The stereodynamics of 5,5'-disubstituted BIPHEPs

Article abstract of DOI:10.1002/chir.22125

We investigated the stereodynamics of 5,5'-substituted tropos BIPHEP ligands (2,2'-bis(diphenylphosphino)-biphenyls) by enantioselective dynamic high-performance liquid chromatography (DHPLC) to elucidate the influence of the substitution pattern and elec

Full text of DOI:10.1002/chir.22125

CHIRALITY 25:126–132 (2013)
The Stereodynamics of 5,5’-Disubstituted BIPHEPs
*
FRANK MAIER AND OLIVER TRAPP
Ruprecht-Karls-Universität Heidelberg, Organisch-Chemisches Institut, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
ABSTRACT
We investigated the stereodynamics of 5,5’-substituted tropos BIPHEP ligands
(2,2’-bis(diphenylphosphino)-biphenyls) by enantioselective dynamic high-performance liquid
chromatography (DHPLC) to elucidate the influence of the substitution pattern and electronics
of the substituents (methyl, methoxy, and hydroxyl groups). By temperature-dependent dynamic
HPLC measurements the activation parameters ΔG╪, ΔH╪, and ΔS╪ could be determined with high
precision, revealing that the activation barrier of these 5,5’-substituted BIPHEP ligands ranges in a
narrow band between 87.8 and 93.0kJmol–1, making them highly attractive as deracemizable
dynamic chiral ligands in asymmetric catalysis. Interestingly, the activation parameters are highly
influenced by a hydroxyl or methoxy group in the 5,5’-position of the BIPHEP ligands. Chirality
25:126–132, 2013. © 2012 Wiley Periodicals, Inc.
KEY WORDS: BIPHEP; dynamic HPLC; interconversion barrier; unified equation; kinetics
INTRODUCTION
disubstituted analogues enables detailed insight into substi-
tution pattern effects on the Gibbs free energy ΔG╪ and the
activation parameters ΔH╪ and ΔS╪. Another advantage of tro-
pos ligands is their potentially applicability in self-amplifying
enantioselective processes.24,25
Axial chiral ligand systems like Noyori’s atropisomeric
binap,1 and tropos BIPHEP ligands used by Mikami et al.2 are
of high interest due to their broad applicability in asymmetric
catalysis. An advantage of tropos ligands like BIPHEP (2,2’-
bis(diphenylphosphino)-biphenyls) over atropos ligands is
their dynamic rotational behavior, allowing to use synthetically
easier accessible racemic mixtures of the ligand, which can
be deracemized at low temperature to yield the desired enan-
tiomerically pure catalyst. Mikami and Noyori reported first
about a novel concept: the use of a racemic BIPHEP-Ru catalyst
bearing a chiral amine to dynamically deracemize the BIPHEP-
Ru complex.3 Treatment of the racemic BIPHEP-Ru catalyst
with a chiral amine led to the deracemization of the catalyst,
which was used in hydrogenations of ketones to chiral alcohols
with excellent enantioselectivities.3 Mikami and colleagues
made further contributions in enantioselective catalysis with
the tropos BIPHEP-ligand by using either enantiopure
diamine coligands in Pd-catalyzed hetero-Diels-Alder reactions4 or
enantiomerically pure counterions to deracemize BIPHEP-Au
complexes, which were applied in intramolecular hydroami-
nations of allenes and enantioselective intermolecular carbon–
carbon bond formations.5–7 Brown et al. reported the use of
enantiomerically pure bicyclo[3.3.1]nona-2,6-diene to deracemize
BIPHEP-Rh complexes for use in asymmetric hydrogenations.8
The deracemization of BIPHEP ligands using a chiral auxiliary
represents a classic example of dynamic kinetic resolution
(see Scheme 1).9
MATERIALS AND METHODS
General
All chemicals used were purchased from Sigma Aldrich (Schnelldorf,
Germany) or Acros Organics (Geel, Belgium). Nuclear magnetic resonance
(1H-NMR, 31P-NMR) spectra were recorded at 300, 122, and 75 MHz,
respectively, on a Bruker AC-300 spectrometer (Rheinstetten, Germany)
in deuterochloroform, benzol-d6, or methanol-d4. High resolution mass
spectra (ESI-HRMS) were acquired on a Jeol JMS-700 instrument. Infrared
(FT-IR) spectra were recorded on a Thermo Fisher Nicolet 6700 FT-IR-Spec-
trometer (Dreieich, Germany).
Synthesis of 5,5’-Disubstituted BIPHEPs
(5,5’-Dimethoxy-[1,1’-biphenyl]-2,2’-diyl)bis(diphenylphosphine
oxide) 1. The (5,5’-dimethoxy-[1,1’-biphenyl]-2,2’-diyl)bis(diphenylpho-
sphine oxide) 1 was synthesized according to modified sequences
developed by Yuxue Liang et al.26 and Wanbin Zhang et al.27 A total of
16.4 g (132 mmol) 4-methoxyphenol was dissolved in 150 ml of dry
nitromethane and AlCl3 (17.6 g, 132 mmol) was added subsequently.
After stirring for 15min at room temperature, DDQ (DDQ: 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone) (15.0 g, 66.1 mmol) dissolved in 200 ml of
nitromethane was added dropwise and the reaction mixture was stirred
for 1 h at room temperature. After addition of 2 M HCl the resulting
mixture was extracted with CH2Cl2. The organic extracts were dried
over MgSO4 and the solvents were removed under reduced pressure.
The residue was purified by column chromatography on silica gel with
petrol ether/EtOAc (10:1) as the eluent, yielding the product (8.5 g, 52%)
as colorless crystals. 1H-NMR (300 MHz, CDCl3) d = 6.96 (d, J = 8.8 Hz,
2H), 6.88 (dd, J = 8.8, 3.1 Hz, 2H), 6.82 (d, J = 3.1 Hz, 2H), 5.37 (bs, 2H),
3.79 (s, 6H).
To understand and control the stereoselectivity of catalysts
bearing tropos ligands it is important to know the factors that
influence the dynamics and the kinetics of highly flexible
systems. Thus, a robust and broadly applicable method to
determine the dynamics and kinetics is required. Recently,
we introduced a method using dynamic HPLC (DHPLC)10–18
and a novel three-column HPLC setup to determine dynamics
and kinetics in dependence of the stationary phase and solvent
used.19 In the past, dynamic chromatographic techniques
were successfully employed to study the stereodynamics of
substituted biphenyl compounds.20–23
Afterwards pyridine (9.4 ml) was added to a solution of the product
(3.44g, 14.0 mmol) in 20 ml of CH2Cl2 and cooled to 0 ꢀC. To this solution
*Correspondence to: Prof. Dr. Oliver Trapp, Ruprecht-Karls-Universität
Heidelberg, Organisch-Chemisches Institut, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany. E-mail: trapp@oci.uni-heidelberg.de
Received for publication 26 July 2012; Accepted 21 September 2012
DOI: 10.1002/chir.22125
Published online 22 December 2012 in Wiley Online Library
(wileyonlinelibrary.com).
In this study we focused on the influence of the substitution
pattern of disubstituted BIPHEP oxides. Comparison of
the investigated 5,5’-disubstituted BIPHEP oxides with 3,3’-
© 2012 Wiley Periodicals, Inc.

STEREODYNAMICS OF 5,5’-DISUBSTITUTED BIPHEPS
127
Scheme 1. Classical dynamic kinetic resolution.
trifluoromethanesulfonic anhydride (Tf2O, 9.40ml, 57.0 mmol) was added
dropwise, and the mixture was stirred at room temperature for 12 h. The
solvent was removed and the residue was diluted with EtOAc, washed with
1 M HCl, saturated aqueous NaHCO3, and brine. The organic extract was
dried over MgSO4 and the solvent was removed under vacuum to yield
the product without further purification as colorless crystals (7.0 g, 98%).
1H-NMR (300 MHz, CDCl3) d = 7.31 (d, J = 9.0Hz, 2H), 7.01 (dd, J= 9.0,
3.2Hz, 2H), 6.95 (d, J =3.2 Hz, 2H), 3.85 (s, 6H).
[M + Na]+: 609.1355; found: 609.1356. IR [cm–1]: 3165, 1561, 1437,
1184, 1104, 1044, 694. CCDC-903879 contain the supplementary crystal-
lographic data for compound 3. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(5-Hydroxy-5’-methyl-[1,1’-biphenyl]-2,2’-diyl) bis(diphenylpho-
sphine oxide) 4. (5-Methoxy-5’-methyl-[1,1’-biphenyl]-2,2’-diyl) bis
(diphenylphosphine oxide) 2 (49.0 mg, 0.08 mmol) was dissolved in
dry CH2Cl2 (2 ml) and BBr3 (1 M in CH2Cl2, 0.37 ml, 0.37 mmol) was
added dropwise at -78 ꢀC and stirred overnight at room temperature.
Water was added to the reaction mixture, extracted with CH2Cl2, and
the organic phase was dried over Na2SO4. The residue was purified by
preparative HPLC (column: Agilent prep-SIL, 100 mm, i.d. 30mm, 10mm
particle size) (n-hexane/2-propanol (95:5)) to yield product 4 as a white solid
(39 mg, 81%). The dynamic separation of the enantiomers was performed
on a Chiralpak IA (n-hexane/2-propanol 70/30 (v/v), 1.0 ml/min,
temperature 15–55 ꢀC, l = 280 nm). 1H-NMR (300 MHz, CDCl3) d =7.89 – 7.80
(m, 4H), 7.61 – 7.32 (m, 13H), 7.27 – 7.13 (m, 5H), 6.98 – 6.89 (m, 2H),
6.69 (dd, J= 13.2, 8.9 Hz, 1H), 6.28 (d, J = 3.9Hz, 1H), 1.79 (s, 3H). 31P-
NMR (121.6 MHz, CDCl3) d = 30.47, 28.08. ESI-HRMS m/z calc for
C37H31O3P2 [M + H]+: 585.1743; found: 585.1743. FT-IR [cm–1]: 2359, 1745,
1458, 1259, 804.
In the final step the reaction product (2.50 g, 4.90 mmol), diphenylpho-
sphine oxide (3.00 g, 14.8 mmol), palladium acetate (110 mg, 0.49 mmol),
and 1,4-bis(diphenylphosphino)butane (dppb, 220 mg, 0.52 mmol) were
dissolved in dry and degassed DMSO (25 ml) and diisopropylethylamine
(4.2 ml). After stirring the mixture at 110 ꢀC for 6 h the next portions
of diphenylphosphine oxide (1.00 g, 4.9 mmol), palladium acetate
(55 mg, 0.25 mmol), and 1,4-bis(diphenylphosphino)butane (dppb,
110 mg, 0.26 mmol) were added and the reaction mixture was stirred at
110 ꢀC for 12 h. After cooling the mixture to room temperature, CH2Cl2
(25 ml) was added and the organic phase was washed with 1 M HCl
and brine. The organic layer was dried over Na2SO4 and concentrated
under vacuum. The residue was purified by column chromatography
on silica gel with petrol ether/2-propanol (4:1) as the eluent, yielding
product 1 (1.3 g, 45%) as a white solid. The dynamic separation of the
enantiomers was performed on a Chiralpak IC (n-hexane/2-propanol
45/55 (v/v), 1.0 ml/min, temperature 20–70 ꢀC, l = 280 nm). 1H-NMR
(300 MHz, C6D6) d = 8.04 – 7.95 (m, 6H), 7.22 – 7.00 (m, 18H), 6.52
(dt, J = 8.6, 1.9 Hz, 2H), 3.29 (s, 6H). 31P-NMR (121.6 MHz, C6D6)
d = 40.02. ESI-HRMS m/z calc for C38H33O4P2 [M + H]+: 615.1849; found:
615.1850. FT-IR [cm–1]: 1589, 1558, 1437, 1264, 1233, 1115, 1029, 953, 816.
(5-Hydroxy-5’-methoxy-[1,1’-biphenyl]-2,2’-diyl)bis(diphenyl-
phosphine oxide) 5. Product 5 was obtained as a byproduct (<5%) of
the reaction to (5,5’-dihydroxy-[1,1’-biphenyl]-2,2’-diyl)bis(diphenylpho-
sphine oxide) 3. The dynamic separation of the enantiomers was
performed on a Chiralpak IA-3 (n-hexane/2-propanol/methanol 90/5/5
(v/v/v), 1.2 ml/min, temperature 10–50 ꢀC, APCI-MS trace). EI-HRMS
m/z calc for C37H31O4P2 [M + H]+: 601.1692; found: 601.1692.
(5-Methoxy-5’-methyl-[1,1’-biphenyl]-2,2’-diyl) bis(diphenylpho-
sphine oxide) 2. (5-Methoxy-5’-methyl-[1,1’-biphenyl]-2,2’-diyl) bis
(diphenylphosphine oxide) 2 was prepared according to the preparation
of product 1, using 4-methoxyphenol and 4-methylphenol as starting
material. (5-Methoxy-5’-methyl-[1,1’-biphenyl]-2,2’-diyl) bis(diphenylpho-
sphine oxide) 2 was obtained as white solid in 26% overall yield over
three steps. The dynamic separation of the enantiomers was performed
on a Chiralpak IC (n-hexane/2-propanol 60/40 (v/v), 1.0 ml/min, temperature
10–50ꢀC, l = 280 nm). 1H-NMR (300 MHz, MeOD) d = 7.79 – 7.24 (m, 20H),
7.18 – 7.02 (m, 3H), 6.74 – 6.67 (m, 2H), 6.58 (t, J= 3.0 Hz, 1H), 3.49 (s, 3H),
2.04 (s, 3H). 31P-NMR (121.6MHz, MeOD) d = 31.39, 30.82. ESI-HRMS m/z
calc for C38H33O3P2 [M+ H]+: 599.1899; found: 599.1908. FT-IR [cm–1] 1592,
1558, 1438, 1224, 1169, 1114, 1030, 816, 723, 692.
Dynamic High-Performance Liquid Chromatography
(DHPLC)
The stereodynamics of the 5,5’-disubstituted BIPHEPs were investigated
by DHPLC, performed on an Agilent Technologies 1200 HPLC (Agilent
Technologies, Palo Alto, CA, USA), with a quadrupole mass spectrometer
Agilent 6120, equipped with an APCI source. Dynamic enantioselective
separations were performed on Chiralpak IA, IA-3, IC, or IC-3 columns
(IA + IC: 250 mm, i.d. 4.6 mm, particle size 5 mm; IA-3 + IC-3: 150 mm,
i.d. 4.6 mm, particle size 3 mm), which were purchased from Chiral
Technologies, Illkirch, France. The solvents used (n-hexane, 2-propanol,
and methanol) were obtained from Sigma-Aldrich (HPLC-grade quality).
Dynamic HPLC measurements of all compounds were performed with
solutions of 1.0 mg substance in 1.0 ml of the solvent mixture, which
was also used for the separation. Elution profiles with distinct plateau
formation were measured between 10 and 70 ꢀC. All measurements were
repeated three times.
(5,5’-Dihydroxy-[1,1’-biphenyl]-2,2’-diyl)bis(diphenylphosphine
oxide) 3. (5,5’-Dimethoxy-[1,1’-biphenyl]-2,2’-diyl)bis(diphenylpho-
sphine oxide) 1 (2.43 g, 3.96 mmol) was dissolved in dry CH2Cl2
(50 ml) and BBr3 (1 M in CH2Cl2, 15.9 ml, 15.9 mmol) was added drop
wise at -78 ꢀC and stirred overnight at room temperature. Water was
added to the reaction mixture, extracted with CH2Cl2, and the organic
phase was dried over Na2SO4. The residue was washed thoroughly with
ethyl acetate to remove byproducts. Product 3 was obtained as a white
solid (2.0 g, 86%). The dynamic separation of the enantiomers was
performed on a Chiralpak IA-3 (n-hexane/2-propanol/methanol 90/5/5
(v/v/v), 1.2 ml/min, temperature 10–40 ꢀC, l = 210 nm). 1H-NMR
(300 MHz, MeOD) d = 7.79 – 7.29 (m, 20H), 7.02 (dd, J = 13.6, 8.6 Hz,
2H), 6.57 (dt, J = 8.6, 2.2 Hz, 2H), 6.38 (dd, J = 3.6, 2.3 Hz, 2H). 31P-NMR
(121.6 MHz, MeOD) d = 31.17. ESI-HRMS m/z calc for C36H28O4P2Na
Determination of Reaction Rate Constants and the Gibbs
Activation Energy
Reaction rate constants were determined using the unified equation,
which allows for the direct calculation of the reaction rate constants
k1 and k–1 and Gibbs activation energies ΔG╪ for all types of first-order
reactions taking place in chromatographic or electrophoretic systems
(for details, see 28–34 in the Literature Cited). Note that only the forward
reaction rate constant k1 is reported, because the reaction rate constant
Chirality DOI 10.1002/chir

128
MAIER AND TRAPP
k
–1 is lower according to the interaction with the chiral selector and the
resulting enantioselectivity ΔΔGR,S, which is mathematically considered
by the principle of microscopic reversibility.35–37 All calculations of the
chromatograms were performed with the software DCXplorer (this
software is available from the corresponding author upon request as an
executable program running under the operating systems Microsoft
Windows XP, Vista, and 7).38
Evaluation of Activation Parameters ΔH╪ and ΔS╪
For the evaluation of activation parameters of the enantiomerization
process of the BIPHEP molecules we determined the reaction rate
constants at temperatures between 10 and 70 ꢀC. Peak coalescence
occurred at higher temperatures due to the fast interconversion process
at elevated temperatures. The Gibbs free activation energy ΔG╪(T) was
calculated according to the Eyring equation (Eq. 1) with kB as the
Boltzmann constant (kB = 1.381 ꢁ 10–23 J K–1), T as the enantiomerization
temperature [K], h as Planck’s constant (h = 6.626 ꢁ 10–34 J sec), and R as
the gas constant (R = 8.31 J K–1 mol–1). The statistical factor k was set to
0.5 for a degenerated interconversion process.
Fig. 1. Crystal structure of BIPHEP 3 determined by X-ray diffraction
analysis. Selected bond distances [Å] and angles [ꢀ] are: P1-C11 1.7934(14),
P2-C21 1.8009(14), C12–C22 1.4977(18), O1–P1–C11 115.33(6), O2–P2–C21
115.17(7), C12–C11–P1 123.42(10), C22–C21–P2 123.68(11). Dihedral angle
between the two phenyl rings: C13–C12–C22–C23: 91.2ꢀ; C11–C12–C22–C21: 93.1ꢀ.
k1h
kkBT
ΔG╪ðTÞ ¼ ꢂRT ln
(1)
The activation enthalpy ΔH╪ was obtained from the slope and the
activation entropy ΔS╪ from the intercept of the Eyring plot (ln(ku1e /T)
as a function of T –1). Deviations of the activation parameters ΔH╪
and ΔS╪ have been calculated by analysis of the confidence interval of the
linear regression with a level of confidence of 95%.
An excellent separation of the interconverting enantiomers
was achieved by enantioselective HPLC using either the
immobilized chiral stationary phase (CSP) Chiralpak IA or
Chiralpak IC (both: 250 mm, i.d. 4.6 mm, 5 mm particle size).
To economize the separation process we used, if possible,
shorter separation columns with smaller particle size to
achieve almost the same separation rates in much less time
(column: Chiralpak IA-3 and IC-3; both: 150 mm, i.d. 4.6 mm,
3 mm particle size). Representative elution profiles of the
enantiomers of BIPHEP 3 from the DHPLC experiments
are depicted in Figure 2.
RESULTS AND DISCUSSION
The series of 5,5’-disubstituted BIPHEP oxides (5,5’-disubsti-
tuted-[1,1’-biphenyl]-2,2’-diyl)bis(diphenylphosphine oxides)
were synthesized according to modified sequences developed
by Yuxue Liang et al.26 and Wanbin Zhang et al.27 (Scheme 2)
Products 1 and 2 could be synthesized from 4-methoxyphe-
nol and 4-methylphenol in three steps with 23% and 26% yield,
respectively. For the oxidative coupling of the starting materials
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and AlCl3
were used. The subsequent treatment of the compounds 1
and 2 with Tf2O (trifluoromethanesulfonic anhydride) in the
presence of Et3N afforded the corresponding ditriflate deriv-
ative in almost quantitative yield. The diphenylphosphine
oxides 3 and 4 were obtained by Pd-catalyzed phosphinoylation
of the triflates with diphenylphosphine oxide (HPPh2O) in
DMSO at an elevated temperature. Demethylation with BBr3
yields the corresponding hydroxyl-BIPHEP derivatives in yields
up to 86%. Diphenylphosphine oxide 3 was fully characterized
by single crystal X-ray analysis (see Fig. 1).
To determine the activation barrier ΔG╪ and the activation
parameters ΔH╪ and ΔS╪ of the enantiomerization by rotation
about the s bond, temperature-dependent dynamic HPLC
experiments were performed between 10 ꢀC and 50 ꢀC. Due
to rapid interconversion at higher temperatures complete
coalescence of the enantiomers was observed. Reaction rate
constants k1 and kꢂ 1 of the enantiomerization of the BIPHEP
oxides were calculated using the analytical function of the
unified equation28,38 considering three experiments at each
temperature. Selected experimental data of BIPHEP 3 deter-
mined from the elution profiles and the calculated reaction
rate constants are summarized in Table 1.
Scheme 2. Synthesis of BIPHEPs 1–5 by oxidative coupling of phenol derivatives using DDQ, subsequent treatment with trifluoromethanesulfonic anhydride
and Pd-catalyzed phosphinoylation of the corresponding triflates with diphenylphosphine oxide. Demethylation of methoxy derivatives 1 and 2 was achieved by
BBr3 yielding compounds 3–4.
Chirality DOI 10.1002/chir

STEREODYNAMICS OF 5,5’-DISUBSTITUTED BIPHEPS
129
Fig. 2. Selected experimental interconversion profiles of the enantioselective DHPLC experiments of BIPHEP 3 between 10 and 50 ꢀC. Chromatographic
conditions: Column: Chiralpak IA-3, 250 mm, 4.6 mm, 3 mm particle size, (n-hexane/2-propanol/methanol 90/5/5 (v/v/v), 1.2 ml/ min, l = 210 nm).
TABLE 1. Experimental data of the enantiomerization of BIPHEP 3 between 10ꢀC and 40ꢀC obtained by enantioselective DHPLC.
Chromatographic conditions: Column, Chiralpak IA-3, 250 mm, 4.6mm, 5 mm particle size, (n-hexane/2-propanol/methanol 90/5/5
(v/v/v), 1.2 ml/ min, l = 210 nm)
T (ꢀC)
tRA (min)
tRB (min)
hp (%)
N 1
N 2
a
k1(10–4 sec–1
)
10.0
10.0
10.0
15.0
15.0
15.0
20.0
20.0
20.0
25.0
25.0
25.0
30.0
30.0
30.0
35.0
35.0
35.0
40.0
40.0
40.0
5.905
5.891
5.880
5.560
5.557
5.547
5.279
5.269
5.269
5.050
5.037
5.037
4.839
4.834
4.814
4.650
4.644
4.635
4.502
4.490
4.485
9.105
9.091
9.080
8.494
8.484
8.467
7.959
7.936
7.935
7.497
7.464
7.464
7.065
7.040
7.020
6.657
6.637
6.629
6.275
6.250
6.232
3.62
3.59
3.50
4.01
4.09
4.07
6.17
6.24
6.12
10.65
10.63
10.57
19.02
18.83
18.77
34.58
34.72
34.60
66.36
67.48
67.07
834
887
883
959
1036
954
991
987
987
967
961
961
950
947
1029
942
939
1030
867
861
947
820
817
815
905
945
941
993
1039
1039
1139
1127
1127
1275
1264
1256
1273
1264
1356
1284
1272
1171
1.65
1.65
1.66
1.64
1.64
1.64
1.63
1.62
1.62
1.60
1.60
1.60
1.58
1.58
1.58
1.55
1.55
1.55
1.51
1.50
1.50
3.98
4.07
3.98
4.88
5.14
4.97
7.60
7.67
7.54
12.5
12.4
12.4
20.8
20.5
21.3
34.2
34.3
35.2
56.5
56.3
57.1
The activation enthalpy ΔH╪ and activation entropy ΔS╪ of
the BIPHEPs were obtained by plotting ln(k1/T ) as a function
of T –1, according to the Eyring equation (see Fig. 3). Elution
profiles showing coalescence at elevated temperature
(>45 ꢀC) were not considered for the calculation of activation
parameters. The Gibbs free energy ΔG╪ and the activation
parameters ΔH╪ and ΔS╪ of all analyzed BIPHEP molecules
are summarized in Table 2.
The investigated Gibbs free energies ΔG╪ of the 5,5’-disub-
stituted BIPHEP oxides varying from 87.8 kJ mol–1 for
BIPHEP 3 to 93.0 kJ mol–1 for BIPHEP 1. Apparently the
more electron-rich BIPHEPs bearing methoxy substituents
like BIPHEP 1 and 5 show a higher intrinsic rotation barrier
Fig. 3. Eyring plot of BIPHEP 3 between 15 ꢀC and 40 ꢀC.
Chirality DOI 10.1002/chir

130
MAIER AND TRAPP
TABLE 2. Activation parameters obtained by enantioselective DHPLC. Temperatures: a, 20 ꢀC; b, 10 ꢀC
ΔG{298K
ΔH{
ΔS{
k1
Solvent
n-hex:IPA:MeOH
BIPHEP
1
tRA (min)
tRB (min)
(kJ mol–1
)
(kJ mol–1
)
(J mol–1 K-1)
(10–4 sec–1
)
CSP
IC
9.5a
17.1a
93.0
90.5
87.8
88.5
90.6
40.8 ꢃ 0.3
69.5 ꢃ 0.3
71.2 ꢃ 0.9
57.9 ꢃ 0.5
38.9 ꢃ 1.0
-175 ꢃ 11
1.61
4.42
12.4
9.53
3.99
45:55:0
60:40:0
90:5:5
2
3
4
5
13.8b
5.9b
6.9b
7.9b
22.4b
9.1b
-70 ꢃ 1
IC
-56 ꢃ 2
IA-3
IA
11.2b
10.8b
-103 ꢃ 2
-173 ꢃ 32
70:30:0
90:5:5
IA-3
than BIPHEPs with hydroxyl substituents in 5,5’-position.
The ΔH╪ values range between 38.9 ꢃ 1.0 kJ mol–1 for
BIPHEP 5 to 71.2ꢃ 0.9 kJmol–1 for BIPHEP 3. The activation
entropy ΔS╪ ranges from -56 ꢃ 2 J mol–1 K–1 for BIPHEP
3 to -175 ꢃ 11 J mol–1 K–1 for BIPHEP 1. The negative values
for the activation entropies indicate an increased organization
of the substrate or its environment at the transition state.
BIPHEPs 3 and 5 were measured under identical separation
conditions. Here the activation entropy ΔS╪ is more negative
for the more electron-rich methoxy-substituted BIPHEP
5 compared to BIPHEP 3, which might be explained by
solvent effects increasing the sterical demand for rotation.
Another explanation might be intermolecular interactions.
We exclude stationary phase effects, because results of a
previous publication indicate only a negligible influence for
this compound class. Similar to a recently described effect
by us about compensation of the activation parameters
ΔH╪ and ΔS╪ for 3,3’-disubstituted BIPHEP molecules,19 we
determined the same phenomena for the 5,5’-disubstituted
BIPHEPs analyzed here. Comparison of BIPHEPs 2 and 5,
where ΔG╪ has almost the same value (90.5 and 90.6kJ mol–1,
respectively), have strongly different activation parameters
(ΔH╪: 69.5 ꢃ 0.3 and 38.9 ꢃ 1.0 kJ mol–1; ΔS╪: -70 ꢃ 1 and
-173 ꢃ 32 J mol–1 K–1, respectively).
With the determined data it is possible to compare the
rotational barriers for the different substitution pattern of
BIPHEP ligands (see Fig. 4). As expected, the unsubstituted
BIPHEP has the lowest rotation barrier (ΔG╪ = 86.8 kJ mol–1)
of the BIPHEPs shown in Figure 4.19 To compare the rotation
barriers of the substitution pattern of the 3,3’-, 5,5’-, and 6,6’-
disubstituted BIPHEP ligands it is important to observe
the same substituents. For methoxy-substituted BIPHEPs
the rotation barrier of the 6,6’-disubstituted BIPHEP ligands
is considerable higher due to steric hindrance. Even at
elevated temperatures, this ligand shows atropisomerism.
Compared to the 5,5’-disubstituted ligand the rotation barrier
of the 3,3’-disubstituted analogue is slightly increased due to
a buttressing effect that increases the steric hindrance along
the s bond.39 Despite a higher rotation barrier for the
3,3’- and the 5,5’-analogue compared to the unsubstituted
Fig. 4. Comparison of the rotation barriers of BIPHEP ligands with different substitution pattern.
Chirality DOI 10.1002/chir

STEREODYNAMICS OF 5,5’-DISUBSTITUTED BIPHEPS
131
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J Sep Sci 2001;24:941–946.
BIPHEP, these ligands are still tropos at room temperature.
It should be noted that the rotation barriers of the oxidized
BIPHEP molecules are approximately 2 kJ mol–1 higher than
the barriers of the nonoxidized analogues.19
13. Trapp O, Caccamese S, Schmidt C, Böhmer V, Schurig V. Enantiomerization
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CONCLUSION
We synthesized and investigated the stereodynamics of
5,5’-substituted (hydroxy, methoxy, and methyl groups) tropos
BIPHEP ligands (2,2’-bis(diphenylphosphino)-biphenyls) by
temperature-dependent enantioselective dynamic HPLC in
presence of the immobilized chiral stationary phases (CSP)
Chiralpak IA or Chiralpak IC to elucidate the influence of the
substitution pattern and electronics of the substituents. The
obtained activation parameters, in particular the activation
enthalpies ΔH╪ and activation entropies ΔS╪, reveal a strong
influence of the substitution pattern and electronics of the
substituents. Interestingly, the activation barriers are in a narrow
range between 87.8 and 93 kJ mol–1, which can be explained
by enthalpy and entropy compensations.40 Furthermore,
the here-determined parameters allow the comparison of the
stereodynamics of 3,3’- and 5,5’-substituted tropos BIPHEP
ligands. These activation parameters can help in designing
novel BIPHEP ligands, which can be deracemized for use in
asymmetric catalysis.
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ACKNOWLEDGMENTS
Generous financial support from the European Research
Council (ERC) (Starting Grant No. 258740, AMPCAT, to O.T.)
is gratefully acknowledged. We thank Dr. Frank Rominger for
the X-ray analysis and structure elucidation of compound 3.
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