Localized Partitioning of Enantiomers in Solid Samples of Sulfoxides: Importance of Sampling Method in Determination of Enantiopurity

Article abstract of DOI:10.1021/acs.joc.0c01094

Localized partitioning of amorphous enantioenriched aryl benzyl sulfoxides in the solid state can lead to substantial variation in enantiopurities, even for sulfoxides which do not show detectable levels of self-disproportionation of enantiomers (SDE) dur

Full text of DOI:10.1021/acs.joc.0c01094

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Note
Localized partitioning of enantiomers in solid samples of sulfoxides;
importance of sampling method in determination of enantiopurity
Aaran Flynn, Alan Ford, and Anita R. Maguire
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01094 • Publication Date (Web): 02 Jul 2020
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Localized partitioning of enantiomers in solid samples of sulfoxides;
importance of sampling method in determination of enantiopurity
Aaran J. Flynn,a Alan Ford,b and Anita R. Maguire*c
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aSchool of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University
College Cork, Cork T12 K8AF, Ireland
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bSchool of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork T12 K8AF, Ireland
cSchool of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State
Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland.
Localized partitioning of amorphous enantioenriched aryl benzyl sulfoxides in the solid state can lead
to substantial variation in enantiopurities, even for sulfoxides which do not show detectable levels of
self-disproportionation of enantiomers (SDE) during chromatography on an achiral stationary phase.
The importance of preparation of representative samples of enantioenriched sulfoxides for chiral
HPLC to enable reproducible results is clear.
Enantioenriched sulfoxides have attracted considerable interest in the field of asymmetric synthesis
largely due to their importance as chiral auxiliaries or as synthetic intermediates with wide ranging
applications. The sulfoxide moiety has been demonstrated to be an efficient chiral auxiliary in carbon–
carbon and carbon–oxygen bond forming reactions, in asymmetric catalysis, in radical addition
reactions, Michael reactions and in cycloaddition reactions.1-8 The ability of the sulfoxide moiety to
promote such reactions is explained in terms of the structural features inherent to the sulfinyl group.
Not only does the sulfinyl group possess a high configurational stability and there can be significant
steric and stereoelectronic differences between the inequivalent organic substituents at the sulfur
atom.
In addition to uses in synthetic methodology, enantiopure sulfoxides have also gained significance in
the pharmaceutical industry due to their important biological activity. One of the most successful
sulfoxide-containing APIs is Astra Zeneca’s esomeprazole, a gastric acid secretion inhibitor,
commercialized as Nexium®. Esomeprazole is the (S)-enantiomer of omeprazole, its racemic
predecessor.
Synthesis of enantioenriched sulfoxides is undertaken primarily employing two principal strategies –
nucleophilic displacement from sulfinate precursors,9 and asymmetric sulfoxidation of prochiral
sulfides mediated by transition metal catalysts.1, 10-13 Extensive reports of asymmetric sulfur oxidation
have appeared over the past 30 years since the seminal reports from Kagan14-15 and Modena16 utilising
titanium mediated oxidation.
Central to these reports are the methods exploited for the determination of enantiopurity of the
resulting sulfoxides. Chiral HPLC, whereby a chiral stationary phase is used to generate diasteromeric
interactions between analyte and stationary phase, is the method of choice since its emergence as a
more accurate and reproducible descriptor of enantiopurity when compared with other analytical
techniques such as 1H NMR analysis using a chiral shift reagent, or measurement of optical rotation.
Of particular interest were the seminal reports of the self-disproportionation of enantiomers (SDE) for
enantioenriched sulfoxides by chromatography on an achiral phase as reported by Kagan and co-
workers in 1994.17-18 Self-disproportionation of enantiomers in fractional crystallization of solids is well
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known, leading to formation of racemates and/or conglomerates, depending on the structure of a
compound.19 Indeed our reports on the solid state properties of sulfoxides highlight that for benzyl p-
tolyl sulfoxide spontaneous resolution occurs to form enantiopure crystals of the conglomerate even
when a racemic synthesis is undertaken, a property not seen with other aryl benzyl sulfoxides.20
Observation of this spontaneous resolution is notable, as it is believed that at most only 5–10% of
crystalline racemates form conglomerates.
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Our group has previously reported on the copper mediated asymmetric oxidation of aryl benzyl
sulfides to the corresponding sulfoxides, with enantioselectivities of up to 97% ee achieved through
ligand and substrate optimization.21-22 During investigation of the further scope of this transformation,
challenges were encountered in relation to the reproducibility of the enantioselectivities with variable
outcomes in the oxidation of certain substrates. Furthermore, it is evident that the efficiency of the
oxidation is very sensitive to variation in the reaction temperature.
One of our initial aims was to optimize the peroxide loading in order to maximize sulfide consumption
while keeping the over-oxidation product, the sulfone, to a minimum. Therefore, the oxidation of
benzyl phenyl sulfide 1 was examined using varying equivalents of hydrogen peroxide (30%) using our
previously reported optimized conditions (Table 1). Previous work in the group demonstrated that the
optimized conditions required Schiff base ligand 4 in conjunction with copper(II) acetylacetonate and
a heterogenous solvent system of hexane and methanol.
We found that the use of 1.5 equivalents of H2O2 was necessary to ensure complete consumption of
the sulfide (Entry 3), and while the use of more oxidant did not lead to any increase in sulfone
formation, the conversion to sulfoxide was hampered, presumably due to degradation of the catalyst
(Entries 4–6).
During optimisation studies exploring the impact of the number of equivalents of H2O2 we
encountered some challenges in reproducibility of enantioselectivities for certain sulfur oxidations,
therefore we looked in more detail at the HPLC sampling method used in conjunction with this work.
Irrespective of peroxide loading, the enantioselectivity of the copper Schiff base catalysed
sulfoxidation was reproducibly in the range of 52–58%, so long as the entirety of the recovered
enantioenriched sulfoxide post chromatography was dissolved prior to dilution for chiral HPLC
analysis; however, if instead of dissolving the complete sample recovered from chromatography, a
portion of the non-crystalline solid material is extracted from the collection flask then the ee
determined by chiral HPLC varies from the representative value.
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Table 1: Investigation of Peroxide Loading and HPLC sampling method
5
Cl
6
7
8
Cl
9
OH
N
t-Bu
10
11
12
13
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15
16
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4
HO
O
S
4
Schiff base ligand (4 mol%)
Cu(acac)2 (2 mol%)
O O
S
S
+
9:1 Hexane: Methanol
H2O2 (30%, X equiv.)
16 h, r.t.
1
2
3
(R)-
% ee (R)-[2]c
Solid
Entry X Equiv.
30% H2O2
1 : 2 : 3a
Solid
Solid
Representative % Yield
Sample 1d Sample 2d Sample 3d Samplee
[2]b
1
2
3
4
5
6
1.1
1.3
1.5
1.7
1.9
2.1
56 : 44 : 0 N/A
N/A
62
73
61
66
60
N/A
67
60
63
64
60
52
56
57
56
56
58
29
74
75
75
70
57
6 : 93 : 1
1 : 98 : 1
4 : 95 : 1
3 : 96 : 1
62
79
65
70
10 : 89 : 1 61
a) Ratio of 1 : 2 : 3 determined from the 1H NMR spectrum of the crude product.
b) After purification by column chromatography.
Determined by HPLC analysis on chiral column (Chiralcel OD-H); absolute configuration determined by comparison of HPLC
elution order to literature values.
d) Solid sample obtained by taking random 3 mg of amorphous sulfoxide product and dissolving in 3 ml of HPLC grade methanol.
e) Representative sample obtained by dissolving entirety of recovered sulfoxide post chromatography.
c)
It is well established that the self-disproportionation of enantiomers (SDE) of sulfoxides is frequently
observed during achiral chromatography,10, 23-28 and accordingly it is essential that representative
samples are utilized for determination of enantiopurity to avoid errors in determination of %ee in
individual samples. However, investigation of the enantiopurity of fractions of enantioenriched benzyl
phenyl sulfoxide 2 recovered from chromatography did not display any evidence of SDE with this
compound (Table 2).
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Table 2: Investigation of Self-Disproportionation of Enantiomers for enantioenriched (R)-benzyl
phenyl sulfoxide
6
7
8
O
S
4
Schiff base ligand (4 mol%)
Cu(acac)2 (2 mol%)
S
9:1 Hexane: Methanol
H2O2 (30%, 1.5 equiv.)
16 h, r.t.
9
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1
2
(R)-
Fraction Number
% Product 2
Recovered b
% ee (R)-2c
Post Column
Chromatographya
1
2
3
4
5
6
7
7
26
30
17
6
58
57
58
58
59
59
57
2
1
a) Fraction obtained post purification by flash column chromatography on silica gel using hexane: ethyl acetate (60:40) as eluent;
At I mmol scale, each fraction was collected in a 40 ml test-tube.
b) Each fraction was concentrated under reduced pressure prior to being dissolved in HPLC grade methanol and diluted to give a
HPLC sample with a concentration of 1 mg/ml.
c)
Determined by HPLC analysis (Daicel Chiracel OD-H); absolute configuration determined by comparison of HPLC elution order
to literature values.
It is clear that with sulfoxides, in addition to the possibility of SDE occurring during column
chromatography, sampling of apparently amorphous solid samples of enantioenriched sulfoxides can
produce samples with varying enantiopurity and accordingly extreme care must be taken when
sampling solid sulfoxides even in cases where apparently homogenous non-crystalline samples are
recovered through evaporation of solutions. Thus, it would seem that we are seeing an example of
localized partitioning in the solid state of amorphous solids, even in the absence of 1) crystallization
and 2) detectable levels of self-disproportionation of enantiomers via achiral chromatography.
Having identified the variation in ee values for enantioenriched (R)-benzyl phenyl sulfoxide as
summarized in Table 1 it was initially thought that the variation may be consistent across a range of
enantioenriched substituted aryl benzyl sulfoxides exhibiting amorphous morphology following
evaporation of eluent after chromatography. To gain a better understanding of the extent of this
phenomenon, a further five enantioenriched sulfoxides were generated using our copper Schiff base
methodology.
For each of the five substrates, the representative ee was measured by combining all fractions
containing the recovered enantioenriched sulfoxide following chromatography, concentrating them
to dryness under reduced pressure to give an amorphous solid and dissolving the entirety of the
sample in HPLC grade methanol. Once dissolved the representative sample was diluted accordingly to
give a 1 mg/ml sample for chiral HPLC analysis. After analysis the representative sample was restored
to the original sample, which was again concentrated under reduced pressure to give the amorphous
solid. From this re-concentrated residue, five individual 3 mg solid samples were randomly selected
and each dissolved in 3 ml of HPLC grade methanol.
As can be seen in Table 3 the significant variation in enantioselectivity that was observed for
enantioenriched benzyl phenyl sulfoxide 2 was not seen consistently across the series of aryl benzyl
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sulfoxides studied, rather it would appear that the variation is strongly dependent on the exact
substitution pattern, and therefore the structure, of the selected aryl benzyl sulfoxide. In the cases of
sulfoxides 5 and 7 the representative samples and solid samples withdrawn from the amorphous
sulfoxide product provided essentially similar %ee data (Entries 1 and 3). Sulfoxide 8 demonstrated a
very minor increase in %ee when a solid sample was taken (Entry 4). Sulfoxide 9 however
demonstrated a somewhat variable decrease in enantiopurity when analysing the solid samples (Entry
5). Sulfoxide 6 gave essentially reproducible solid sample data, however this ee value was approx. 10%
greater than the representative enantiomeric excess of 37% (Entry 2).
Table 3: Comparison of sampling methods for substituted aryl benzyl sulfoxides
O
Representative sample
Solid sample
Entirety of sample dissolved in methanol
and diluted down to a 1 mg/ml solution
S
3 mg of sample weighed out and
dissolved in 3 ml of methanol -
Repeated 5 times
R2
R1
Solid Sampleb
% ee (R)
Sample
3
Entry Sulfoxidea
R1
R2
Representative % ee (R) % ee (R)
% ee (R)
Sample
4
% ee (R)
Sample
5
%ee (R)b
Sample
1
Sample
2
1
2
3
4
5
[5]
[6]
[7]
[8]
[9]
3-Me
4-MeO
2-Me
4-Me
-
-
-
-
-
31
37
71
55
55
30
48
72
60
28
48
71
58
32
47
72
56
30
47
71
57
32
47
70
55
4-Cl
51
42
56
39
50
a) Sulfoxides 5–9 were generated as per ‘Experimental Procedure for Asymmetric Sulfide Oxidation’
b) Determined by HPLC analysis (Chiralpak IB for sulfoxide 5, Phenomenex Lux Amylose-1 for sulfoxides 6-9); absolute
configuration determined by comparison of HPLC elution order to literature values.
Thus far, all HPLC sampling of the solid amorphous material had been carried out in a random manner,
so that no indication could be made as to whether the partitioning of the solid state was occurring in
an ordered predictable manner while evaporated under reduced pressure. Thus enantioenriched 2-
naphthyl benzyl sulfoxide 11 was generated using our copper Schiff base methodology to give a
sample with 62% ee (Entry 1, Table 4). As in previous instances the representative sample was
restored to the bulk sample, dissolved, and concentrated under reduced pressure in a 100 ml round
bottom flask. Solid amorphous material was collected from both the upper and lower parts of the flask
to give a %ee of 59% and 73% respectively (Entries 2 and 3), indicating localized partitioning of the
enantiomers of the sulfoxide throughout the evaporation process. Thus the degree of partitioning is
dependent on several factors which may include size of collection vessel post chromatography, choice
of eluent system for chromatography, and relative rate of evaporation of solvents during solid
acquisition post chromatography, in addition to the exact sulfoxide structure.
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Table 4: HPLC sampling of enantioenriched (R)-2-naphthyl benzyl sulfoxide
5
6
7
Solid sample
3 mg of sample weighed out and
dissolved in 3 ml of methanol
8
9
10
11
12
13
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60
4
Schiff base ligand (4 mol%)
O
S
O
S
O
Cu(acac)2 (2 mol%)
+
S
9:1 Toluene: Methanol
1.5 equiv. 30% H2O2, r.t., 16 h
10
11
12
(R)-
Representative sample
Entirety of sample dissolved in methanol
and diluted down to a 1 mg/ml solution
Entry HPLC sampling method used
Part of 100 ml round bottom % ee (R)
flask sample taken from
11
62
73
59
1
2
3
Representative sample
3 mg/ml solid sample
3 mg/ml solid sample
Entirety
Bottom
Top
a) Determined by HPLC analysis (Phenomenex Lux Amylose-1); absolute configuration determined by comparison of HPLC elution
order to literature values.
In conclusion, observation of localized partitioning of enantiomers in amorphous non-crystalline
samples of sulfoxides even in the absence of detectable levels of self-disproportionation of
enantiomers via chromatography on an achiral phase can be rationalized on the basis of the strong
intermolecular non-covalent interactions in the solid state between R and S enantiomers of sulfoxides.
Observation of this behaviour with highly polar compounds such as sulfoxides, and moreover
considering the significant variation in the nature of the substituents on sulfur as opposed to
stereogenic carbon, is arguably not surprising. According to Hunter’s hydrogen-bond parameter table
sulfoxides are among the most potent hydrogen bond acceptors leading to strong intermolecular
interactions in the solid state.29 Accordingly, when conducting studies in asymmetric sulfoxidation
additional care should be taken to eliminate potential errors in the determination of enantiomeric
excess not only via self-disproportionation of enantiomers in sulfoxide samples through
chromatography, but also through localized partitioning in the solid state, even in the absence of
crystallisation.
Experimental Section
General Procedures: All solvents were distilled prior to use by the following methods: methanol was
distilled from magnesium methoxide and stored over 3Å molecular sieves; toluene was distilled from
sodium benzophenone ketyl; ethyl acetate was distilled from potassium carbonate; and hexane was
distilled prior to use. All commercial reagents were used without further purification unless otherwise
stated. Hydrogen peroxide was standardised by titration using potassium permanganate.
1H (300 MHz) NMR spectra were recorded on a Bruker Avance 300 NMR spectrometer. All spectra
were recorded at 300 K in deuterated chloroform (CDCl3) using tetramethylsilane (TMS) as an internal
standard. Chemical shifts (δH) are reported in parts per million (ppm) relative to TMS, and coupling
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constants are expressed in hertz (Hz). Splitting patterns in 1H NMR spectra are designated as s (singlet),
d (doublet), dd (doublet of doublets) and m (multiplet).
6
7
8
9
Flash column chromatography was carried out using Kieselgel silica gel 60, 0.035−0.075 mm (Merck).
Thin-layer chromatography (TLC) was carried out on precoated silica gel plates (Merck 60 PF254).
Visualization was achieved by UV (254 nm).
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The enantiopurity of chiral compounds was measured using chiral stationary phase high-performance
liquid chromatography (HPLC), carried out on either a Chiralcel OD-H, Phenomenex Lux Amylose-1, or
a Chiralpak IB column. Details of the column conditions and mobile phase employed are included in
the Experimental Section; data for the plots were extracted at 254 nm, at which wavelength all of the
compounds exhibited good absorption. In all instances baseline resolution was obtained, and injection
of racemic reference samples for each run confirmed the accuracy of the integration of the
chromatograms, regardless of retention time.
HPLC analysis was performed on a Waters alliance 2695 separations module with a Waters alliance
2996 photodiode array detector. High temperature chiral HPLC analysis was obtained using an Igloo®
column heater/cooler.
Experimental Procedure for Asymmetric Sulfide Oxidation: Copper(II) acetylacetonate (5.2 mg, 2.0
mol %) was added to a 25 ml round-bottom flask containing Schiff base ligand 4 (11.6 mg, 4.0 mol%),
and 9:1 hexane (or toluene)/methanol (1 ml). The resulting mixture was stirred at r.t. for 5 min, and
then a solution of sulfide (1 mmol) in 9:1 hexane (or toluene)/methanol (1 ml) was added. After a
further 5 min of stirring at r.t., hydrogen peroxide (0.170 ml, 30%, 1.5 mmol) was added dropwise to
the mixture. The reaction mixture was stirred at r.t. for a further 16 h. Water (10 ml) and
dichloromethane (10 ml) were then added and the phases separated; the organic layer was washed
with water (2 x 10 ml) and brine (10 ml), dried with MgSO4, filtered, and concentrated under reduced
pressure to give the crude product. The product was purified by flash column chromatography on
silica gel (60:40 hexane/ ethyl acetate) to afford the enantioenriched sulfoxide as an amorphous white
solid. Each of sulfoxides 2, 5–9 and 11 were prepared and purified using these conditions.
(R)-(+)-Benzyl phenyl sulfoxide 2 (Table 1, Entry 3)21, 30
White solid (162 mg, 75%, 57% ee); 1H NMR (CDCl3, 300 MHz) 7.51–7.34 (m, 5H), 7.33–7.20 (m, 3H),
7.03–6.94 (m, 2H), 4.10 (d, 1H, J = 12.5 Hz), 3.99 (d, 1H, J = 12.5 Hz); HPLC: tR (R) = 18.6 min, tR (S) =
22.5 min [Chiralcel OD-H; flow rate 1 ml min-1; hexane/2-PrOH (95:5); 40°C].31
(R)-(+)-Benzyl m-tolyl sulfoxide 5 (Table 3, Entry 1)21, 32
White solid (199 mg, 86%, 31% ee); 1H NMR (CDCl3, 300 MHz) 7.33–7.11 (m, 7H), 7.04–6.94 (m, 2H),
4.05 (d, 1H, J = 12.5 Hz), 3.95 (d, 1H, J = 12.5 Hz), 2.32 (s, 3H); HPLC: tR (R) = 23.1 min, tR (S) = 25.6 min
[Chiralpak IB; flow rate 0.5 ml min-1; hexane/2-PrOH (90:10); 20°C].
(R)-(+)-Benzyl p-methoxy sulfoxide 6 (Table 3, Entry 2)22, 33
White solid (143 mg, 58%, 37% ee); 1H NMR (CDCl3, 300 MHz) 7.35–7.18 (m, 5H), 7.03–6.86 (m, 4H),
4.10 (d, 1H, J = 12.4 Hz), 3.95 (d, 1H, J = 12.4 Hz), 3.82 (s, 3H); HPLC: tR (R) = 49.7 min, tR (S) = 54.4 min
[Lux Amylose-1; flow rate 0.5 ml min-1; hexane/2-PrOH (90:10); 20°C].
(R)-(+)-Benzyl o-tolyl sulfoxide 7 (Table 3, Entry 3)21, 34
White solid (174 mg, 76%, 71% ee); 1H NMR (CDCl3, 300 MHz) 7.74–7.66 (m, 1H), 7.37–7.16 (m, 5H),
7.13–7.06 (m, 1H), 7.00–6.92 (m, 2H), 4.07 (d, 1H, J = 12.6 Hz), 3.98 (d, 1H, J = 12.6 Hz), 2.06 (s, 3H);
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HPLC: tR (R) = 24.3 min, tR (S) = 26.9 min [Lux Amylose-1; flow rate 0.5 ml min-1; hexane/2-PrOH (90:10);
20°C].
6
7
(R)-(+)-Benzyl p-tolyl sulfoxide 8 (Table 3, Entry 4)21, 35
White solid (150 mg, 65%, 55% ee); 1H NMR (CDCl3, 300 MHz) 7.32–7.14 (m, 7H), 7.05–6.92 (m, 2H),
4.07 (d, 1H, J = 12.6 Hz), 3.96 (d, 1H, J = 12.6 Hz), 2.38 (s, 3H); HPLC: tR (R) = 29.4 min, tR (S) = 33.0 min
[Lux Amylose-1; flow rate 0.5 ml min-1; hexane/2-PrOH (90:10); 20°C].
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(R)-(+)-4-Chlorobenzyl phenyl sulfoxide 9 (Table 3, Entry 5)22, 33
1
White solid (88 mg, 35%, 55% ee); H NMR (CDCl3, 300 MHz) 7.52–7.32 (m, 5H), 7.25–7.18 (m, 2H),
6.94–6.84 (m, 2H), 4.02 (d, 1H, J = 12.8 Hz), 3.96 (d, 1H, J = 12.8 Hz); HPLC: tR (S) = 68.4 min, tR (R) =
70.9 min [Lux Amylose-1; flow rate 0.5 ml min-1; hexane/2-PrOH (95:5); 20°C].
(R)-(+)-2-Naphthyl benzyl sulfoxide 11 (Table 4, Entry 1)22, 33
White solid (186 mg, 70%, 62% ee); δH (300 MHz, CDCl3) 7.93–7.78 (m, 4H), 7.62–7.51 (m, 2H), 7.41
(dd, 1H, J = 8.6, 1.8 Hz), 7.31–7.17 (m, 3H), 7.02–6.96 (m, 2H), 4.17 (d, 1H, J = 12.6 Hz), 4.08 (d, 1H, J =
12.6 Hz); HPLC: tR (R) = 46.7 min, tR (S) = 55.3 min [Lux Amylose-1; flow rate 0.5 ml min-1; hexane/2-
PrOH (90:10); 20°C].
Supporting Information
Copies of chiral-phase HPLC chromatographs for compounds 2, 5–9 and 11
Author Information
*E-mail: a.maguire@ucc.ie (A.R.M)
ORCID
Aaran J. Flynn: 0000-0003-3115-9965
Alan Ford: 0000-0002-4316-4350
Anita R. Maguire: 0000-0001-8306-1893
Notes
There are no conflicts to declare
Acknowledgements
Financial support from the Synthesis and Solid State Pharmaceutical Centre supported by Science
Foundation Ireland, co-funded under the European Regional Development Fund (grant numbers:
12/RC/2275 and 12/RC/2275_2) is gratefully acknowledged.
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