimer.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 11. Low temperature spectra of (M)-10, showing the absence of additional signals at -140°C.
Spectra of racemic 10 are reported in Figure S10 of SI.
2
We found that the NMR spectra of a CDFCl sample of enantiopure (M)-10 were completely
different from those observed for compounds 2-5. The low temperature NMR analysis of (M)-10 did
not reveal any additional signals down to -140 °C. In fact, we observed only a large downfield shift of
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the amide proton while the neighboring hydrogen H3 moved upfield from 7.9 ppm to 7.3 ppm, crossing
with the NH signal (Figure 11). The very same behavior was obtained when a sample of racemic 10
was used (see Figure S10 of the SI). No additional signals were detected down to -140 °C, and the
same chemical shifting of the NH and H-3 signals occurred. However, when compared to compound 2,
the downfield shift of the NH signal is less pronounced, while the upfield shift of H-3 remains
comparable.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The dimerization energies for the hetero- and homodimer of compound 10 were calculated and
found to be 5.9 and 5.8 kcal/mol at the counterpoise-corrected B3LYP/6-31G(d) level (20.9 and 17.8
kcal/mol at the M062X/6-31G(d) level). Thus, calculations predict for the dimers of 10 the same
stabilization as for compound 2, while the experimental NMR of 10 at low temperature does not show
the second set of signals. This suggests again that the experimental results are more reliable than the
computational analysis and that dimerization does not take place. On the other hand, the absence of the
second set of signals can be explained by considering the same conformational change observed for 2.
In the case of compound 10, the constraints imposed by the fixed aryl-aryl angle impede the
accommodation of a geometry necessary for effective intramolecular hydrogen bonding. Because the
intramolecular hydrogen bond is diminished, the barrier for the interconversion falls below the limit of
the dynamic NMR technique. Accordingly, the spectrum observed at -140 °C can still be attributed to
1
fast dynamic exchange within the C -H-bond conformation. Unfortunately, spectra at lower
temperature could not be obtained due to crystallization of the compound.
NMR Diffusion experiments
2 2 4 3
DOSY spectra were acquired for compounds 2 and 10 in C D Cl that is in a solvent similar to CDCl
but with increased viscosity. The NMR spectra were collected with the BPP-STE sequence using an
array of gradient strength from 1 to 62 G/cm, and a diffusion delay of 50 ms. The residual signal of the
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solvent was used as internal standard to compare different spectra. Since the derived hydrodynamic
radius is related to the diffusion coefficient, the ratios of the diffusion coefficient of each compound vs
that of the solvent correspond to the relative ratios of the hydrodynamic radii between solute and
solvent. As the hydrodynamic radius of the solvent is the same, we can directly compare the radii of the
solutes. The derived hydrodynamic radius for 2, racemic 10 and for enantiopure (M)-10 were very
similar (SI). For the three compounds the ratio with the solvent radius is 2.30:1 (± 0.05), and was
almost invariant when more concentrated samples (10 times) were used. Since dimerization should be
favored at increasing concentration, these results further point to the importance of intramolecular
hydrogen bonding.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
3
3
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0
Comparison with tertiary amides
To further verify whether interactions involving the NH moiety are exclusively responsible for the
observed stereochemical behavior of secondary amides, we synthesized the tertiary amides 6-9. As a
1
representative example, the H NMR spectrum of the tertiary bisanilide 9 recorded in CDCl
3
at room
temperature shows a number of broad signals in both the N-Me and CH
3
CO regions corresponding to at
least three equilibrating species (Figure S11 in SI). While in secondary amides only the Z amide
conformer is usually populated, in tertiary amides both conformations are present. The three sets of
signals were therefore assigned to the three possible diastereoisomers generated by hindered rotation
around the two N-CO bonds. Two isomers with the same conformation of the partial double bond of
the amide moiety have global C
2
symmetry and can be referred to as ZZ-9 and EE-9. The third
conformation with global C
EZ-9.
1
symmetry displays opposite orientation of the two amides and is named
Single crystals of compound 9 were obtained by evaporation of an acetonitrile solution and the
X-ray structure confirmed the different conformational preference (Figure 12). In the solid state, a C
2
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5
5
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5
5
6
conformation is present, with both amides having E geometry. The dihedral angle C1-C2-N-CO is -
25.1° while the aryl-aryl torsion angle was determined as 70.0°.
1
0
1
2
3
4
5
6
7
8
9
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8
9
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3
4
5
6
7
8
9
0
Figure 12. X-ray structure of compound 9.
2 2
When a CDFCl /CDF Cl (5/1 v/v) NMR sample of 9 was analyzed at low temperatures, certain signals
further broadened and eventually split into a large number of peaks (Figure S12 in the SI), following
the classical evolution of a conformational exchange. The trend resembles what was observed for the
binaphthyl ester 1 and the new signals in the lowest temperature spectrum have been ascribed to a
number of diastereoisomers formed when the rotation about the two N-aryl bonds is frozen. From a
theoretical point of view, up to 9 different stereoisomers can be formed and up to 14 singlets in the N-
3
Me and 14 in the CH CO region should appear. For each diastereoisomer generated by the hindered
rotation about the N-CO bond (i.e. ZZ, EE, EZ) three possible orientations of the two amides can be
considered depending on the reciprocal orientation of the two N-Me (or C=O) groups (Figure S13 in
2 1
the SI). The ZZ and EE N-CO conformers yield two C and one C conformations each, thus a total of 8
signals are expected, while the EZ yields three C -symmetric conformers, corresponding to additional 6
1
lines. Unfortunately, partial signal overlapping and the presence of several conformers scarcely
populated made it difficult to establish with full accuracy the number of species present. Thus, the
stereochemical analysis of the tertiary anilides 6-9 confirmed that there is dynamic exchange between
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several conformational isomers due the perpendicular disposition of the amide moiety with respect to
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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4
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5
6
the aryl rings. Although the system is complicated by the presence of tertiary amide E/Z isomers
(contrary to the secondary bisanilides where only the Z isomer is present), from a stereodynamic point
0
1
2
3
4
5
6
7
8
9
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0
of view compounds 6-9 behaves like the binaphthyl ester 1.
CONCLUSIONS
We have investigated the conformational preference of a series of 2,2’-bisanilides using
variable temperature NMR spectroscopy, NMR titration and diffusion experiments, IR spectroscopy,
computational analysis and crystallography. In addition to the generally expected C
2
-NH-in species,
the formation of a C -H bond conformation having the two amide moieties linked by an intramolecular
1
hydrogen bond was detected at low temperatures. The formation of a dimeric species in solution was
ruled out by means of steric considerations, DMSO titration and DOSY experiments, and supported by
chemical shift calculations and comparison with the behavior of known biphenyl carbinols. The
interconversion kinetics of the two conformational species of bisanilide 2 were determined by NMR
lineshape analysis and the temperature dependence of the conformational ratio gave unique insights
into enthalpic and entropic terms that affect the equilibrium which favors formation of an
o
intramolecular hydrogen bond below -107 C.
EXPERIMENTAL SECTION
All reagents and solvents were commercially available and used without further purification.
Reactions were carried out under inert atmosphere and anhydrous conditions. Flash chromatography
1
was performed on silica gel, particle size 40-63 µm. NMR spectra were obtained at 600 MHz ( H-
13
3 3
NMR) and 150 MHz ( C-NMR) using the residual signals of the solvents (CD CN or CDCl ) as
1
6
chemical shift reference. 2,2’-Diaminobiphenyl and (M)-6,6’-dimethyl-2,2’-diaminobiphenyl were
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
'
commercially available. N,N-Dimethyl-2,2’-diaminobiphenyl was prepared according to the
1
7
literature.
,1’-Biphenyl-2,2’-diamine diisobutyramide, 2. 2,2’-Diaminobiphenyl (50 mg, 0.27 mmol, 1 eq) and
NEt (94 µL, 0.68 mmol, 2.5 eq) were dissolved in 5 mL of dichloromethane and cooled to 0 °C.
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Isobutyryl chloride (68 µL, 0.65 mmol, 2.4 eq) was added and the mixture was slowly warmed to room
temperature and stirred for 2 hours. The reaction was quenched with water and extracted with
dichloromethane. The combined organic layers were dried over MgSO
Purification by flash chromatography on silica gel (CH Cl :EtOAc 85:15) afforded 85 mg (0.26 mmol,
5%) of a white solid. Mp 137-139 °C. Crystal suitable for X-ray diffraction were obtained by slow
4
and concentrated in vacuo.
2
2
9
1
3 3
evaporation of a CHCl solution. H NMR (600 MHz, CD CN, +25 °C): δ = 0.91 (d, J = 6.8 Hz, 6H),
0.96 (d, J = 6.8 Hz, 6H), 2.28 (septet, J = 6.8 Hz, 2H), 7.18 (dd, J = 7.6Hz, 1.7Hz, 2H), 7.27 (dd, J =
13
7
.6Hz, 8.1Hz, 2H), 7.42 (dd, J = 8.1 Hz, 7.6 Hz, 2H), 7.63 (s, 2H), 7.77 (d, J = 8.1 Hz, 2H). C NMR
(
3 3 3
150 MHz, CD CN, +25 °C): δ = 19.4 (2CH ), 19.5 (2CH ), 36.3 (2CH), 125.8 (2CH), 126.2 (2CH),
1
7
29.4 (2CH), 131.4 (2CH), 133.6 (2Cq), 136.9 (2Cq), 176.8 (2CO). Anal. Calcd. for C20
4.05; H, 7.46; N, 8.63. Found: C, 74.01; H, 7.73; N, 8.59.
24 2 2
H N O : C,
1
8
1,1’-Biphenyl-2,2’-diamine bis(trifluoromethylacetamide) 3. 2,2’-Diaminobiphenyl (60 mg, 0.33
mmol, 1 eq) and NEt (95 µL, 0.68 mmol, 2 eq) were dissolved in 5 mL of dichloromethane and cooled
3
to 0 °C. Trifluoroacetic anhydride (114 µL, 0.82 mmol, 2.5 eq) was added and the mixture was slowly
warmed to room temperature and stirred for 4 hours. The reaction was quenched with water and
extracted with dichloromethane. The combined organic layers were dried over MgSO
4
and
concentrated in vacuo. Purification by flash chromatography on silica gel (CH Cl :EtOAc 85:15)
2
2
afforded 92 mg (0.24 mmol, 75%) of a brown solid. Mp 163-165 °C. Crystal suitable for X-ray
1
diffraction were obtained by slow evaporation of a CHCl
3
solution. H NMR (600 MHz, CD
3
CN, +25
°
C): δ = 7.30 (d, J = 7.6 Hz, 2H), 7.45 (dd, J = 7.6 Hz, 7.9 Hz, 2H), 7.54 (dd, J = 7.9 Hz, 7.6 Hz, 2H),
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13
7
3
.69 (d, J = 7.9Hz, 2H), 8.71 (bs, 2H). C NMR (150 MHz, CD CN, +25 °C): δ = 116.8 (q, JCF = 288
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
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3
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4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
6
3
Hz, 2CF ), 126.7 (2CH), 128.5 (2CH), 130.3 (2CH), 131.7 (2CH), 133.5 (2Cq), 134.5 (2Cq), 156.6
1
9
(
3
2CO). F NMR (376 MHz, CDCl ): δ = -76.1.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
19
1
,1’-Biphenyl-2,2’-diamine dibenzamide, 4. 2,2’-Diaminobiphenyl (80 mg, 0.43 mmol, 1 eq) and
3
NEt (150 µL, 1.09 mmol, 2.5 eq) were dissolved in 5 mL of dichloromethane and cooled to 0 °C.
Benzoyl chloride (106 µL, 0.91 mmol, 2.1 eq) was added and the mixture was slowly warmed to room
temperature and stirred for 2 hours. The reaction was quenched with water and extracted with
dichloromethane. The combined organic layers were dried over MgSO
4
and concentrated in vacuo.
:EtOAc 85:15) afforded 130 mg (0.33
CN, +25 °C): δ = 7.28-7.33
2 2
Purification by flash chromatography on silica gel (CH Cl
1
mmol, 75%) of a white solid. Mp 182-185 °C. H NMR (600 MHz, CD
3
1
3
(m, 4H), 7.41-7.48 (m, 6H), 7.53 (m, 2H), 7.66 (m, 4H), 7.81 (d, J = 7.4Hz, 2H), 8.58 (s, 2H). C
NMR (150 MHz, CD CN, +25 °C): δ = 126.6 (2CH), 126.8 (2CH), 127.9 (4CH), 129.5 (4CH), 129.6
2CH), 131.4 (2CH), 132.7 (2CH), 135.1 (2Cq), 135.3 (2Cq), 136.8 (2Cq), 167.1 (2CO).
3
(
1
,1’-Biphenyl-2,2’-diamine acetamide, 5. 2,2’-Diaminobiphenyl (612 mg, 0.33 mmol, 1 eq) and 4-
aminopyridine (40 mg, 0.033 mmol, 1 eq) were dissolved in 4 mL (40 mmol, 12 eq) of acetic
anhydride. The dark orange mixture was stirred for 1 hour at 75 °C. The reaction was quenched with 20
mL of HCl (0.2M). The solution was diluted with 20 mL of dichloromethane and the organic phase was
separated. The aqueous phase was extracted with DCM (3 x 15 mL); the combined organic layers were
washed with a saturated aqueous solution of NaHCO
3
(20 mL) and brine (20 mL), then dried over
Na SO . Purification by flash chromatography on silica gel (hexane:ethyl acetate 80:20) afforded 680
2
4
mg (2.54 mmol, 76%) of a white solid. Mp 152-156 °C. Crystal suitable for X-ray diffraction were
1
obtained by slow evaporation of a acetonitrile solution. H NMR (600 MHz, CD
3
CN, +25 °C): δ = 1.84
(s, 6H), 7.21 (dd, J = 7.6Hz, 1.6Hz, 2H), 7.27 (dd, J = 7.6 Hz, 7.6 Hz, 2H), 7.42 (dd, J = 7.6Hz, 8.1Hz,
1
3
2
3 3
H), 7.62 (s, 2H), 7.83 (d, J = 8.1Hz, 2H). C NMR (150 MHz, CD CN, +25 °C): δ = 23.7 (2CH ),
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9
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2
2
2
2
2
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6
1
25.5 (2CH), 126.1 (2CH), 129.4 (2CH), 131.8 (2CH), 132.5 (2Cq), 136.9 (2Cq), 170.0 (2CO). Anal.
Calcd. for C16 : C, 71.62; H, 6.01; N, 10.44. Found: C, 71.36; H, 5.73; N, 10.32.
16 2 2
H N O
N,N'-(6,6'-dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide) 10 and (M)-N,N'-(6,6'-
dimethyl-[1,1'-biphenyl]-2,2'-diyl)bis(2-methylpropanamide) (M)-10. In an oven-dried two-necked
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
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1
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8
9
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7
8
9
0
2
0
round
bottomed
flask
6,6’-dimethyl-2,2’-diaminobiphenyl
or
(M)-6,6’-dimethyl-2,2’-
diaminobiphenyl (0.24 mmol, 1 eq.) was dissolved in 2 mL of anhydrous dichloromethane and the
solution was cooled at 0 °C. Triethylamine (1.44 mmol, 6 eq.) and isobutyryl chloride (0.96 mmol, 4
eq) were added in sequence. The solution was stirred at room temperature until complete consumption
of the starting material (TLC, 3 hours). The reaction mixture was diluted with dichloromethane (10
mL) and quenched with 1M HCl (5 mL) at 0 °C. The organic layer was washed with brine (10 mL) and
3 2 4
saturated aqueous solution of NaHCO (2 x 5 mL). The organic phase was dried over Na SO and the
solvent was removed under reduced pressure to afford the product as a pale brown amorphous solid in
1
82 % yield (69 mg, 0.19 mmol). H NMR (600 MHz, CDCl
3
, +25 °C) δ = 0.92 (d, J = 6.6 Hz, 6H),
0
2
.97 (d, J = 6.6 Hz, 6H), 1.97 (s, 6H), 2.23 (septet, J = 6.6 Hz, 2H), 6.98 (bs, 2H), 7.15 (d, J = 7.8 Hz,
1
3
H), 7.34 (dd, J = 7.8 Hz, 7.9 Hz, 2H), 8.03 (d, J = 7.8 Hz, 2H). C NMR (150 MHz, CDCl
), 19.1 (2CH ), 19.5 (2CH ), 36.2 (2CH), 120.3 (2CH), 126.4 (2CH), 127.1 (2Cq), 129.0
2CH), 135.7 (2Cq), 137.0 (2Cq), 175.4 (2CO). GC-MS (m/z): 352 (25) [M] , 309 (5) [M-iPr] , 282
3
, +25 °C)
δ = 19.0 (2CH
3
3
3
+
+
(
(25), 239 (25), 212(20), 195 (100), 180 (15), 71(15). Anal. Calcd. for C22
N, 7.95. Found: C, 74.78; H, 8.39; N, 7.85.
28 2 2
H N O : C, 74.97; H, 8.01;
N,N'-([1,1'-Biphenyl]-2,2'-diyl)bis(N-methyl-2-dimethylpropanamide) 6. In an oven-dried round
balloon purged with nitrogen a solution of N,N'-dimethyl-2,2'-diaminobiphenyl (0.47 mmol, 1 eq.) in
dichloromethane (4 mL) was cooled at 0 °C and 5.7 mmol (12 eq) of TEA was added. Isobutyryl
chloride (3.8 mmol, 8 eq) was added dropwise and the reaction mixture was stirred and allowed to
return to the room temperature in 3h. The reaction was quenched with HCl (1M), and the phases were
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separated. The aqueous phase was extracted with DCM (3 x 10 mL). The combined organic layers were
washed with a saturated aqueous solution of NaHCO (20 mL) and brine (20 mL), and dried over
Na SO . The solvent was removed under reduced pressure and the desired product was obtained as a
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
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7
8
9
0
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3
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7
8
9
0
white solid (113 mg, 0.32 mmol) by semi-preparative HPLC in 70% yield. Column: LUNA-C18 (250 x
1
21.20 mm), MeCN/H
MHz, CDCl
.7Hz, 4H), 1.17-1.27 (bs, 2H). 2.25 (bs, 0.3H) 2.39 (sept, J = 6.7Hz, 0.3H), 2.59 (sept, J = 6.7Hz,
2
O 80/20, 20 ml/min, λ 254 nm, t
R
: 4.72 min. Mp 152-154 °C. H NMR (600
3
, +25 °C): δ = 0.80 (bs, 1H), 1.4 (d, J = 6.7Hz ,1H), 1.08 (d, J = 6.7Hz, 4H), 1.14 (d, J =
6
1.4H), 2.79-2.87 (bs, 4H), 2.95 (bs, 0.7H), 3.07 (bs, 1H), 3.37 (bs, 0.3H), 7.24 (bs, 1H), 7.29 (bm,
13
2
.6H), 7.33 (bm, 0.6H), 7.39 (bm, 2.2H), 7.43(bm, 1.4H), 7.47 (bs, 0.2H). C NMR (150 MHz, CDCl
3
7
,
,
+
25 °C): δ = 18.8, 19.0, 19.6, 20.3, 20.7 (b), 30.4, 31.4, 31.6 (b), 35.6 (b), 128.1, 128.2, 128.7, 129.2
1
29.3
4
, 129.4, 129.5, 130.9, 131.2, 134.0, 134.7, 141.4, 141.8, 177.5, 177.8 (b). Anal. Calcd. for
C
22 28 2 2
H N O : C, 74.97; H, 8.01; N, 7.95. Found: C, 74.57; H, 8.43; N, 7.83.
N,N'-([1,1'-biphenyl]-2,2'-diyl)bis(2,2,2-trifluoro-N-methylacetamide) 7. A solution of 1.0 mL of
trifluoroacetic anhydride was cooled to 0 °C and 0.1 mmol (1 eq.) of N,N'-dimethyl-[1,1'-biphenyl]-
2
,2'-diamine were added. The solution was stirred for 1 hour at room temperature and then diluted with
ethyl acetate and quenched with HCl (1M, 10 mL). The organic layer was washed with brine (10 mL)
and a saturated aqueous solution of NaHCO (10 mL). The organic phase was dried over Na SO and
the solvent was evaporated under reduced pressure to afford a sticky solid. A sample was purified by
3
2
4
preparative HPLC on the LUNA-C18 phase (250 x 21.20 mm), MeCN/H
nm, t
MHz, CDCl
2
O 70/30, 20 ml/min, λ 254
1
R
: 9.14 min. The HPLC purification gave 32mg (0.08 mmol,80%) of a sticky solid. H NMR (600
3
, +25 °C) δ = 2.80 (s, 1.2H), 2.86 (bs, 0.6H), 2.95-3.07 (bm, 1.8H), 3.15 (bs, 0.9H), 3.54-
19
3
.66 (bs, 1.5H), 7.24-7.52 (bm, 8H). F NMR (564 MHz, CDCl
3
, +25 °C) δ = -66.1, -66.2, -67.2, -
, +25 °C) δ = 37.1, 37.4 (b), 39.7 (b), 116.4 (q, J
291.7Hz, CF3), 127.2 (b), 128.4, 128.9, 129.1 (b), 129.7, 129.8, 130.0 (b), 130.5, 131.0, 133.4 (b),
1
3
70.2, -70.3, -70.6, -70.8. C NMR (150 MHz, CDCl
3
=
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1
34.0 (b), 134.7, 138.2, 140.0 (b), 140.7 (b), 156.1(b), 157.4, 157.6, 157.8, 158.1. HRMS (ESI-QTOF)
Calcd. for C18 : 405.1032. Found: 405.1038. Anal. Calcd. for C18 : C, 53.47; H,
.49; N, 6.93. Found: C, 53.12; H, 3.85; N, 6.69.
H
15
F
6
N
2
O
2
14 6 2 2
H F N O
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General procedure for the preparation of tertiary amides 8 and 9.
In an oven dried Schlenk tube under nitrogen atmosphere 0.2 mmol (1 eq.) of amide was dissolved in 1
mL of anhydrous THF and the solution was cooled at 0 °C. NaH (60% dispersion in mineral oil, 0.5
mmol, 2.5 eq.) was added and the reaction mixture was stirred for 15 minutes at ambient temperature,
then MeI (0.6 mmol, 3 eq.) was added at 0 °C. The reaction mixture was stirred at ambient temperature
until complete consumption of the starting material (TLC, 2-6 hours) and then quenched with a
saturated solution of NH
4
Cl (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL),
SO . The solvent
the combined organic layers were washed with brine (10 mL) and then dried over Na
2
4
was removed under reduced pressure to afford the desired product which was used as is or purified by
semi-preparative HPLC for the VT-NMR analysis.
N,N'-([1,1'-Biphenyl]-2,2'-diyl)bis(N-methylbenzamide) 8. Using 4 in the protocol described above,
1
we obtained 56 mg (67% yield) of a white solid. Mp 157-159 °C. H NMR (600 MHz, CDCl
3
, +25 °C)
δ = 1.98 (s, 0.4H), 3.07 (bs, 2.9H), 3.56 (s, 2.7H), 5.95 (bs, 1.3H), 6.85 (bdd, J = 6.0 Hz, J = 6.0 Hz,
1
3
0
1
1
.8H), 7.03-7.20 (bm, 4.2H) , 7.20-7.69 (bm, 9.1H). C NMR (150 MHz, CDCl
25.6, 126.5 (b), 127.1, 127.2, 127.6, 128.2, 128.4, 128.7, 129.3, 129.5, 129.8, 130.9 (b), 132.5, 135.0,
35.2, 135.3, 136.0 (b), 141.2, 142.0, 168.9, 169.7, 172.0 (b). Anal. Calcd. for C28 : C, 79.98;
3
, +25 °C) δ = 37.7,
24 2 2
H N O
H, 5.75; N, 6.66. Found: C, 79.53; H, 5.65; N, 6.66
28
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Page 29 of 33
The Journal of Organic Chemistry
1
2
3
N,N'-([1,1'-biphenyl]-2,2'-diyl)-bis(N-methylacetamide) 9. Using 5 in the protocol described above,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
we obtained 38 mg (63% yield) of a white solid. Mp 175-177 °C. Crystals suitable for X-ray analysis
1
were obtained by slow evaporation of a CDCl
3
solution. H NMR (600 MHz, CDCl
3
, +25 °C) δ = 1.85
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(s, 1.2H), 2.01 (bs, 4.1H), 2.16 (bs, 0.7H), 2.77 (bs, 4.1H), 2.87 (bs, 0.5H), 2.96 (s, 1.5H), 3.37 (bs,
0.7H), 7.24 (bd, 1.9H), 7.27 (d, J = 7.2Hz, 1.4H), 7.31 (bd, 0.6H), 7.37 (bm, 0.5H), 7.41-7.44 (bm,
13
3
3
.5H). C NMR (150 MHz, CDCl , +25 °C) δ = 22.0, 22.5, 22.6, 22.7, 35.4, 36.6, 127.9, 128.1, 128.2,
129.1, 129.2, 129.3, 131.2, 132.4, 135.0, 136.1, 141.8, 142.1, 170.7, 170.9, 171.0. Anal. Calcd. for
: C, 72.95; H, 6.80; N, 9.45. Found: C, 72.57; H, 6.49; N, 9.85.
18 20 2 2
C H N O
Variable Temperature NMR. Variable temperature NMR spectra were recorded with a spectrometer
1
13
1
operating at a field of 14.4 T (600 MHz for H and 150.8 MHz for C NMR). Low temperature H
NMR spectra were acquired without spinning using a 5 mm dual direct probe with a 9000 Hz sweep
width, 3.0 µs (30° tip angle) pulse width, 3 s acquisition time and 1 s delay time. A shifted sine bell
weighing function equal to the acquisition time (i.e., 3 s) was applied prior to the Fourier
1
3
transformation. Usually 32 to 64 scans were collected. Low temperature 150.8 MHz C NMR spectra
were acquired without spinning and under proton decoupling conditions with a 38000 Hz sweep width,
4
.5 µs (45° tip angle) pulse width, 1 s acquisition time and 1 s delay time. A line broadening function
of 1–2 Hz was applied before the Fourier transformation. Usually 256 to 1024 scans were collected.
Temperature calibrations were performed using a digital thermometer and a Cu/Ni thermocouple
placed in an NMR tube filled with isopentane or 1,1,2,2-tetrachloroethane (for the low and high
temperature range, respectively). The conditions were kept as equal as possible with all subsequent
work. The uncertainty in temperature measurements can be estimated as ±1 °C. Line shape simulations
2
1
were performed using a PC version of the QCPE DNMR6 program. Electronic superimposition of the
original spectrum and of the simulated one enabled the determination of the most reliable rate constant.
29
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