Pd- η3-C6H9 complexes of the Trost modular ligand: High nuclearity columnar aggregation controlled by concentration, solvent and counterion

Article abstract of DOI:10.1039/c5sc01181g

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η³-C₆H₉ intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η³-C₆H₉ species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η³-C₆H₉ cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D₄₇) isotopologues of the resulting complexes ([1]⁺), we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.

Full text of DOI:10.1039/c5sc01181g

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Pd-h -C H complexes of the Trost modular ligand:
6
9
high nuclearity columnar aggregation controlled
Cite this: Chem. Sci., 2015, 6, 5793
by concentration, solvent and counterion†
a
a
bc
d
Daugirdas Tomas Racys,‡ Julian Eastoe, Per-Ola Norrby, Isabelle Grillo,
e
f
Sarah E. Rogers and Guy C. Lloyd-Jones*
Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric
induction in an extraordinarily wide range of reactions involving palladium p-allyl intermediates. Prior
3
mechanistic investigations into reactions involving Pd-h -C
H
6 9
intermediates have focussed on the
monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also
3
recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-h -C
6
H
9
species
that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the
mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions.
Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics,
3
and small-angle neutron scattering (SANS), of a Pd-h -C
6
H
9
cation bearing the 1,2-diaminocyclohexane
Received 2nd April 2015
Accepted 12th June 2015
TML ligand (2). Using both nondeuterated and perdeuterated (D47) isotopologues of the resulting
+
complexes ([1] ), we show that a two-stage oligomerisation-aggregation process forms self assembled
DOI: 10.1039/c5sc01181g
cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how
concentration, solvent and counter-anion all modulate the extent of oligomerisation.
www.rsc.org/chemicalscience
high-enantiopurity chiral building blocks. However, reactions
involving the TML can exhibit memory effects, and a high
The Trost modular ligand (TML) series has been applied to an sensitivity of the enantioselectivity to reaction temperature,
extraordinarily wide range of allylic alkylation (Tsuji-Trost) catalyst concentration, solvent and nucleophile counter-ion.
Introduction
8,9
1
2
reactions. Under carefully optimised conditions, these ligands
frequently provide very high enantioselectivity in reactions that
have proven challenging with other chiral ligands, particularly
3
–6
those involving cyclic allylic substrates. These features have
led to broad use of the TML in the synthesis of natural prod-
7
ucts, as well as industrial application for the construction of
a
School of Chemistry, University of Bristol, Office S314, Cantock's Close, Clion,
Bristol BS8 1TS, UK. E-mail: Julian.Eastoe@bristol.ac.uk
Our previous mechanistic studies of this system focussed on
b
+
3
AstraZeneca Pharmaceutical Development, Global Medicines Development,
the monomeric cationic complex [1] , in which a Pd(h -C
6 9
H )
Pepparedsleden 1, SE-431 83 M ¨o lndal, Sweden. E-mail: per-ola.norrby@
unit is chelated by the 1,2-diaminocyclohexane-derived TML
astrazeneca.com
10
+
ligand (2). The monomeric cation [1] was identied as an
intermediate capable of leading to high asymmetric induction
on attack of, for example, a malonate anion nucleophile,
Scheme 1. Detailed NMR studies facilitated by isotopic labelling
c
Department of Chemistry and Molecular Biology, University of Gothenburg,
Kemig a˚ rden 4, #8076, SE-412 96 G ¨o teborg, Sweden
d
ILL, CS20156, 38042 Grenoble Cedex 9, France. E-mail: grillo@ill.fr
e
ISIS-STFC, Rutherford Appleton Laboratory, Chilton, Oxon, OX11 0QX, UK. E-mail:
10
sarah.rogers@stfc.ac.uk
– in conjunction with MM-DFT simulations – led to a model in
f
School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains
which the amide units in the catalyst facilitate enantioselective
Road, Edinburgh, Scotland EH9 3JJ, UK. E-mail: guy.lloyd-jones@ed.ac.uk
11
ligand-accelerated catalysis.
†
Electronic supplementary information (ESI) available: Synthesis and
For the ligand-accelerated catalysis to function efficiently,
Characterisation of compounds, and full details of aggregation studies by NMR,
SANS, and MM3. See DOI: 10.1039/c5sc01181g
+
cation [1] requires a degree of exibility. This exibility is
provided by the 13-membered chelate ring, but at a cost:
Building, University Avenue, Glasgow, Lanarkshire G12 8QQ, UK. E-mail: complex [1] can readily undergo ring-opening oligomerisation
‡
Current address: School of Chemistry, University of Glasgow, Joseph Black
+
daugirdas.racys@glasgow.ac.uk.
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Scheme 1 Asymmetric allylic alkylation of racemic 2-cyclohexenyl
acetate; 2 ¼ 1,2-diaminocyclohexane TML ligand, THAB ¼ tetrahexyl-
ammonium bromide.
Fig. 1 Speciation of [(R,R)-1][BAr
F
] (BAr
F
¼ B(C
6
F
5
)
4
) determined by
31
1
ꢀ
P{ H} NMR (CD Cl , 25 C). Solid lines through data are solely a guide
2 2
to the eye. Inset shows proportion (%) of [Pd]tot that is in oligomeric
form.
1
6
3
allyl complexes of ligand 2 are h -C H complexes with triate
3
5
12
counter anions: one a racemic tetranuclear cyclo-oligomer, the
other an acyclic dinuclear bis-P,O-chelate.
The extent of solution-phase oligomerisation of cationic
17
+
31
1
+
complexes of type [1] can be conveniently estimated by P{ H}
Scheme 2 Oligomerisation of [1] erodes enantioselectivity during
1
0,12
asymmetric Pd-catalysed allylic alkylation mediated by 2 (as Scheme NMR spectroscopy.
Analysis of [(R,R)-1][BAr
Cl , 3,5-(CF , or C
indicates a maximum monomer concentration ([1] ) of about
] complexes in
(“BAr ”),
4
1
). Nu ¼ nucleophile.
CH
2
Cl
2
, where Ar ¼ C
6
5
3
)
2
C
6
H
3
6
F
5
F
+
+
12
4 mM, Fig. 1. In THF, the monomer maximum is lower (approx.
to generate polynuclear species ([1] )
n
, Scheme 2. Competing
1.6 mM) and decreases as [Pd]tot is raised above 10 mM. With
nucleophilic attack on the oligomer, rather than the monomer
1] is, in part, responsible for a reduction in overall enantio-
selectivity under non-optimised conditions.
To date, the structure and origin of the formation of these
oligomeric species has not been studied in detail. Herein, we
+
smaller, less charge-diffuse, counter-anions such as chloride or
triate, the maximum monomer concentrations are lower still.
[
13,14
18
We were unable to t simple analytical solutions for mono-
3
1
mer-oligomer distributions to any of the P NMR data, indic-
ative that physicochemical effects dominate over simple
solution-phase equilibria, even at low [Pd]tot.
0
describe an investigation of the oligomerisation of D and D47
+
isotopologues of [1] , employing NMR spectroscopy, molecular
mechanics (MM), molecular dynamics (MD), and contrast
variation small-angle neutron scattering (SANS). The data
obtained indicate that the impact of a rst-stage of depletion of
We thus elected to study the oligomeric species by SANS – a
technique that can be used for characterising the shape and
1
9
dimensions of self-assembly structure and colloids. We
2
0
+
began with [(R,R)-1][BAr
thesised the perdeuterated enantiomeric complex [(S,S)-[D47]-
][BAr ]. Not only does this facilitate SANS in a non-deuter-
ated solvent, thus providing greater neutron scattering
F
], and, to aid the studies, also syn-
the monomeric species [1] from the catalyst pool, via cyclic
oligimerisation, is amplied by
a second-stage process
1
F
involving columnar aggregation of the oligomers, leading to
species with very high nuclearity (up to 56 Pd centres). The
effects of solvent, ligand enantiopurity and counter-ion on the
degree of aggregation are explored in detail, and it is concluded
that a relatively small and restricted set of conditions facilitate
dissolution of the complexes in a low aggregation state,
consistent with the extensive optimisation frequently required
for these catalyst systems.
1
9
contrast, it also allows pseudo racemic and pseudo scalemic
mixtures to be prepared by mixing [(S,S)-[D47]-1][BAr ] with
F
[
(R,R)-1][BAr ]. The perdeuterated complex was synthesised
F
from benzoic acid ([D ]-3), chlorobenzene ([D ]-4) and
5
5
cyclohexene ([D10]-5), Scheme 3. A major hurdle was the
2
1
ortho-metallation of ester [D
5 2
]-6 with (TMP) Mg$LiCl, which
proceeded with an unexpectedly large net kinetic isotope
2
2
H D
effect (k /k z 30). This required an excess of base to be
employed, and interfered with a planned direct phosphina-
tion of the metallated intermediate. Instead, the intermediate
was trapped with I . The iodide [D ]-7 was then converted to a
Results and discussion
Preliminary NMR studies and synthesis of [D47]-[1][B(C F ) ]
6 5 4
2
4
15
23
Despite extensive efforts, we have been unable to crystallise any more conventional Grignard reagent, before reaction with
3
10,24
Pd(h -C
6
H
9
) complexes of 2, in either oligomeric or monomeric chlorophosphine [D10]-8
forms. Indeed, to date, the only the X-ray crystal structures of Pd- thus acid [D14]-10.
to give phosphine [D14]-9, and
2
5
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26
Cyclohexene [D10]-5, was epoxidised, to give [D10]-11, and
27
28
this ring-opened to give aminoalcohol [D ]-12. Aziridine
1
0
[
D ]-13, obtained under Mitsunobu conditions, was converted
10
29
to azide [D ]-14. Aer diastereoisomer separation, hydro-
genolysis gave (S,S)-diamine [D10]-15, which was coupled with
acid [D14]-10 to afford Trost ligand [D38]-2. The chloro-bridged
dimer [D18]-16, prepared from [D10]-5, was converted to
cationic complex [D ]-17, and then reacted with [D38]-2 to
generate [(S,S)-[D47]-1][BAr ] in good yield.
1
0
30
31
9
F
SANS analysis of aggregation of [1][BAr ] in THF
F
3
2
We began with SANS analysis of enantiopure [(R,R)-1][BAr ] in
F
ꢀ
THF-D at 25 C, with [Pd] concentrations 16 to 64 mM, well
above the oligomerisation threshold. The combined data sets,
8
tot
33
presented here as plots of scattered intensity (I(Q), y-axis) versus
momentum transfer (Q, x-axis) were analysed with a range of
different standard models for possible aggregate form factors,
19
34
corresponding to various simple shapes, Fig. 2. This clearly
identied the particles as cylindrical or rod-like, and Guinier
˚
analyses (see ESI, Fig. S69†) established the radii (8-9 A) and
˚
lengths (150-200 A) as essentially invariant across the range of
[Pd]tot explored. In other words, the number density of aggre-
gates changes in response to [Pd]tot, but not their average
35
dimensions, clearly indicative of a set of factors that tightly
control the particle scale.
3
1
We have previously used P NMR spectroscopy to analyse
the constitution of the solution-phase (i.e., lower-order) oligo-
mers generated from various complexes of type [1][BAr ] in
4
10,12
CD Cl .
Using PPCOSY in combination with pairs of isoto-
2
2
pically-differentiated ligands ([D ]-2), we were able to determine
n
F F
Scheme 3 Synthesis of pseudo enantiomer [(S,S)-[D47]-1][BAr ]; BAr
ꢀ
t
¼
B(C F ) . Conditions: (i) SOCl , toluene, 100 C; (ii) KO Bu, THF
6 6 4 2
ꢀ
ꢀ
ꢀ
ꢀ
0
C; 84%; (iii) (TMP)
2
Mg$2LiCl, THF, 0 C to 30 C; (iv) I
2
, THF, -30 C;
i
ꢀ
4
Et
9%; (v) PrMgCl, THF, -40 C, 2 h; (vi) Mg, LiCl, THF, reflux; (vii)
O, -40 C; 29%; (ix) [D10]-8 drop-wise
addition, THF, -78 C; 68%; (x) KOH, THF, r.t., 24 h; (xi) HCl; 58%; (xii)
ꢀ
2
NPCl
2
, THF; (viii) HCl, Et
2
ꢀ
ꢀ
5
% Ru(PPh
3
)
3
Cl
2
, D
2
O, 10% SDS, microwave, 140 C, 1 h; (xiii) mCPBA,
CH Cl , NaHCO
2
ꢀ
2
3
; 51%; (xiv) (S)-1-phenylethylamine, MeCN, LiBr,
ꢀ
6
0
C; 74%; (xv) DIAD, PPh
CeCl $7H O, MeCN/H
raphy; 61%; (xviii) 20% Pd(OH)
Pd(OH) /C, MeOH, 2 M HCl/Et
CH Cl , r.t.; (xxi) EDCI$HCl, HOBt$H
Et
3
, THF, 0 C to r.t.; 62%; (xvi) NaN
3
,
3
2
2
O 9 : 1, reflux; (xvii) silica-gel chromatog-
2
/C, MeOH, r.t., 1 atm H
2
; (xix) 20%
ꢀ
Fig. 2 SANS profiles of 1.6 to 64 mM (0.25-10.0 wt/vol%) {[(R,R)-1]
2
2
O, HCO
2
NH
4
, 65 C; (xx) KOH,
i
ꢀ
ꢁ1
O, Pr
2
NEt, CH
, AcOH, Ac
, MeCN, CH
2
Cl
O, 2 h, 95 C;
Cl , r.t.; (xxvi)
2
, r.t.; (xxii) [BArF]}
n
8
in THF-D , 25 C; I(Q) ¼ scattered intensity, Q/A˚
¼
2
2
2
ꢀ
momentum transfer ¼ (4p/l)sin(q/2); where scattering angle ¼ q and
neutron wavelength ¼ l. The fitted curves correspond to a cylindrical
particle form factor. The sample with 1.6 mM [Pd]tot has form factor
fitted to radius # 11 A˚ and length # 50 A˚ . All other samples are fitted to
radius 8-9 A˚ and length 150-200 A˚ .
2
O, HCl; 30%; (xxiii) NaCl, NaOAc, CuCl
2
2
ꢀ
(
xxiv) [D10]-5, 60 C, 20 h; 13% (xxv) KBAr
F
2
2
2 2
CH Cl , r.t.; 99%. See ESI† for full details.
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that the oligomers are: i) non-chelated species (i.e. each of the
ligands (2) in the oligomer are coordinated to two different Pd
centres); ii) present in predominantly homochiral form (i.e.
+
+
[
(R,R)-1] and [(S,S)-1] oligomerise independently), and iii)
contain no ‘free’ (i.e. not Pd-coordinated) P-centres in the ligand
2). Although a cyclic oligomer structure (Scheme 2) is fully
(
consistent with these features, we were unable to determine the
number (n) of ring-opened monomer units incorporated within
the cyclo-oligomer ([1][BAr
4 n
]) .
As [Pd]tot in THF or CH Cl solutions of complexes of type [1]-
2
3
2
1
[
BAr ] is increased, the P NMR bandshape of the signals
4
arising from the cyclo-oligomer do not change in appearance,
but the samples do become increasingly turbid. This behaviour
suggests that in response to an increase in [Pd]tot, cyclo-oligo-
Fig. 4 SANS data and cylinder form factor fits for pseudo racemic
mers ([1][BAr
instead aggregate to form larger particles, {([1][BAr
taining ‘m’ cyclo-oligomers. It is these high nuclearity particles
4
])
n
do not incorporate more monomer (n), but
ꢀ
complex ([(S,S)-[D47]-1][BAr
F
] + [(R,R)-[D
0
]-1][BAr
F
]) in THF-D
8
at 25 C,
4
])
}
n m
, con- at [Pd]tot ranging from 13 to 51 mM.
12
that are detected by SANS.
again consistent with a statistical distribution of cyclo-oligo-
In racemic or scalemic samples of [1][BAr ], the homochiral
F
37
mers in the aggregate.
cyclo-oligomers, ([1][BAr ]) , could aggregate in three general
F
n
forms: discrete homochiral, ordered heterochiral (e.g., alter-
nating or co-block), or statistically distributed. SANS data of
Molecular mechanics (MM) and dynamics (MD)
mixtures of [(R,R)-1][BAr
F F
] and [(S,S)-1][BAr ] representing Computational modelling was employed to probe the factors
enantiopure, scalemic, and racemic samples, was uniform that control the aggregation phenomena, and to estimate the
38
across the series, within experimental error, Fig. 3. The absence size (n) and number of cyclo-oligomers in the particle (m). The
36
of a change in particle number density is consistent with a number of atoms in the aggregates (>2,000, vide infra) means
statistical cyclo-oligomer distribution in which there is no that density functional theory (DFT) calculations of their
signicant impact of homo- or hetero-chirality on the particle structures would demand currently unattainable computational
shape or size.
resources and inordinate simulation times. On the other hand,
F
] + molecular mechanics (MM) can provide a good approximation
SANS data of the pseudo racemate [(S,S)-[D47]-1][BAr
[
(R,R)-[D
0
]-1][BAr
F
]) in H
8
-THF, and in D
8
-THF, Fig. 4, and in just a small fraction of the computational time required by
-THF, show that DFT. Although MM in general calculates only a steric energy,
enantiomerically pure [(S,S)-[D47]-1][BAr
F
] in D
0
the fully and partially deuterated systems retain the concen- not the full free energy, and ignores bond dissociation energies,
tration-independent, cylindrical aggregate shape. A major accurate results can be obtained from MM3 calculations
difference is, however, observed in the dimensions: [D ]-[1]- provided that comparisons are isodesmic and, more impor-
4
7
˚
˚
39
[
BAr ] forms shorter (130 A), slightly wider (10 A radius) cylin- tantly, isoparametric. This requirement is fullled for all
F
0 F
ders than [D ]-[1][BAr ]. The pseudo racemic mixture measures comparisons of ring oligomers and their non-covalent aggre-
˚
˚
as an average of its precursors (9-10 A radius, 150 A length), gates. We began by conrming that the structure of the 84-atom
+
monomeric cationic P,P-chelate [1] , optimised at MM3 level of
theory with dielectric constant 3 ¼ 9.0, was almost identical to
that obtained using DFT (B3LYP-D3) in a polarisable continuum
38
model for dichloromethane. Further calculations involving
ion-pairs, oligomers and aggregates were then performed using
MM3 to provide analysis of the energies involved, albeit at a
coarse-grained level of detail.
Comparison of the MM3 optimised energies for monomeric
P,P-chelate [1][BArF] with a series of homochiral cyclo- oligo-
mers, ([1][BArF])
n
, normalised by the number of Pd atoms
(n, the x-axis in Fig. 5) conrmed cyclo-oligomerisation to be
exothermic, and probably also exergonic up to tetramers (n ¼ 4).
The cyclic dimer (n ¼ 2) still suffers from ring strain, and a more
substantial stability is afforded by trimerisation (n ¼ 3) then
40
tetramerisation (n ¼ 4).
Further increase in oligomer ring size (n ¼ 5, 6, 8) yields a
modest reduction in the system energy but generates species
Fig. 3 Fitted SANS profiles and cylinder form factor fits for 32 mM
˚
with signicantly higher radii than the 8-9 A cylinder radius
enantio-pure, racemic and scalemic samples of [1][BAr
F
] in THF-D
8
,
ꢀ
25 C.
detected by SANS. In summary, the tetranuclear species (n ¼ 4),
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Fig.
5
MM3 energies (3 ¼ 9.0) of cyclo-oligomeric complexes Fig. 7 MM3 energies (3 ¼ 9.0) of {([1][BAr
])
as a function of monomers incorporated (n, x-axis). {4 ꢂ monomer), as a function of number (m) of cyclo-oligomeric tetramers
])} is
pre-orientated assembly of four monomeric aggregated.
]) is an aggregate formed from two tetra-
F 4 m
]) } (normalised per
(
(
[1][BAr
[1][BAr
F
n
F
a
P,P-chelates; {([1][BAr
F 4 2
}
meric cyclo-oligomers (see m ¼ 2 in Fig. 7).
between cationic cyclo-oligomers. The estimated formation
energies, (DE, Fig. 7) of such species {([1][BAr ]) as a function
F
4 m
}
of ‘m’ indicated that columnar aggregates are readily attainable,
with the growing entropic cost (TDS) placing limits on the
34,40
aggregate length.
These conclusions were further probed by molecular-
dynamics (MD) simulations in which the MM3-minimised
structures {([1][BAr ]) } were computationally excited (300-700 K)
F
4 m
over short periods (300 ps) to test the relative structural integrity
of the aggregate as a function of ‘m’. In the low dielectric constant
medium used for the model, most systems (m ¼ 4 to 16) did not
undergo any signicant changes in their tertiary structure at 300
K. As the energy input was increased the aggregate models
exhibited varying degrees of structural deformation, undergoing
rapid fragmentation at the highest energies. The most signicant
observations were made at intermediate energies (500-550 K):
aggregates with m ¼ 10-14 (e.g., Fig. 8, m ¼ 12) retained a cylinder
shape, albeit mildly distorted, over the full 300 ps simulation
time, whereas higher or lower order aggregates signicantly
F 4
Fig. 6 MM3 structure of tetranuclear cyclo-oligomer ([1][BAr ]) . For
F
clarity, only two of the four BAr anions are shown. Colour coding: Pd,
yellow; P, orange; O, red; N, dark blue; C, light grey; B, pink; F, green;
3
6 9
h -C H , light blue.
Fig. 6, appears to be the dominant, if not exclusive, cyclo-olig-
omer, and aggregation of these cyclic tetramers ([1][BAr ]) was
F
4
thus probed by MM3 as a process to generate the cylindrical
particles, Fig. 7.
Positively charged rod-like structures with dissociated or
removed anions were estimated by MM3 to be very much higher
in energy than those where the anions were closely associated
with the cationic cyclo-oligomeric building blocks. Anion
interactions were thus explored more deeply, and although BAr
F
41
is considered a weakly coordinating anion, the charge deloc-
alisation over its surface reduces repulsive interactions with
other BArF anions, and the presence of uorine makes it
signicantly lipophilic. Indeed, the calculations indicated a
F 4 F
Fig. 8 MM3 structure of {([1][BAr ]) }12. The monomer [1][BAr ] (top
4
2
favourable interleaving of the BAr anions in sandwich layers
F
left), with palladium coloured orange, is shown for scale.
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F
deformed, in some cases losing one or more BAr anions. The
average dimensions of the MM3 aggregates with m ¼ 10-14
˚
˚
(
radius 8-9 A and length 150-200 A) are consistent with the
particle dimensions determined by SANS, Fig. 2 and 3.
The effect of counter-ion and solvent on shape and extent of
aggregation
3
1
The effect of solvent type on aggregation was probed by MM,
{
[
P
1
H} NMR (Fig. 9) and SANS, also comparing [1][BAr
1][OTf] to explore the impact of counter-ion. The aggregation
mode for [1][BAr ] determined by MM3, e.g., Fig. 8, involves
F
] with
F
multiple close-range electrostatic interactions that reduce the
overall energy of the system. It is therefore not surprising that
the solvent dielectric constant (3 ) was found to modulate
aggregation, and thus also solubility, with precipitation being
the ultimate consequence of strong aggregation.
r
43
Fig. 10 SANS data and cylinder form factor fits for [1][BAr ] in various
solvents at 25 C.
F
ꢀ
As indicated in Fig. 9, both [1][OTf] and [1][BAr
oligomerise and aggregate in all of the solvents that were
explored, becoming essentially insoluble at the extremes of 3
e.g., in alkanes, most ethers, chloroform, aromatic hydrocar-
bons, and at the opposite end of the scale, in water). The lip-
ophilicity and charge-density of the anion also affects the
F
] readily
The [1][OTf] aggregates behaved differently. Although,
r
,
˚
cylinders of radius 8-10 A were again detected in all cases,
(
indicative of {([1][OTf])4}m aggregates, the exibility, lengths
and charge distribution in the particles were very different to
those formed from [1][BAr
, [1][OTf] forms cylindrical aggregates (up to 160 A˚ ;
In CD Cl
F
].
solubility: [1][BAr
and at the opposite end of the 3
1][BAr ]) is soluble in aqueous-organic mixtures.
SANS was employed to explore how the macromolecular
composition of aggregates {([1][X]) is affected by solvation.
F
] (but not [1][OTf]) readily dissolves in THF,
2
2
r
scale, [1][OTf] (but not
Fig. 11) apparently with a degree of exibility, a phenomenon
that can be attributed to the small and interactive triate anion
being less able to rigidify the structures than the larger and
[
F
n m
}
more lipophilic BAr anion. The anion effect became even more
F
Although [1][BAr ] is not soluble in organic-aqueous mixtures,
F
pronounced in media of higher dielectric constant. In acetoni-
SANS data were attainable in polar aprotic solvents (e.g., MeCN,
trile-based solvent mixtures (3
r
¼ 47-58) the SANS data indicated
3
¼ 37.5; and DMSO, 3 ¼ 47). This conrmed that cylindrical
r
r
an additional minor structure factor contribution (S(Q)),
consistent with weakly charged particles, Fig. 12. Weak repul-
sive interactions might arise from solvation-induced ion-pair
separation of triate from the cationic Pd(II) oligomeric cores.
The increased cationic repulsion between the cyclo-oligomers
aggregates were still formed, but were signicantly shorter than
those in THF, Fig. 10. Medium length cylinders were detected in
a 50 : 50 mixture of THF and acetonitrile, consistent with the
r
intermediate solvent polarity (3 z 23). In all cases, the cylinders
˚
were of radius 8-10 A, strongly suggesting the prevalence of the
tetranuclear cyclo-oligomer building blocks, with the solvent
modulating only the aggregation number ‘m’: {([1][BAr ]) } .
˚
appears to result in much shorter cylinders, just 30 A in length,
31
44
with misleadingly simple P NMR spectra. Similar conclu-
sions were drawn from MD simulations with the medium set at
F
4 m
31
1
F
Fig. 9 Oligomerisation ( P{ H} NMR, %) of [1][BAr ] and [1][OTf] at
[
Pd]tot ¼ 15 mM in solvents of various dielectric constant (3
r
); overlaid Fig. 11 SANS data and flexible cylinder form factor fits for [1][OTf] in
ꢀ
areas in green (OTf) and blue (BAr
complexes are insoluble.
F
) indicate regions where the CD
2
Cl
2
at 25 C; fits are for radius 8-9 A˚ and lengths: 78 A˚ (13 mM);
156 A˚ (25 mM) and 332 A˚ (50 mM).
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Fig. 12 SANS data and cylinder form factor fits (including an effective
Fig. 13 Summary of upper-range aggregate cylinder lengths of [1]
[BArF] and [1][OTf] samples as determined by SANS experiments, in
selected solvents., with [Pd]tot ¼ 25 mM.
Hayter-Penfold structure factor S(Q) to account for charged particles)
ꢀ
for [1][OTf] in CD
3
CN at 25 C.
3
¼ 35: only the shortest aggregates {([1][OTf]) } were struc-
r
4 2-4
effectively stabilise charged particles. Here the role of the bulky
and relatively lipophilic anions is to solvate the monomer [1] .
turally stable at elevated energies (500 K; 300 ps). All higher
aggregates (m > 4) underwent rapid fragmentation.
Finally, to probe the relevance of the higher aggregates to
asymmetric alkylation (Scheme 1) SANS data were acquired on
+
Smaller harder, less lipophilic anions are less able to solvate the
monomer, and have the indirect effect of shiing the equilib-
rium towards the oligomer; an undesirable feature for catalysis.
The diminutive size of the anion also results in greater exibility
of the resulting columnar aggregates, which are more ionic in
nature, reducing their solubility in less polar solvents.
Overall, although the solvent polarity, counter-anion (X), and
net concentration ([Pd]tot) all affect the degree of oligomerisa-
tion and aggregation (Fig. 13) of monomer [1][X], the solvent
perhaps offers the greatest degree of scope for optimisation
F
reaction mixtures in which [1][BAR ] was employed as a
pre-catalyst (10 mol%) for addition of tetrabutylamonium
dimethylmalonate to cyclohexenylacetate in THF. While the
effects of substrate background scattering, varying acquisition
times and shorter Q-range slightly affected the data quality, it
remained clear that the dominant structures in solution, for the
whole duration of the catalytic process, were large cylinders.
This result is consistent with previous conclusions that, in THF,
the catalytic turnover proceeds via a small pool of highly-active
monomeric catalyst species, in competition with cyclo-oligo-
2 2
under the conditions of catalysis. In this regard, CH Cl is
favourable: solutions can be virtually free of oligomer at
ambient temperature, provided [Pd]tot # 4 mM. Intriguingly,
10,12
mers and aggregates.
47
SANS studies of ionic and non-ionic surfactants have revealed
specic solvent combinations that can lead to “dead zones”
where aggregation is suppressed, even for concentrated solu-
tions. If such “dead zone” solvent combinations can be found
Conclusions
+
13
Since the initial report that [1] readily oligomerises, and that for complexes of type [1][X], this may be highly advantageous for
this is a largely undesirable property of an otherwise highly improving catalytic productivity whilst maintaining selectivity.
efficient catalyst, e.g., Scheme 1, there has been limited under-
standing of the oligomer structures.
through NMR spectroscopy, SANS, and MM/MD simulations of
10,12
We have now identied,
Acknowledgements
45
+
[
[D
chelate-opening to form
[1][BAr ]) ; this being thermodynamically favoured over higher instruments SANS2d and LOQ at ISIS). The Bristol Chemical
n
]-1][BAr
F
] (n ¼ 0, 47), that monomeric cations [1] undergo We thank the ILL (France), ISIS (UK), and STFC (UK) for
a
tetranuclear cyclo-oligomer facilities (instruments D11, D16, D22 and D33 at ILL, and
(
F
4
and lower nuclearity species. A second-stage process involving Synthesis Centre for Doctoral Training (EPSRC EP/G036764/1),
columnar-like interactions between the cyclo-oligomers then AstraZeneca and the University of Bristol provided a PhD
forms aggregates {([1][BAr
comprise alternating layers of cyclo-oligomer and interleaved
BAr
anions in the form of cylindrical particles (m ¼ 10-14;
radius 8-9 A; length 150-200 A) containing up to 56 Pd(h -C
centres, ligands (2) and BAr anions.
F 4 m
]) } . In THF these aggregates studentship to DTR.
F
Notes and references
3
˚
˚
6
9
H )
F
1 B. M. Trost, M. R. Machacek and A. Aponick, Acc. Chem. Res.,
2006, 39, 747–760.
The identity of the counter-anion has a pronounced effect on
the proportion of oligomer generated from the monomer.
Bulky, weakly-coordinating anions, reduce the extent of oli-
gomerisation, particularly in low polarity solvents that cannot
2 Z. Lu and S. Ma, Angew. Chem., Int. Ed., 2007, 47, 258–297.
3 B. M. Trost and R. C. Bunt, J. Am. Chem. Soc., 1994, 116,
4089–4090.
46
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4
(a) S. Fuchs, V. Berl and J.-P. Lepoittevin, Eur. J. Org. Chem., 22 The large KIE (k
H
/k
D
z 30, by comparison of approximate
2
007, 7, 1145–1152; (b) M. J. Moschitto, D. N. Vaccarello and
rates of metallation of the deuterated and non-deuterated
substrates), may arise from multiple primary effects,
involving the TMP-amide, and in situ generated [D]-TMP,
or from tunnelling.
C. A. Lewis, Angew. Chem., Int. Ed., 2015, 54, 2142–2145.
B. M. Trost and F. D. Toste, J. Am. Chem. Soc., 2003, 125,
5
6
3090–3100.
B. M. Trost and G. Dong, J. Am. Chem. Soc., 2006, 128, 6054– 23 It was found that slow addition of [D10]-8 to the Grignard
ꢀ
6
055.
drop-wise at -78 C, reduced extensive by-product formation.
24 F. M. Piller, P. Appukkuttan, A. Gavryushin, M. Helm and
P. Knochel, Angew. Chem., Int. Ed., 2008, 47, 6802–6806.
7
8
9
B. M. Trost and N. Asakawa, Synthesis, 1999, 1491–1494.
B. M. Trost and R. C. Bunt, J. Am. Chem. Soc., 1996, 118, 235.
G. C. Lloyd-Jones and S. C. Stephen, Chem.–Eur. J., 1998, 4, 25 E. Filali, G. C. Lloyd-Jones and D. A. Sale, Synlett, 2009, 205–
539–2549. 208.
0 C. P. Butts, E. Filali, G. C. Lloyd-Jones, P.-O. Norrby, 26 K. Ishibashi and S. Matsubara, Chem. Lett., 2007, 36, 724–
2
1
D. A. Sale and Y. Schramm, J. Am. Chem. Soc., 2009, 131,
945–9957.
1 D. J. Berrisford, C. Bolm and K. B. Sharpless, Angew. Chem.,
Int. Ed., 1995, 34, 1059–1070.
725.
9
27 M. Chandrasekhar, G. Sekar and V. K. Singh, Tetrahedron
Lett., 2000, 41, 10079–10083.
28 A. K. Chakraborti, S. Rudrawar and A. Kondaskar, Eur. J. Org.
Chem., 2004, 3597–3600.
1
1
2 J. Eastoe, I. J. S. Fairlamb, J. M. Fern ´a ndez-Hern ´a ndez,
E. Filali, J. C. Jeffery, G. C. Lloyd-Jones, A. Martorell, 29 V. M. Mastranzo, E. Santacruz, G. Huelgas, E. Paz,
A. Meadowcro, P.-O. Norrby, T. Riis-Johannessen,
D. A. Sale and P. M. Tomlin, Faraday Discuss., 2010, 145,
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and C. A. de Parrodi, Tetrahedron: Asymmetry, 2006, 17,
1663–1670.
27–47.
27
1
3 I. J. S. Fairlamb and G. C. Lloyd-Jones, Chem. Commun., 2000, 30 In contrast to the report of Singh, hydrogenolysis with
447–2448. Pd(OH) /C under acidic conditions in methanol failed to
4 Stoichiometric reaction of [(R,R)-[1][BAr
2
2
1
4
]
(Ar
¼
3,5-
cleave the a-methylbenzyl auxiliary. Instead, aer
reduction of the azide, the hydrogen source was changed
to ammonium formate: (a) A. D. Brown, M. E. Bunnage,
P. A. Glossop, K. James, C. A. L. Lane, R. A. Lewthwaite
and D. A. Price, WO 2005/092840 PCT/IB2005/000619,
2005; (b) T. Bieg and W. Szeja, Synthesis, 1985, 76–77.
(
CF
3
)
2
C
6
H
3
) with tetrabutylammonium dimethylmalonate
ꢀ
in THF at 21 C: [Pd] ¼ 1 mM affords alkylation product
tot
in 98% ee, whereas product of 6 % ee is obtained when
10
[
Pd]tot ¼ 27 mM.
5 Around 100 attempts were made to crystallise the following
complexes ([(R,R)- and rac [1][X], BAr
CF , [Al(OC(CF ] and OTf) using diffusion,
1
X
¼
F
, B((3,5- 31 The dimer was prepared using the literature procedure [see:
(
3
)
2
C
6
H
3
)
4
3
)
3
)
4
(a) B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton and
T. J. Dietsche, J. Am. Chem. Soc., 1978, 100, 3407–3415; (b)
S. Imaizumi, T. Matsuhisa and Y. Senda, J. Organomet.
Chem., 1985, 280, 441–448]. However we identied
degradation of the crude organometallic complex during
the early work-up stages. Constant exposure of the crude
material to air, avoiding vacuum operations until the
complex has been puried, signicantly increases the yield
of 17.
evaporation, cooling, seeding, co-crystallisation, and other
methods, from a variety of binary and ternary solvent
mixtures, including but not limited to chloroform, CH Cl /
2
2
pentane, 1,2-dichloroethane/hexane, THF/heptane, 1,2-
diuorobenzene/1,3-diuorobenzene, tetrachloroethane/
hexauorobenzene, MeCN/mesitylene, aqueous MeCN/
MTBE, water, diethyl ether, etc. without success.
1
6 For examples of X-ray structures of Pd complexes of 2 that
are inactive as catalysts for allylic alkyation, see: (a) 32 SANS experiments were conducted at the Institut Laue-
K. R. Campos, M. Journet, S. Lee, E. J. J. Grabowski and
R. D. Tillyer, J. Org. Chem., 2005, 70, 268–274; (b)
C. Amatore, A. Jutand, L. Mensah and L. Ricard, J.
Organomet. Chem., 2007, 692, 1457–1464.
7 C. P. Butts, J. Crosby, G. C. Lloyd-Jones and S. C. Stephen,
Chem. Commun., 2000, 1707–1708.
Langevin (ILL) in Grenoble, France. Data was acquired in
two detector movements on separate instrument: high-Q
data on D16, and low-Q data on D22.
33 Very similar results were obtained on SANS2D at ISIS, UK
using a different batch of complex, indicative of the
reproducibility of the data.
1
1
1
2
8 D. C. Smith and G. M. Gray, J. Chem. Soc., Dalton Trans., 34 Measurements were also conducted at higher and lower
3
1
1
2
000, 677.
temperatures. Consistent with analysis by P{ H} NMR
spectroscopy, aggregation is reversible, and favoured by
lower temperatures. No signicant change in particle
dimensions was detected by SANS within the relatively
9 J. Eastoe, Surfactant Chemistry, Wuhan University Press,
Wuhan, China, 2005.
0 Peruoro tetraphenylborate [B(C F ) ] (“BAr ”) was chosen
ꢁ
6
5 4
F
ꢀ
to avoid SANS data being complicated by neutron scattering
narrow range of temperatures explored (10–40 C).
from protons or deuterons in the counter-ion, as this could 35 At higher concentrations the radius shrank slightly, possibly
then be used without perturbation in the perdeuterated
complex.
due to the accompanying increase in the ionic strength of
the medium.
12
21 C. J. Rohbogner, A. J. Wagner, G. C. Clososki and P. Knochel, 36 It should be noted that most of the concentrations employed
Org. Synth., 2009, 86, 374–384.
for the SANS experiments were, by necessity, well above the
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r
oligomerisation and aggregation threshold. Changes in 43 The impact of solvent dielectric constant (3 ) on ion-pair
particle number due to differential selectivity between
separation can be predicted by the Bjerrum length
2
homochiral and heterochiral aggregation of cyclo-
oligomers may be small, and thus hard to distinguish.
7 The resolution of the SANS instrument was insufficient to
completely rule out the possibility that the scattering
prole is the composite of two curves arising from
segregated (homochiral) cylinders.
equation: l ¼e /(4p3 3 k T) which indicates that the ion
B
0 r B
separation distance, l , is inversely proportional to the
B
3
3
r
dielectric constant (3 ) of the media in which the solute is
dissolved. The equation presumes point charges, although
the general principles may still apply to more complex
systems such as [1][X].
8 (a) MM3 studies were conducted using Schr ¨o dinger 44 These systems present an apparently simple pair of doublets
MacroModel, version 9.9, Schr ¨o dinger, LLC, New York, NY,
(J ¼ 38 Hz), almost identical in appearance, but not chemical
2
Pd
2
012, employing a modied form of the force eld
shi, to the pair of doublets (
cationic chelate [1] . However, it is very evident from the
J ) in the monomeric
PP
+
12
˚
reported in: (b) H. Hagelin, M. Svensson, B. Akermark and
P.-O. Norrby, Organometallics, 1999, 18, 4574–4583; (c) DFT
studies were conducted using Jaguar, version 7.9, Soware,
Schr ¨o dinger, LLC, New York, NY, 2012.
SANS data that the solutions are dominated by oligomers
3
1
4 m
{([1][OTf]) } , and from careful inspection of the P NMR
spectrum that the monomer is indeed also present, but
3
4
9 See "Molecular Mechanics and Comparison of Force Fields",
T. Liljefors, K. Gundertoe, P.-O. Norrby and I. Pettersson, in 45 The enantiomerically pure species [[D47]-1][BAr
Computational Medicinal Chemistry for Drug Discovery, ed. P.
Bultinck, J. P. Tollenaere, H. De Winter and W. Langenaeker,
Marcel Dekker, New York, 2004, pp. 1–28.
only in very low proportions (# 4%).
F
] is among
the most synthetically complex perdeuterated species to
have been prepared to date. For other examples see: (a)
F. Aussenac, M. Laguerre, J.-M. Schmitter and
E. J. Dufourc, Langmuir, 2003, 19, 10468–10479; (b)
R. G. Alken, US pat., US2005069276A1, 2005; (c) M. Schulz,
J. Hirschmann, A. Draksharapu, G. Bindra, S. Soman,
A. Paul, R. Groarke, M. T. Pryce, M. S. Rau, W. R. Browne
and J. G. Vos, Dalton Trans., 2011, 40, 10545–10552; (d)
T. Abe, A. Miyazawa, H. Konno and Y. Kawanishi, Chem.
Phys. Lett., 2010, 491, 199–202; (e) C. Lenges, P. White and
M. Brookhart, J. Am. Chem. Soc., 1999, 121, 4385–4396; (f)
M. Ogasawara, K. Takizawa and T. Hayashi,
Organometallics, 2002, 21, 4853–4861; (g) R. Brainard,
T. Miller and G. Whitesides, Organometallics, 1986, 5,
1481–1490.
0 Note that incorporation of each monomeric unit carries an
entropic penalty of ca. 20–40 kJ/mol, not readily calculated
by our current methods. To circumvent the entropy
problem associated with molecularity, we compare
assemblies with oligomers of the same size, and nd that
tetrameters are favored over monomers [([1][BAr ]) versus
F
4
{
4([1][BAr ])}, Figure 5] whereas an assembly of two
F
tetramers is slightly favored over the octamer [{([1]
BAr ]) versus ([1][BAr ]) , Figure 5]. The dimensions of
the MM3-minimsed tetramer are similar to that of the Pd/
[
F
4
}
2
F 8
3
ligand core of a cyclic tetranuclear complex [(h -C
Pd) (2) ][OTf ], determined by single crystal X-ray
diffraction.
1 I. Krossing and I. Raabe, Angew. Chem., Int. Ed., 2004, 43,
066–2090.
3 5
H -
4
4
4
12
4 F 4
46 All of the BAr anions tested, as well as Al(OR ) (“Krossing
4
4
anions”: I. Krossing, Chem.–Eur. J., 2001, 7, 490–502), were
effective in this regard.
2
2 A variety of other anion arrangements explored by MM3 47 M. J. Hollamby, R. Tabor, K. J. Mutch, K. Trickett, K.,
modelling did not reveal any plausible alternative modes
of aggregation, that would be compatible with the SANS
data.
J. Eastoe, R. K. Heenan and I. Grillo, Langmuir, 2008, 24,
12235–12240.
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