Supramolecular-directed chiral induction in biaryl derivatives

Article abstract of DOI:10.1021/jo9015425

(Chemical Equation Presented) A thermodynamically controlled resolution has allowed for the generation of diastereomerically enriched complexes, by chirality transfer from an enantiopure building block to a dynamically racemic biaryl derivative. A switcha

Full text of DOI:10.1021/jo9015425

pubs.acs.org/joc
enantio-enriched compounds.2 The conformer population
Supramolecular-Directed Chiral Induction in
Biaryl Derivatives
of a dynamically racemic mixture (rapidly interconverting
enantiomers) can be disturbed from equilibrium by a
chiral bias. Some examples of this strategy have been repor-
ted,1a-c,e,f,h,3 and this paper details our preliminary efforts in
the induction and control of axial chirality in stereolabile
biaryls, by means of hydrogen bonding. Further, the effects
of orthogonal binding motifs (aromatic interactions with
respect to hydrogen bonding) have proven to be a tool to
switch the sense of chiral induction.
J. Etxebarria,† H. Degenbeck,† A.-S. Felten,† S. Serres,†
N. Nieto,† and A. Vidal-Ferran*,†,‡
†Institute of Chemical Research of Catalonia (ICIQ),
Av. Paısos Catalans 16, 43007 Tarragona, Spain, and
¨
‡Catalan Institute for Research and Advanced Studies
(ICREA), Pg. Lluis Companys 23, 08010 Barcelona, Spain
We envisaged that supramolecular complexes of the type 1
could be formed from enantiopure diamines 3a-g and free
rotating (tropos)3a biphenyl-2,20-diols 2a-c by two simulta-
neous hydrogen bonding interactions between the amino and
hydroxyl substituents (Scheme 1). It was reasoned that the
multipoint interactions would increase the strength of the
complexation process through the chelate effect,4 thus pre-
ferentially leading to cyclic structures.
avidal@iciq.es
Received July 17, 2009
SCHEME 1. Design of Hydrogen Bonding-Mediated
Complexes 1
A thermodynamically controlled resolution has allowed
for the generation of diastereomerically enriched com-
plexes, by chirality transfer from an enantiopure building
block to a dynamically racemic biaryl derivative. A swit-
chable sense of induction could be achieved depending on
the substituents of the chiral block.
Aliphatic amino and phenolic groups can be regarded as
complementary hydrogen bonding acceptors and donors,
the hydrogen bonding between them has been well studied
both experimentally5 and theoretically.6 The ortho-substit-
uents of the phenolic OH groups were essential to our
approach: their electronic character, acceptor or donator,
should be reflected in an enhanced (or decreased) acidity of
the phenol group, and hence in the strength of any resulting
hydrogen bond.6 For this purpose, compounds 2 with do-
nator (R1 = Me, 2b; R1 = OMe, 2c) and acceptor groups
(R1 = NO2, 2a) were synthesized. Another key strategy was
altering the N-substituents which, through steric interactions
Hydrogen bonding has long been used as a driving force
for chiral recognition and binding, and a great number of
chiral supramolecular complexes have been prepared with
this strategy.1 In most cases, chemical and physical proper-
ties associated with chirality are due to “static” stereochem-
istry, the fixed spatial arrangements of atoms. Conversely,
dynamic stereochemistry deals with molecular changes and
constitutes an interesting alternative strategy for generating
(1) See for example: (a) Mizutani, T.; Takagi, H.; Hara, O.; Horiguchi,
T.; Ogoshi, H. Tetrahedron Lett. 1997, 38, 1991–1994. (b) Takagi, H.;
Mizutani, T.; Horiguchi, T.; Kitagawa, S.; Ogoshi, H. Org. Biomol. Chem.
2005, 3, 2091–2094. (c) Eelkema, R.; Feringa, B. L. J. Am. Chem. Soc. 2005,
127, 13480–13481. (d) Breit, B. Angew. Chem., Int. Ed. 2005, 44, 6816–6825.
(e) Morioka, K.; Tamagawa, N.; Maeda, K.; Yashima, E. Chem. Lett. 2006,
35, 110–111. (f) Ishii, Y.; Onda, Y.; Kubo, Y. Tetrahedron Lett. 2006, 47,
8221–8225. (g) Ikeda, T.; Hirata, O.; Takeuchi, M.; Shinkai, S. J. Am. Chem.
Soc. 2006, 128, 16008–16009. (h) Suzuki, T.; Ohta, K.; Nehira, T.; Higuchi,
H.; Ohta, E.; Kawai, H.; Fujiwara, K. Tetrahedron Lett. 2008, 49, 772–776.
(i) Yu, J.; RajanBabu, T. V.; Parquette, J. R. J. Am. Chem. Soc. 2008, 130,
7845–7847. (j) Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. Rev. 2008,
108, 1–73. (k) Breuil, P. A. R.; Patureau, F.; Reek, J. N. H. Angew. Chem., Int.
Ed. 2009, 48, 2162-2165 and references cited therein.
(3) See for example: (a) Walsh, P. J.; Lurain, A. E.; Balsells, J. Chem. Rev.
2003, 103, 3297–3344. (b) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929-6941 and references cited
therein.
(4) (a) Blackman, A. G. C. R. Chim. 2005, 8, 107–119. (b) Bowman, D. C.
J. Chem. Educ. 2006, 83, 1158–1160.
(5) (a) Gurka, D.; Taft, R. W.; Joris, L.; Schleyer, P. v. R. J. Am. Chem.
Soc. 1967, 89, 5957–5958. (b) Kraemer, R.; Zundel, G. J. Chem. Soc.,
Faraday Trans. 1990, 86, 301–305. (c) Koll, A.; Rospenk, M.; Sobczyk, L.
J. Chem. Soc., Faraday Trans. 1 1981, 77, 2309–2314. (d) Albrecht, G.;
Zundel, G. J. Chem. Soc., Faraday Trans. 1 1984, 80, 553–561. (e) Pawelka,
Z.; Kuc, T. Pol. J. Chem. 2001, 75, 845–855.
(6) (a) Gilli, P.; Pretto, L.; Bertolasi, V.; Gilli, G. Acc. Chem. Res. 2009,
42, 33–44. (b) Szatylowicz, H. J. Phys. Org. Chem. 2008, 21, 897–914.
(c) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310–5324. (d) Fedorowicz,
A.; Koll, A.; Mavri, J. Theor. Chem. Acc. 2003, 109, 220–228.
(2) Wolf, C. Dynamic Stereochemistry of Chiral Compounds: Principles
and Applications; The Royal Society of Chemistry: Cambridge, UK, 2008.
8794 J. Org. Chem. 2009, 74, 8794–8797
Published on Web 10/16/2009
DOI: 10.1021/jo9015425
r
2009 American Chemical Society

Etxebarria et al.
JOCNote
TABLE 1. UV and CD Spectral Data of Hydrogen-Bonded Complexes
entry
complex
solvent
UV data: λmax
,
a ε b
Kc
CD Data: λmax,
a Δε b
e
1
2
3
4
5
6
7
8
9
10
2a þ (1R,2R)-3c
2b þ (1R,2R)-3c
2c þ (1R,2R)-3c
2a þ (1R,2R)-3a
2a þ (1R,2R)-3b
2a þ (1R,2R)-3c
2a þ (1R,2R)-3d
2a þ (1R,2R)-3e
2a þ (1R,2R)-3f
2a þ (1R,2R)-3g
THF
THF
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
386, 7.4 ꢀ 103
280, 2.2 ꢀ 104
278, 2.9 ꢀ 104
385, 6.9 ꢀ 103
386, 6.7 ꢀ 103
383, 6.4 ꢀ 103
382, 6.9 ꢀ 103
384, 6.6 ꢀ 103
385, 6.0 ꢀ 103
379, 8.5 ꢀ 103
8.1 ꢀ 105
1.3 ꢀ 103
2.2 ꢀ 102
2.0 ꢀ 105
2.7 ꢀ 105
2.0 ꢀ 105
5.6 ꢀ 104
2.7 ꢀ 105
3.9 ꢀ 105
2.5 ꢀ 104
-
e
-
e
-
389, 0.07
395, 0.25
381, 0.51
384, 0.98
394, 0.34
395, 0.37
344, -1.55
aIn nm. bIn M-1 cm-1. cIn M-1, mean value of at least two measurements. dUV data for 2: 2a (352, 7.3 ꢀ 103 in THF; 358, 7.1 ꢀ 103 in toluene); 2b
3
(274, 9.8 ꢀ 103 in THF); 2c (273, 2.1 ꢀ 04 in THF). eNot measured.
with the biaryl derivatives, would be responsible for the
chiral induction. A wide range of diamines with sterically
different N-substituents were synthesized, 3a-g, in order to
study their influence on the complexation and chiral induc-
tion processes. An ester group was incorporated in the
biphenyl-2,20-diol subunit, allowing for the simple transfor-
mation into a wide variety of binding groups for future
catalytic applications.
Compounds 2a-c and amines 3a-g were synthesized in
good yields by well-established synthetic transformations.7
Complexation studies between biaryl derivatives 2 and
chiral diamines 3 were made by means of UV-vis spectros-
copy. Titration of a solution of 2 with 3 led to a decrease in
intensity of the initial biaryl band and the appearance of a
new red-shifted band (see Table 1). Equilibrium constants
were extracted by analyzing the UV-vis titration data7 and
are summarized in Table 1.
not a major process.10 The UV-vis spectrum of sodium 5,50-
bis(methoxycarbonyl)-3,30-dinitrobiphenyl-2,20-bis(olate)
(Na2-2a) in a THF solution11 shows an intense band with
a maximum centered at 441 nm.7 Under identical conditions,
a mixture of 2a and 3c showed an absorption band with
a maximum centered at 386 nm. Assuming that the intensity
of the absorption at 441 nm arises exclusively from the
phenolate chromophore from the complexation process
between 2a and 3c, then the extent of the proton transfer
can be estimated to 8% as a maximum. Regarding the sterics
of the complexation process, K values for 2a and 3a-g are
similar (cf. entries 4-10, Table 1), indicating that the size of
the substituents of the amino groups has a small effect on the
strength of the complexation process.
SCHEME 2. Charged Assisted H-Bond and Proton Transfer
The formation of complexes derived from 2a could be
confirmed by NMR, clearly showing an interaction between
the biaryl and amine in a 1:1 ratio. In all cases, NMR signals
for the complexes were in agreement with a C2-symmetric
averaged structure. Variable-temperature 1H NMR analysis
(298-200 K, toluene-d8) showed only one set of signals
across the whole range of studied temperatures, indicating
that either one main diastereoisomer was present or that the
exchange processes were faster (even at 200 K) than the
NMR time scale.
The binding constant K was found to decrease 3 orders of
magnitude between 2a and 2c (cf. entries 1-3, Table 1).
Literature precedents suggest that a doubly charged-assisted
H-bond ((CAHB;6a Scheme 2; i.e. hydrogen bonds derived
from an acid-base equilibrium, such as between the nitro
derivative 2a and amines 3)5,6,8 would be stronger than an
ordinary hydrogen bond, such as in 2b, 2c, and 3. pKa values
of the o-nitrophenol unit and the protonated amine are
relatively close9 and a (CAHB should be facilitated.
(CAHB can lead to a complete proton transfer. However,
UV-vis studies on our system suggest that proton transfer is
The complexation of 2a and 3c was investigated by
isothermal calorimetry (ITC). Very good agreement between
the K values obtained by UV and ITC (K = 2 ꢀ 105 M-1 in
toluene and K = 5 ꢀ 105 M-1 in THF, both at 298 K; see
entries 1 and 6 in Table 1 for K values obtained by UV) was
observed. A 1:1 ratio between 2a and 3c was deduced from
ITC data.7 ΔH and ΔS values (-14.2 kcal/mol, -23.3 cal/
mol/K, 298 K in toluene) were also extracted from the
titration data. ΔH is in agreement with a (CAHB between
acidic phenols and amines (ΔH=-9.8 kcal/mol for p-nitro-
phenol and dibutylamine8d). An overall decrease for ΔS in
the complexation process was expected as a consequence of
the entropically unfavorable chelate formation process.
Each conformer of 2 could react with the enantiopure
amine 3 forming two different diastereomeric complexes 1
(see Scheme 3), via a thermodynamically controlled resolu-
tion. The stereochemical outcome of such an asymmetric
process would depend on the relative thermodynamic stabi-
lities of (R,R,M)-1 and (R,R,P)-1.
(7) See the Supporting Information for details.
CD spectra of complexes 1 showed a Cotton effect in
all cases (see Table 1), indicating that the biphenyl unit is
twisted with a predominant screw sense. The diastereoisomer
(8) (a) Mizutani, T.; Takagi, H.; Ueno, Y.; Horiguchi, T.; Yamamura, K.;
Ogoshi, H. J. Phys. Org. Chem. 1998, 11, 737–742. (b) Hudson, R. A.; Scott,
R. M.; Vinogradov, S. N. Spectrochim. Acta, Part A 1970, 26, 337–343.
(c) Baba, H.; Matsuyama, A.; Kokubun, H. Spectrochim. Acta, Part A 1969,
25, 1709–1722. (d) Libus, W.; Mecik, M.; Sulek, W. J. Solution Chem. 1977, 6,
865–879. (e) Dwivedi, P. C.; Banga, A. K.; Sharma, N. Spectrochim. Acta,
Part A 1986, 42A, 623–629. (f) Pillay, M. K.; Umamaheswari, A. J. Indian
Chem. Soc. 1991, 68, 62–64.
(9) pKa of 7.2 (Wang, S.-P.; Chen, H.-J. J. Chromatogr., A 2002, 979,
439-446) and 10.7 (Fu, S. Analyst 1998, 123, 1487-1492) have been reported
for 2-nitrophenol and dimethylammonium. ΔpKa = pKa(Ar-OH) - pKa-
(HNþR3) can be estimated as 3 for our system.
(10) This result is in agreement with reported data in the literature, as the
extent of proton transfer in CCl4 for several chloro-substituted phenol-
amine systems with ΔpKa ≈ 3 has been reported to be roughly less than 15%;
see: Albrecht, G.; Zundel, G. J. Chem. Soc., Faraday Trans. 1 1984, 80, 553–
561.
(11) Na2-2a was generated by treatment of a solution of 2a in THF with a
slight excess of NaH. THF was used instead of toluene for solubility reasons.
J. Org. Chem. Vol. 74, No. 22, 2009 8795

Etxebarria et al.
JOCNote
SCHEME 3. Diastereoselective Complexation between 2 and 3
These studies indicated that the most stable diastereoi-
somer for the isobutyl-substituted complex has a P config-
uration (entry 1, Table 2), while calculations on the mesityl-
substituted complex (2a þ 3g) indicate an M configuration of
the chiral biaryl unit (entry 5, Table 2). Each of the two
mesityl substituents is arranged in off-face stacking with the
nitro-substituted aryl rings, thus facilitating simultaneous
π(CH) interactions between the aromatic rings.14 Finally,
calculations predict a slightly higher energy gap between
diastereoisomers differing in the configuration at the biaryl
unit (2.4 kcal/mol for the isobutyl and 3.6 kcal/mol for the
mesityl complexes), which may account for the higher mag-
nitude of the Cotton effect in the mesityl-substituted com-
plex.
The geometry optimized coordinates from the most stable
2a þ 3c diastereoisomer (RC,RC,SN,SN,P; entry 1, Table 2)
were used in a time-dependent density functional theory
(TDDFT) prediction of circular dichroism data, using
B3LYP and aug-cc-pVDZ,7 since this methodology has
proven to be reliable in CD predictions.16 Agreement be-
tween experimental and computed CD data is good
(Figure 1)17 and the P-helical screw sense of the biaryl unit
in the isobutyl-substituted complex was confirmed by com-
parison of the experimental sign of the Cotton effect with its
calculated value.
populations are biased during the complexation process, and
the observed CD signal is a factor of the degree of twist and
the relative populations of the complexes (which would
cancel each other out if equimolarly present). Complexes
derived from (R,R)-3a-f showed a positive Cotton effect
and the highest CD amplitude was observed for the amine 3d
(see Figure 1): the bulky N-neopentyl substituents on 3d
preferentially twist the biaryl unit to a greater extent. This
observation should only be considered as an estimate, since it
has been reported that major alterations in the cromophore,
i.e. dihedral angle in the biaryl unit, lead to changes in the
position and intensity of the CD bands in related chromo-
phores.12 Strikingly, the sense of helical screw of the biaryl
unit is reversed in the complex containing N-mesitylmethyl
amine 3g (entry 10, Table 1). These results indicate that the
dynamically racemic biaryl derivative 2a can be readily fixed
upon complexation with either a P- or M-torsion depending
on the nature of the N-substituents.
To gain a deeper insight into the three-dimensional struc-
ture of these complexes, full level DFT geometry optimiza-
tion of all the C2-symmetric diastereoisomers 2a þ (R,R)-3c
(positive Cotton effect) and 2a þ (R,R)-3g (negative Cotton
effect) was carried out. Due to its good performance with
weak noncovalent interactions, MPWB1K13 density func-
tional theory was used.7 Computed relative energies are
summarized in Table 2.
FIGURE 1. CD data for complexes 1.15
In conclusion, a thermodynamically controlled resolution
has allowed the generation of diastereomerically enriched
supramolecular complexes, by chirality-transfer from an
enantiopure building block to a dynamically racemic biaryl
derivative. The formation of two doubly charged-assisted
H-bonds can be regarded as the driving force for the genera-
tion of highly stable complexes (K > 105 M-1). This work
shows the potential of noncovalent interactions [hydrogen
bond and π(CH)] for transmission and control of chirality at
the molecular level: a chirally oriented conformation can be
created not only by stereogenic elements of a chiral inducer,
but also by additional supramolecular interactions which are
capable of reversing the sense of induction. Work is in
TABLE 2. Computed Relative Energies for 2a þ 3c and 2a þ 3g
diastereoisomer
diastereoisomer
entry 2a þ (1R,2R)-3c energya entry 2a þ (1R,2R)-3g energya
1
2
3
4
RC,RC,SN,SN,Pb
RC,RC,RN,RN,P
RC,RC,SN,SN,M
RC,RC,RN,RN,M
0.0
0.2
2.4
3.2
5
6
7
8
RC,RC,RN,RN,M
RC,RC,SN,SN,P
RC,RC,RN,RN,P
RC,RC,SN,SN,M
0.0
3.6
5.0
10.4
aIn kcal/mol. bThe first two characters refer to configuration of the
N-substituted carbons in the amine unit 3, the following two indicate the
configurations for the tetrahedral nitrogen atoms upon complexation
[R or S; substituent priorities: C(ring) > C(N-substituent) > H(O) >
H(N)] and the last one indicates the sense of screw of the chiral axis in the
biaryl unit.
(14) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J. J. Chem. Soc.,
Perkin Trans. 2 2001, 651–669.
(12) Di Bari, L.; Pescitelli, G.; Salvadori, P. J. Am. Chem. Soc. 1999, 121,
7998–8004.
(13) (a) Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory Comput.
2006, 2, 364–382. (b) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput.
2007, 3, 289–300.
(15) Amines 3a-g were CD-silent in the 310-460 nm range.
(16) Stephens, P. J.; McCann, D. M.; Butkus, E.; Stoncius, S.; Cheeseman,
J. R.; Frisch, M. J. J. Org. Chem. 2004, 69, 1948–1958.
(17) The computed amplitude of the CD data was normalized to the
experimental values.
8796 J. Org. Chem. Vol. 74, No. 22, 2009

Etxebarria et al.
JOCNote
progress to exploit this strategy in the preparation of sensors
and chiral ligands for asymmetric transformations of interest.
60.5 (CH), 117.9 (C), 127.1 (CH), 132.3 (C), 136.3 (CH), 140.1
(C), 160.0 (C), 165.8 (C); MS (TOF MS ESþ) calcd for
[C36H50N4O10H]þ required 699.36, found 699.4; calcd for
[C36H50N4O10Na]þ required 721.34, found 721.3.
Experimental Section
Preparation of Hydrogen Bonded Complexes 1. Compounds 2
(0.024 mmol) and 3 (0.024 mmol) were mixed and dried under
vacuum for 12 h. The required solvent (dry and degassed CDCl3
(1.00 mL) was used for NMR analysis of the hydrogen bonded
complexes) was then added. See the Supporting Information for
the spectroscopical data of 2a þ (1R,2R)-3a-g. As a represen-
tative example, 2a þ (1R,2R)-3e: 1H NMR (400 MHz, CDCl3) δ
0.89 (m, 5H), 1.15 (m, 10H), 1.42 (m, 2H), 1.66 (m, 12H), 2.13
(m, 2H), 2.39 (m, 3H), 2.77 (dd, J = 11.7, 6.5 Hz, 2H), 3.94 (s,
6H), 8.23 (d, J=2.4 Hz, 2H), 8.57 (d, J=2.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 24.3 (CH2), 25.5 (CH2), 26.1 (CH2),
29.1 (CH2), 30.8 (CH2), 36.7 (CH), 52.0 (CH3), 52.1 (CH2),
Acknowledgment. We thank MICINN (Grant CTQ2008-
00950/BQU), DURSI (Grant 2009GR623), Consolider In-
genio 2010 (Grant CSD2006-0003), and ICIQ Foundation
for financial support. Prof. Feliu Maseras (ICIQ) is grate-
fully acknowledged for advice in the computational studies.
Supporting Information Available: Experimental details,
characterization data, and NMR spectra for compounds 1, 2,
and 3, general procedures used for UV-vis, CD and computa-
tional data, and molecular modeling coordinates. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8797