Synthesis of enantiopure 2-iodomandelic acid and determination of its absolute configuration by VCD spectroscopy

Article abstract of DOI:10.1007/s11696-018-0568-6

Racemic 2-iodomandelic acid 1 was synthesized from commercially available 2-iodobenzoic acid 2. Acyl chloride 3 was reacted with diethyl malonate, then the formed diester was hydrolysed and decarboxylated in a one-pot reaction. The obtained 2-iodoacetophenone 4 was reacted with bromine and the dibromoacetophenone derivative 5 was hydrolysed to give the racemic 2-iodomandelic acid (±)-1. Optical resolution of (±)-1 via diastereomeric crystallization with strychnine afforded enantiopure (R)-(?)-1. Absolute configuration of (?)-1 and of its methyl ester (?)-6 was determined by VCD spectroscopy.

Full text of DOI:10.1007/s11696-018-0568-6

Chemical Papers
https://doi.org/10.1007/s11696-018-0568-6
ORIGINAL PAPER
Synthesis of enantiopure 2‑iodomandelic acid and determination
of its absolute confguration by VCD spectroscopy
Anikó Nemes1 · Elemér Vass1 · István Jalsovszky1 · Dénes Szabó1
Received: 14 March 2018 / Accepted: 1 August 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
Racemic 2-iodomandelic acid 1 was synthesized from commercially available 2-iodobenzoic acid 2. Acyl chloride 3 was
reacted with diethyl malonate, then the formed diester was hydrolysed and decarboxylated in a one-pot reaction. The obtained
2-iodoacetophenone 4 was reacted with bromine and the dibromoacetophenone derivative 5 was hydrolysed to give the
racemic 2-iodomandelic acid ( )-1. Optical resolution of ( )-1 via diastereomeric crystallization with strychnine aforded
enantiopure (R)-(−)-1. Absolute confguration of (−)-1 and of its methyl ester (−)-6 was determined by VCD spectroscopy.
Keywords Mandelic acid derivatives · Building block · Optical resolution · Determination of absolute confguration
Introduction
To date, numerous stereoselective synthetic routes were
developed for optically active mandelic acid derivatives,
such as C–H activation (Dastbaravardeh et al. 2015; Xiao
et al. 2016), hydrogenation of α-ketoesters (Carpentier and
Mortreux 1997; Meng et al. 2008; Yin et al. 2009), arylation
of carbonyl compounds (Bolm et al. 2001), biocatalytic pro-
cesses (Patterson et al. 1981) and asymmetric Friedel–Crafts
reactions (Yuan et al. 2004; Li et al. 2006; Gathergood et al.
2000). These methods were used mostly for substituting H or
halogen atoms in the ortho-position with functional groups
attached through C-, O-, or N atoms to the aromatic ring.
The direct synthesis of pure 1,2-disubstituted aromatic
compounds is usually difcult due to the formed regioiso-
mers. Thus, in these cases, starting from commercially avail-
able ortho-disubstituted materials and use functional group
conversions is more advantageous, because the purifcation
is easier. Since aromatic iodides show enhanced reactivity
in transition metal catalyzed coupling reactions (Nicolaou
et al. 2005; Jana et al. 2011; Daugulis et al. 2009; Kunz
et al. 2003), enantiopure 2-iodomandelic acid 1 ofers new
synthetic pathway for natural product syntheses.
Optically active mandelic acid derivatives are important chiral
building blocks for natural products and active pharmaceutical
ingredients (APIs). For example (+)-clavilactone A is a tyros-
ine kinase inhibitor, and a lead compound for new antitumor
molecules (Takao et al. 2013). (+)-Monocerin has antifungal,
insectidal and plant pathogenic properties (Kwon et al. 2008).
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0568-6) contains
supplementary material, which is available to authorized users.
Racemic 1 was synthesized by the decomposition of
2-iodosophenylacetic acid in low yield (Lefer et al. 1963).
In this paper, we present the laboratory (multigram) scale
synthesis of ( )-1 from cheap, commercially available
2-iodobenzoic acid, and an optimized optical resolution
process, extended with the determination of the absolute
configuration by vibrational circular dichroism (VCD)
spectroscopy (Freedman et al. 2003; Stephens et al. 2008),
* Anikó Nemes
neagaft@elte.hu
* Dénes Szabó
szabod@elte.hu
1
Institute of Chemistry, Eötvös Loránd University, Pázmány
Péter sétány 1/A, Budapest 1117, Hungary
Vol.:(0123456789)
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Chemical Papers
combined with quantum chemical calculations at DFT level.
Optically pure methyl (R)-(−)-2-iodomandelate (R)-(−)-6
was also synthesized for VCD measurements to verify the
absolute confguration.
sat. NaCl (400 mL) and evaporated in vacuo. The remain-
ing oil was dissolved in the mixture of AcOH (300 mL),
H2O (200 mL) and 98 m/m % H2SO4 (40 mL) and heated
for 10 h. The reaction mixture was cooled to rt, alkalized
to pH 12 with 20 m/m % NaOH and extracted with Et2O
(3×400 mL). The combined Et2O phases were washed with
sat. NaCl (3×200 mL) and dried over Na2SO4. The solvent
was distilled of, and the crude product was purifed by dis-
tillation in vacuo. Yield: 208 g (85%), colorless liquid, bp
143–144 °C/15 mmHg.
Experimental
Materials and instruments
All starting materials and solvents were purchased from
Molar Chemicals Kft (Hungary).
1H NMR (CDCl3) δ: 2.60 (3H, s, CH3), 7.11 (1H,
3
4
td, JHH = 7.6 Hz, JHH = 2.2 Hz, Ar-5), 7.38 (1H, dd,
4
Optical rotations were measured on a Polamat A, Zeiss,
Jena polarimeter (concentration c is given as g/100 ml).
Melting points were determined using a Boetius apparatus.
1H and 13C NMR spectra were recorded on a Bruker Avance
250 spectrometer (250 MHz for 1H) in CDCl3 with the sig-
nals of the solvent as the internal standard.
3JHH = 7.7 Hz, JHH = 1.0 Hz, Ar-4), 7.44 (1H, dd,
3JHH = 7.6 Hz, JHH = 2.0 Hz, Ar-3), 7.92 (1H, dd,
4
3JHH = 7.9 Hz, JHH = 1.0 Hz, Ar-6). 13C NMR (CDCl3) δ:
4
29.9 (CH3), 91.4 (Ar-2), 128.5 (Ar-5), 128.7 (Ar-6), 132.2
(Ar-4), 141.3 (Ar-3), 144.4 (Ar-1), 202.2 (CO).
2,2‑Dibromo‑1‑(2′‑iodophenyl)ethan‑1‑one (5)
Synthesis of racemic 2‑iodomandelic acid
To the solution of 2-iodoacetophenone 4 (24.6 g, 0.1 mol)
in AcOH (40 mL) Br2 (10 mL, 32 g, 0.2 mol) was added
in one portion (heat evolution). After stirring for 10 min,
the reaction mixture was poured into water (400 mL) and
the unreacted Br2 was neutralized by adding sat Na2S2O3
and extracted with CHCl3 (3 × 100 mL). The combined
organic phases were dried over Na2SO4, and the solvent was
removed by evaporation in vacuo. To the crude product Et2O
(30 mL) and EtOH (30 mL) was added, and the product was
crystallized at −20 °C. Yield: 81 g (66%) mp 60–62 °C.
1H NMR (CDCl3) δ: 6.67 (1H, s, CH3), 7.21 (1H,
2‑Iodobenzoyl chloride (3)
To 2-iodobenzoic acid 2 (496 g, 2 mol) SOCl2 (292 mL,
4 mol) was added. The reaction mixture was heated under
refux for 1 h then the unreacted SOCl2 was removed by
distillation. The crude product was purified by distilla-
tion in vacuo. Yield: 448 g (84%) colorless liquid, bp
136–140 °C/15 mmHg.
1H NMR (CDCl3) δ: 7.25 (1H, ddd, JHH = 7.9 Hz,
3
4
3JHH = 7.5 Hz, JHH = 1.7 Hz, Ar-5), 7.51 (1H, ddd,
3
4
3JHH = 7.9 Hz, JHH = 7.5 Hz, JHH = 1.2 Hz, Ar-4), 8.05
3
4
td, JHH = 7.6 Hz, JHH = 1.6 Hz, Ar-5), 7.43 (1H,
(1H, dd, 3JHH =7.7 Hz, 4JHH =0.9 Hz, Ar-3), 8.08 (1H, dd,
3
3
d, JHH = 7.7 Hz, Ar-4), 7.51 (1H, d, JHH = 7.7 Hz,
4
3JHH = 7.3 Hz, JHH = 1.3 Hz, Ar-6). 13C NMR (CDCl3) δ:
4JHH =1.7 Hz, Ar-3), 7.92 (1H, d, 3JHH =8.0 Hz, Ar-6). 13
C
94.2 (Ar-2), 128.7 (Ar-5), 133.8 (Ar-6), 134.7 (Ar-4), 138.3
(Ar-3), 142.3 (Ar-1), 167.3 (CO).
NMR (CDCl3) δ: 41.5 (CH), 92.3 (Ar-2), 128.6 (Ar-5), 130.3
(Ar-6), 133.1 (Ar-4), 140.4 (Ar-3), 140.7 (Ar-1), 190.0 (CO).
2‑Iodoacetophenone (4)
Racemic 2‑iodomandelic acid [( )‑1]
To the suspension of Mg (27 g, 1.1 mol) in absolute EtOH
(25 mL) CCl4 (2.5 mL) was added. At the beginning of
the gas evolution Et2O (1500 mL) and then the solution of
diethyl malonate (176 g, 1.1 mol) in abs. EtOH (100 mL)
and Et2O (125 mL) was added at a rate that maintains
reflux (0.5 h). The reaction mixture was heated under
refux for 3 h then the solution of 2-iodobenzoyl chloride
3 (266.5 g, 1 mol) in Et2O (250 mL) was added and the
mixture was boiled for an additional 2 h. After cooling to
rt 65 m/m % H2SO4 (200 g) was added. The phases were
separated and the aqueous phase was extracted with Et2O
(400 mL). The combined organic phases were washed with
The suspension of fnely powdered 2,2-dibromo-1-(2-iodo-
phenyl)ethan-1-one 5 (80 g, 0.2 mol) in 0.5 M KOH (1.6 L)
was stirred at rt for 2 days then at 90 °C for 1 h. Then, the
reaction mixture was cooled to rt and washed with Et2O
(3 × 200 mL). The aqueous phase was cooled to 0 °C and
acidifed with azeotropic HCl (140 mL) and was extracted
with Et2O (6×200 mL). The combined organic phases were
dried over Na2SO4, and the solvent was removed by evapo-
ration in vacuo. The crude product was purifed by crystal-
lization from toluene (200 mL) at rt. Yield: 35.5 g (64%),
mp 108–110 °C.
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1H NMR (CDCl3) δ: 5.21 (1H, s, CH), 5.70 (2H, br s,
range of 1800–800 cm−1 was used to optimize the instru-
ment for the fngerprint region. The instrument was cali-
brated for VCD intensity with a CdS multiple-wave plate.
A CaF2 cell of 0.207 mm pathlength and sample concen-
trations of ~ 20 (saturated solution) and 40 mg/mL were
used for (−)-1 and (−)-6, respectively. The spectra were
averaged for 10 h (corresponding to~ 36 000 accumulated
scans). Baseline correction was achieved by subtracting
the spectrum of the solvent obtained under the same con-
ditions. The IR spectra were calculated from the single-
channel absorption (DC) spectra of the sample and solvent,
respectively.
3
4
OH, COOH), 6.80 (1H, td, JHH = 7.5 Hz, JHH = 1.7 Hz,
Ar-5), 7.15 (1H, td, 3JHH =7.5 Hz, 4JHH =0.8 Hz, Ar-4), 7.25
(1H, dd, 3JHH =7.8 Hz, 4JHH =1.6 Hz, Ar-3), 7.92 (1H, dd,
4
3JHH = 8.0 Hz, JHH = 0.7 Hz, Ar-6). 13C NMR (CDCl3) δ:
76.7 (CH), 99.6 (Ar-2), 128.4 (Ar-5), 128.8 (Ar-6), 130.1
(Ar-4), 139.8 (Ar-3), 142.4 (Ar-1), 174.7 (CO).
Optical resolution of racemic 2‑iodomandelic acid
To a solution of racemic 2-iodomandelic acid ( )-1
(10.00 g, 36 mmol) in 0.1 M NaOH (360 mL) was added
strychnine nitrate (7.15 g, 18 mmol) at 90 °C. The mix-
ture was heated on a steam bath for 5.5 h and allowed to
stand at rt overnight. The precipitate was fltered and dried
to give the diastereomeric salt with (−) rotation {10.32 g,
mp 149–155 °C, [α]578 = −116 (c=0.5 DMF)}. To liberate
acid (−)-1, (10.00 g), the latter salt was suspended in 1 M
HCl (50 mL) and extracted with DCM (3 × 70 mL). The
combined organic phases were dried over Na2SO4, and the
solvent was evaporated to aford (−)-1 {2.03 g, 40%, mp
97–104 °C, [α]578 = −130 (c=0.5 DMF)}.
Quantum chemical calculations
Preliminary conformational search for (R)-1 and (R)-6 was
performed with the Hyper Chem 8.0.3 software package
by systematic variation (increments of 60°– 180°) of
dihedral angles θ1–θ4 (for defnition, see Fig. 1), using
MM+ force feld, with no cut-ofs and keeping conformers
within a 20 kcal/mol relative energy limit. Starting from
the results of MM calculations, fnal geometry optimiza-
tions and the computation of vibrational frequencies and
VCD rotatory strengths were carried out with the Gaussian
09 software package (Frisch et al. 2013) at DFT level using
the B3PW91 functional combined with the 6-31G(d) basis
set for C, H, O and the LanL2DZ basis set for the iodine
atoms with predefned efective core potential (ECP). The
calculated vibrational frequencies were scaled by a fac-
tor of 0.963, proved to be suitable for vibrational spectra
calculated at similar B3LYP/6-31G(d)/LanL2DZ level for
chiral Rh complexes of amino acids (Szilvágyi et al. 2011).
VCD curves were simulated from the calculated wave-
number and rotatory strength data using Lorentzian band
The aqueous filtrate of the (+) salt was evaporated
to~100 ml, acidifed with 37 m/m % HCl (10 mL) to pH~2
and extracted with DCM (100 mL). The organic solution
was dried over Na2SO4, and the solvent was evaporated. The
crude product was crystallized from toluene (30 ml) at rt
to give (+)-1 {1.08 g, 20%, mp 93–100 °C, [α]578 =+108
(c=0.5 DMF)}.
Methyl (R)‑(−)‑2‑iodomandelate [(R)‑(−)‑6]
To the solution of (R)-(−)-2-iodomandelic acid in Et2O
(20 mL) 2.8 M etheral diazomethane solution (1.8 mL) was
added. The solution was stirred for 20 min, then the solvent
was removed in vacuo to aford (R)-(−)-6. Yield: 1.07 g
(96%), mp 92–95 °C, [α]578 = −77 (c=0.5 DMF).
shape and a half-width at half-height value of 10 cm−1
.
1H NMR (CDCl3) δ: 3,64 (1H, br s, OH), 3.77 (3H, s,
3
CH3), 5.50 (1H, s, CH), 7.03 (1H, ddd, JHH = 8.0 Hz,
3JHH =8.0 Hz, 4JHH =1.7 Hz, Ar-5), 7.22–7.43 (2H, m, Ar-3,
Ar-4), 7.92 (1H, dd, 3JHH =8.0 Hz, 4JHH =0.7 Hz, Ar-6). 13
C
NMR (CDCl3) δ: 53.55 (CH3), 77.0 (CH), 99.4 (Ar-2), 128.5
(Ar-5), 129.1 (Ar-6), 130.6 (Ar-4), 140.3 (Ar-3), 144.2 (Ar-
1), 174.1 (CO).
VCD measurements
The VCD spectra of (−)-1 and (−)-6 at a resolution of
4 cm−1 were recorded in CDCl3 solution using a Bruker
PMA 37 VCD/PM-IRRAS module connected to an Equi-
nox 55 FT-IR spectrometer (Bruker Optics, Germany).
The ZnSe photoelastic modulator of the instrument was
set to 1400 cm−1 and an optical flter with a transmission
Fig. 1 Defnition of dihedral angles θ1–θ4 describing the conforma-
tional fexibility of (R)-1 and (R)-6
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Scheme 1 Synthesis of ( )-1
Scheme 2 Optical resolution of ( )-1 with strychnine
The theoretical VCD curves of the (R)-1 monomer and
its ester derivative (R)-6 were obtained as population-
weighted sums of the calculated spectra of individual con-
formers, considering a Boltzmann distribution. Theoretical
VCD spectrum was also calculated for the H-bonded cyclic
dimer of the most stable conformer of (R)-1, using the
same level of theory.
Results and discussion
2-Iodoacetophenone 4 and 2-iodomandelic acid 1 were
prepared by a slightly modifed method given for the syn-
thesis of 2-nitroacetophenone (Reynolds and Hauser 1963)
and 4-bromomandelic acid, respectively, (Klingenberg,
1963). Starting material 2-iodobenzoic acid 2 was con-
verted into acyl chloride 3 using thionyl chloride, and then
it was reacted with ethoxymagnesiummalonic ester (Price
and Tarbell 1963). The formed diester was hydrolyzed
and decarboxylated yielding crude 2-iodoacetophenone 4
which was purifed by vacuum distillation. Bromination of
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Fig. 3 Relevant conformers of (R)-6 with predicted populations of
more than 1% at the B3PW91/6-31G(d)/LanL2DZ level of theory (for
details see Table S3 in the Supporting Information)
To one equiv of ( )-1 were added 1 equiv of NaOH and
0.5 equiv of strychnine nitrate (B × HNO3). One of the
diastereomeric salts [(−)-1 × B] separated in crystalline
form, from which (−)-1 was regenerated with aqueous
NaOH solution. This method provided the enantiopure
(−)-1 {ee > 99%, [α]578 = − 130 (c = 0.5, DMF)}. (+)-1
was isolated from the mother liquor after partial evapora-
tion and acidifcation in 77% ee {[α]578 = + 108 (c = 0.5,
DMF)} (Scheme 2.). After crystallization from toluene,
the ee of 1 was 94% {[α]578 = + 115 (c = 0.5, DMF)}.
Enantiomeric excess (ee) of the products was determined
by 1H NMR spectroscopy using (S)-1-methylbenzylamine
as chiral solvating agent (see Supporting Information). The
calculated ee values of the products based on the measured
optical rotation are slightly diferent from that obtained by
1H NMR method, due to the presence of impurities in the
crude products.
Fig. 2 Relevant conformers (a–d) of (R)-1 with predicted popula-
tions of more than 1% and the structure of H-bonded dimer a–a at
the B3PW91/6-31G(d)/LanL2DZ level of theory (for details see
Tables S1–S2 in the Supporting Information)
The conformational analysis on (R)-1 resulted in 20
conformers at the B3PW91/6-31G(d)/LanL2DZ level of
theory, out of which only four, denoted a–d (Fig. 2), have
an estimated population of more than 1% (92.9, 1.5, 1.3 and
1%, respectively). These structures feature an intramolecu-
lar H-bond. The low number of favourable conformers is a
result of steric hindrance caused by the bulky iodine atom
in ortho-position, as well as of the stabilizing efect of intra-
molecular H-bonds involving the α-OH group. The main
conformer (a), as well as its H-bonded dimer a–a of C2 sym-
metry (Fig. 2) were supposed to essentially contribute to the
IR and VCD spectrum. H-bonded dimers of higher energy
conformers (such as a–c, c–c, b–b, the latter formed via the
carbonyl oxygen and α-OH groups) were also considered
but could be ruled out based on their very high calculated
Gibbs-free energies relative to dimer a–a.
the pure 4 aforded the dibromoacetophenone 5 in moder-
ate yield. The hydrolysis of 5 and the consecutive Canniz-
zaro reaction of the intermediate α-keto-aldehyde (Engler
and Wöhrle 1887) resulted in the target ( )-1 (Scheme 1).
Optical resolution of racemic 1 was carried out by dias-
tereomeric crystallization (Faigl et al. 2008). To fnd the
optimal conditions for the optical resolution of ( )-1 we
tested several methods (Nemes et al. 2017), using strych-
nine, brucine, optochin, quinine, quinidine cinchonine,
cinchonidine, (S)-1-methylbenzylamine and ephedrine
as resolving agents. It is worthy to note, that although
ephedrine was successful resolving agent for other man-
delic acid derivatives (Collet and Jacques 1973; Valnte
et al. 1995), in the case of ( )-1, the crystallization trials
did not give flterable precipitate. We obtained the enantio-
pure (−)-1 using 0.5 equiv of the organic base strychnine
as a resolving agent in warm aqueous media (Scheme 2).
The methyl ester (R)-6 has even less low-energy conform-
ers (two out of a total number of 18 calculated conformers
at the B3PW91/6-31G(d)/LanL2DZ level of theory), struc-
tures a and b shown in Fig. 3, having populations of 98.1
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Fig. 4 Experimental IR and VCD spectra of (−)-1 obtained in CDCl3 in comparison with the calculated spectra of the monomer and H-bonded
dimer forms of (R)-1 (at the B3PW91/6-31G(d)/LanL2DZ level of theory)
and 1.1%, respectively. Esterifcation of the carboxyl group
not only reduces the number of conformers to be considered
but also eliminates the formation of H-bonded dimers via
carboxyl groups, simplifying the interpretation of spectra.
The experimental IR and VCD spectra of (−)-1 in com-
parison with the calculated spectra of the monomer and
H-bonded dimer form of (R)-1 are shown in Fig. 4. The
experimental IR spectrum of (−)-1 shows a strong absorp-
tion band at 1719 cm−1, assigned to the out-of-phase cou-
pled νC= O vibration of the H-bonded dimer, overlapped
with a medium intensity νC= O band of the monomer at
1750 cm−1. Similarly, in the VCD spectrum, the strong
negative band at 1718 cm−1 corresponds to the H-bonded
dimer, while the weak negative shoulder at~1748 cm−1 is
the νC=O contribution of the monomer. The in-phase-cou-
pled νC=O band of the dimer, practically absent from the
IR spectrum (due to the local centrosymmetric arrangement
of the two carboxyl groups), shows up as a weak-positive
band at ~ 1658 cm−1 in the VCD spectrum. Despite the
often-found non-robust character of the C= O stretching
modes in VCD (for a defnition of robustness, based on the
ratio of rotatory and dipole strengths, see Góbi and Magyar-
falvi 2011) the VCD bands measured in the carbonyl region
are in very good agreement in terms of both position and
sign with the calculated spectral features of the dimer and
monomer forms of (R)-1. In our case the νC= O mode of
conformers a–c is more-or-less robust (with~10.0, 11.1 and
19.7 ppm |R/D| ratios, respectively), and only non-robust for
conformer d (for which |R/D|=3.5). Relatively good agree-
ment is also found in the fngerprint region of the VCD spec-
trum, and similarly, the spectrum shows the contribution of
both the monomer and H-bonded dimer forms.
To reduce the complications due to strong intermolecular
interactions (e.g., H-bonded dimer formation) and improve
the quality of the experimental VCD spectrum (limited by
the poor solubility of the sample), the methyl ester deriva-
tive (−)-6 of (−)-2-iodomandelic acid has also been investi-
gated. This compound has a much better solubility in CDCl3,
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Fig. 5 Experimental IR and VCD spectra of (−)-6 obtained in CDCl3 in comparison with the calculated spectra of (R)-6 (at the B3PW91/6-
31G(d)/LanL2DZ level of theory)
Innovation Ofce (K115764), and the Central Hungarian Operational
allowing to obtain higher-intensity VCD spectrum under the
same experimental setup. The experimental IR and VCD
spectra of (−)-6 in comparison with the calculated spectra
of (R)-6 are presented in Fig. 5. Although the band intensity
ratios in the calculated IR spectrum do not perfectly match
those in the experimental one, which in our opinion is mostly
a weakness of the used basis set combination (6-31G(d)/
Land2LDZ), the theoretical and experimental VCD spectra
are very similar throughout the whole spectral range covered
by the measurement, permitting to unambiguously assign the
absolute confguration of (−)-6 to R. This is reinforcing the
assignment of (−)-1 to the R enantiomer of 2-iodomandelic
acid, as esterifcation of the carboxylic group does not afect
the absolute confguration of the compound.
Program (KMOP-4.2.1/B-10-2011-0002) for supporting this work.
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1H NMR spectroscopy using (S)-1-methylbenzylamine as
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Acknowledgements The authors thank Professor József Rábai the
stimulating discussions and the National Research Development and
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