Daugirdas Tomas
Racys‡
a,
Julian
Eastoe
a,
Per-Ola
Norrby
bc,
Isabelle
Grillo
d,
Sarah E.
Rogers
e and
Guy C.
Lloyd-Jones
*f
aSchool of Chemistry, University of Bristol, Office S314, Cantock's Close, Clifton, Bristol BS8 1TS, UK. E-mail: Julian.Eastoe@bristol.ac.uk
bAstraZeneca Pharmaceutical Development, Global Medicines Development, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. E-mail: per-ola.norrby@astrazeneca.com
cDepartment of Chemistry and Molecular Biology, University of Gothenburg, Kemigården 4, #8076, SE-412 96 Göteborg, Sweden
dILL, CS20156, 38042 Grenoble Cedex 9, France. E-mail: grillo@ill.fr
eISIS-STFC, Rutherford Appleton Laboratory, Chilton, Oxon OX11 0QX, UK. E-mail: sarah.rogers@stfc.ac.uk
fSchool of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh, Scotland EH9 3JJ, UK. E-mail: guy.lloyd-jones@ed.ac.uk
First published on 15th July 2015
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.
Our previous mechanistic studies of this system focussed on the monomeric cationic complex [1]+, in which a Pd(η3-C6H9) unit is chelated by the 1,2-diaminocyclohexane-derived TML ligand (2).10 The monomeric cation [1]+ was identified 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 – in conjunction with MM-DFT simulations – led to a model10 in which the amide units in the catalyst facilitate enantioselective ligand-accelerated catalysis.11
Scheme 1 Asymmetric allylic alkylation of racemic 2-cyclohexenyl acetate; 2 = 1,2-diaminocyclohexane TML ligand, THAB = tetrahexylammonium bromide. |
For the ligand-accelerated catalysis to function efficiently, cation [1]+ requires a degree of flexibility. This flexibility is provided by the 13-membered chelate ring, but at a cost: complex [1]+ can readily undergo ring-opening oligomerisation to generate polynuclear species ([1]+)n, Scheme 2.12 Competing nucleophilic attack on the oligomer, rather than the monomer [1]+ is, in part, responsible for a reduction in overall enantioselectivity under non-optimised conditions.13,14
Scheme 2 Oligomerisation of [1]+ erodes enantioselectivity during asymmetric Pd-catalysed allylic alkylation mediated by 2 (as Scheme 1). Nu = nucleophile. |
To date, the structure and origin of the formation of these oligomeric species has not been studied in detail. Herein, we describe an investigation of the oligomerisation of D0 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 first-stage of depletion of the monomeric species [1]+ from the catalyst pool, via cyclic oligimerisation, is amplified by a second-stage process 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.
The extent of solution-phase oligomerisation of cationic complexes of type [1]+ can be conveniently estimated by 31P{1H} NMR spectroscopy.10,12 Analysis of [(R,R)-1][BAr4] complexes in CH2Cl2, where Ar = C6Cl5, 3,5-(CF3)2C6H3, or C6F5 (“BArF”), indicates a maximum monomer concentration ([1]+) of about 4 mM, Fig. 1. In THF, the monomer maximum is lower (approx. 1.6 mM) and decreases as [Pd]tot is raised above 10 mM. With smaller, less charge-diffuse, counter-anions such as chloride or triflate, the maximum monomer concentrations are lower still. We were unable to fit simple analytical solutions18 for monomer-oligomer distributions to any of the 31P NMR data, indicative that physicochemical effects dominate over simple solution-phase equilibria, even at low [Pd]tot.
We thus elected to study the oligomeric species by SANS – a technique that can be used for characterising the shape and dimensions of self-assembly structure and colloids.19 We began with [(R,R)-1][BArF],20 and, to aid the studies, also synthesised the perdeuterated enantiomeric complex [(S,S)-[D47]-1][BArF]. Not only does this facilitate SANS in a non-deuterated solvent, thus providing greater neutron scattering contrast,19 it also allows pseudo racemic and pseudo scalemic mixtures to be prepared by mixing [(S,S)-[D47]-1][BArF] with [(R,R)-1][BArF]. The perdeuterated complex was synthesised from benzoic acid ([D5]-3), chlorobenzene ([D5]-4) and cyclohexene ([D10]-5), Scheme 3. A major hurdle was the ortho-metallation of ester [D5]-6 with (TMP)2Mg·LiCl,21 which proceeded with an unexpectedly large net kinetic isotope effect (kH/kD ≈ 30).22 This required an excess of base to be employed, and interfered with a planned direct phosphination of the metallated intermediate. Instead, the intermediate was trapped with I2. The iodide [D4]-7 was then converted to a more conventional Grignard reagent,23 before reaction with chlorophosphine [D10]-810,24 to give phosphine [D14]-9, and thus acid [D14]-10.25
Scheme 3 Synthesis of pseudo enantiomer [(S,S)-[D47]-1][BArF]; BArF = B(C6F6)4. Conditions: (i) SOCl2, toluene, 100 °C; (ii) KOtBu, THF 0 °C; 84%; (iii) (TMP)2Mg·2LiCl, THF, 0 °C to 30 °C; (iv) I2, THF, -30 °C; 49%; (v) iPrMgCl, THF, -40 °C, 2 h; (vi) Mg, LiCl, THF, reflux; (vii) Et2NPCl2, THF; (viii) HCl, Et2O, -40 °C; 29%; (ix) [D10]-8 drop-wise addition, THF, -78 °C; 68%; (x) KOH, THF, r.t., 24 h; (xi) HCl; 58%; (xii) 5% Ru(PPh3)3Cl2, D2O, 10% SDS, microwave, 140 °C, 1 h; (xiii) mCPBA, CH2Cl2, NaHCO3; 51%; (xiv) (S)-1-phenylethylamine, MeCN, LiBr, 60 °C; 74%; (xv) DIAD, PPh3, THF, 0 °C to r.t.; 62%; (xvi) NaN3, CeCl3·7H2O, MeCN/H2O 9:1, reflux; (xvii) silica-gel chromatography; 61%; (xviii) 20% Pd(OH)2/C, MeOH, r.t., 1 atm H2; (xix) 20% Pd(OH)2/C, MeOH, 2 M HCl/Et2O, HCO2NH4, 65 °C; (xx) KOH, CH2Cl2, r.t.; (xxi) EDCI·HCl, HOBt·H2O, iPr2NEt, CH2Cl2, r.t.; (xxii) Et2O, HCl; 30%; (xxiii) NaCl, NaOAc, CuCl2, AcOH, Ac2O, 2 h, 95 °C; (xxiv) [D10]-5, 60 °C, 20 h; 13% (xxv) KBArF, MeCN, CH2Cl2, r.t.; (xxvi) CH2Cl2, r.t.; 99%. See ESI† for full details. |
Cyclohexene [D10]-5,26 was epoxidised, to give [D10]-11, and this ring-opened27 to give aminoalcohol [D10]-12.28 Aziridine [D10]-13, obtained under Mitsunobu conditions, was converted to azide [D10]-14.29 After diastereoisomer separation, hydrogenolysis30 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, prepared31 from [D10]-5, was converted to cationic complex [D9]-17, and then reacted with [D38]-2 to generate [(S,S)-[D47]-1][BArF] in good yield.
We have previously used 31P NMR spectroscopy to analyse the constitution of the solution-phase (i.e., lower-order) oligomers generated from various complexes of type [1][BAr4] in CD2Cl2.10,12 Using PPCOSY in combination with pairs of isotopically-differentiated ligands ([Dn]-2), we were able to determine 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][BAr4])n.
As [Pd]tot in THF or CH2Cl2 solutions of complexes of type [1][BAr4] is increased, the 31P NMR bandshape of the signals 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-oligomers ([1][BAr4])n do not incorporate more monomer (n), but instead aggregate to form larger particles, {([1][BAr4])n}m, containing ‘m’ cyclo-oligomers. It is these high nuclearity particles that are detected by SANS.12
In racemic or scalemic samples of [1][BArF], the homochiral cyclo-oligomers, ([1][BArF])n, could aggregate in three general forms: discrete homochiral, ordered heterochiral (e.g., alternating or co-block), or statistically distributed. SANS data of mixtures of [(R,R)-1][BArF] and [(S,S)-1][BArF] representing enantiopure, scalemic, and racemic samples, was uniform across the series, within experimental error, Fig. 3. The absence of a change in particle number density36 is consistent with a statistical cyclo-oligomer distribution in which there is no significant impact of homo- or hetero-chirality on the particle shape or size.
Fig. 3 Fitted SANS profiles and cylinder form factor fits for 32 mM enantio-pure, racemic and scalemic samples of [1][BArF] in THF-D8, 25 °C. |
SANS data of the pseudo racemate [(S,S)-[D47]-1][BArF] + [(R,R)-[D0]-1][BArF]) in H8-THF, and in D8-THF, Fig. 4, and enantiomerically pure [(S,S)-[D47]-1][BArF] in D0-THF, show that the fully and partially deuterated systems retain the concentration-independent, cylindrical aggregate shape. A major difference is, however, observed in the dimensions: [D47]-[1][BArF] forms shorter (130 Å), slightly wider (10 Å radius) cylinders than [D0]-[1][BArF]. The pseudo racemic mixture measures as an average of its precursors (9-10 Å radius, 150 Å length), again consistent with a statistical distribution of cyclo-oligomers in the aggregate.37
Fig. 4 SANS data and cylinder form factor fits for pseudo racemic complex ([(S,S)-[D47]-1][BArF] + [(R,R)-[D0]-1][BArF]) in THF-D8 at 25 °C, at [Pd]tot ranging from 13 to 51 mM. |
Comparison of the MM3 optimised energies for monomeric P,P-chelate [1][BArF] with a series of homochiral cyclo- oligomers, ([1][BArF])n, normalised by the number of Pd atoms (n, the x-axis in Fig. 5) confirmed cyclo-oligomerisation to be exothermic, and probably also exergonic up to tetramers (n = 4). The cyclic dimer (n = 2) still suffers from ring strain, and a more substantial stability is afforded by trimerisation (n = 3) then tetramerisation40 (n = 4).
Fig. 5 MM3 energies (ε = 9.0) of cyclo-oligomeric complexes ([1][BArF])n as a function of monomers incorporated (n, x-axis). {4 × ([1][BArF])} is a pre-orientated assembly of four monomeric P,P-chelates; {([1][BArF])4}2 is an aggregate formed from two tetrameric cyclo-oligomers (see m = 2 in Fig. 7). |
Fig. 7 MM3 energies (ε = 9.0) of {([1][BArF])4}m (normalised per monomer), as a function of number (m) of cyclo-oligomeric tetramers aggregated. |
Further increase in oligomer ring size (n = 5, 6, 8) yields a modest reduction in the system energy but generates species with significantly higher radii than the 8-9 Å cylinder radius detected by SANS. In summary, the tetranuclear species (n = 4), Fig. 6, appears to be the dominant, if not exclusive, cyclo-oligomer, and aggregation of these cyclic tetramers ([1][BArF])4 was 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 BArF is considered a weakly coordinating anion,41 the charge delocalisation over its surface reduces repulsive interactions with other BArF anions, and the presence of fluorine makes it significantly lipophilic. Indeed, the calculations indicated a favourable interleaving of the BArF anions in sandwich layers42 between cationic cyclo-oligomers. The estimated formation energies, (ΔE, Fig. 7) of such species {([1][BArF])4}m as a function of ‘m’ indicated that columnar aggregates are readily attainable, with the growing entropic cost (TΔS) placing limits on the aggregate length.34,40
These conclusions were further probed by molecular-dynamics (MD) simulations in which the MM3-minimised structures {([1][BArF])4}m were computationally excited (300-700 K) 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 = 4 to 16) did not undergo any significant 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 significant observations were made at intermediate energies (500-550 K): aggregates with m = 10-14 (e.g., Fig. 8, m = 12) retained a cylinder shape, albeit mildly distorted, over the full 300 ps simulation time, whereas higher or lower order aggregates significantly deformed, in some cases losing one or more BArF anions. The average dimensions of the MM3 aggregates with m = 10-14 (radius 8-9 Å and length 150-200 Å) are consistent with the particle dimensions determined by SANS, Fig. 2 and 3.
Fig. 8 MM3 structure of {([1][BArF])4}12. The monomer [1][BArF] (top left), with palladium coloured orange, is shown for scale. |
As indicated in Fig. 9, both [1][OTf] and [1][BArF] readily oligomerise and aggregate in all of the solvents that were explored, becoming essentially insoluble at the extremes of εr, (e.g., in alkanes, most ethers, chloroform, aromatic hydrocarbons, and at the opposite end of the scale, in water). The lipophilicity and charge-density of the anion also affects the solubility: [1][BArF] (but not [1][OTf]) readily dissolves in THF, and at the opposite end of the εr scale, [1][OTf] (but not [1][BArF]) is soluble in aqueous-organic mixtures.
SANS was employed to explore how the macromolecular composition of aggregates {([1][X])n}m is affected by solvation. Although [1][BArF] is not soluble in organic-aqueous mixtures, SANS data were attainable in polar aprotic solvents (e.g., MeCN, εr = 37.5; and DMSO, εr = 47). This confirmed that cylindrical aggregates were still formed, but were significantly shorter than those in THF, Fig. 10. Medium length cylinders were detected in a 50:50 mixture of THF and acetonitrile, consistent with the intermediate solvent polarity (εr ≈ 23). In all cases, the cylinders were of radius 8-10 Å, strongly suggesting the prevalence of the tetranuclear cyclo-oligomer building blocks, with the solvent modulating only the aggregation number ‘m’: {([1][BArF])4}m.
The [1][OTf] aggregates behaved differently. Although, cylinders of radius 8-10 Å were again detected in all cases, indicative of {([1][OTf])4}m aggregates, the flexibility, lengths and charge distribution in the particles were very different to those formed from [1][BArF].
In CD2Cl2, [1][OTf] forms cylindrical aggregates (up to 160 Å; Fig. 11) apparently with a degree of flexibility, a phenomenon that can be attributed to the small and interactive triflate anion being less able to rigidify the structures than the larger and more lipophilic BArF anion. The anion effect became even more pronounced in media of higher dielectric constant. In acetonitrile-based solvent mixtures (εr = 47-58) the SANS data indicated an additional minor structure factor contribution (S(Q)), consistent with weakly charged particles, Fig. 12. Weak repulsive interactions might arise from solvation-induced ion-pair separation of triflate from the cationic Pd(II) oligomeric cores. The increased cationic repulsion between the cyclo-oligomers appears to result in much shorter cylinders, just 30 Å in length, with misleadingly simple 31P NMR spectra.44 Similar conclusions were drawn from MD simulations with the medium set at εr = 35: only the shortest aggregates {([1][OTf])4}2-4 were structurally stable at elevated energies (500 K; 300 ps). All higher aggregates (m > 4) underwent rapid fragmentation.
Fig. 11 SANS data and flexible cylinder form factor fits for [1][OTf] in CD2Cl2 at 25 °C; fits are for radius 8-9 Å and lengths: 78 Å (13 mM); 156 Å (25 mM) and 332 Å (50 mM). |
Fig. 12 SANS data and cylinder form factor fits (including an effective Hayter-Penfold structure factor S(Q) to account for charged particles) for [1][OTf] in CD3CN at 25 °C. |
Finally, to probe the relevance of the higher aggregates to asymmetric alkylation (Scheme 1) SANS data were acquired on reaction mixtures in which [1][BARF] 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-oligomers and aggregates.10,12
The identity of the counter-anion has a pronounced effect on the proportion of oligomer generated from the monomer. Bulky, weakly-coordinating anions,46 reduce the extent of oligomerisation, particularly in low polarity solvents that cannot effectively stabilise charged particles. Here the role of the bulky and relatively lipophilic anions is to solvate the monomer [1]+. Smaller harder, less lipophilic anions are less able to solvate the monomer, and have the indirect effect of shifting the equilibrium towards the oligomer; an undesirable feature for catalysis. The diminutive size of the anion also results in greater flexibility 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 oligomerisation and aggregation (Fig. 13) of monomer [1][X], the solvent perhaps offers the greatest degree of scope for optimisation under the conditions of catalysis. In this regard, CH2Cl2 is favourable: solutions can be virtually free of oligomer at ambient temperature, provided [Pd]tot ≤ 4 mM. Intriguingly, SANS studies of ionic and non-ionic surfactants47 have revealed specific solvent combinations that can lead to “dead zones” where aggregation is suppressed, even for concentrated solutions. If such “dead zone” solvent combinations can be found for complexes of type [1][X], this may be highly advantageous for improving catalytic productivity whilst maintaining selectivity.
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 = 25 mM. |
Footnotes |
† Electronic supplementary information (ESI) available: Synthesis and Characterisation of compounds, and full details of aggregation studies by NMR, SANS, and MM3. See DOI: 10.1039/c5sc01181g |
‡ Current address: School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow, Lanarkshire G12 8QQ, UK. E-mail: E-mail: daugirdas.racys@glasgow.ac.uk. |
This journal is © The Royal Society of Chemistry 2015 |