(R)-Phenyl­ethyl­ammonium (R)-4-chloro­mandelate

Optical resolution of a racemic mixture of (±)-4-chloro­mandelic acid (4-ClMA) was obtained using (R)-phenyl­ethyl­amine (R-PEA) as a resolving agent. A pair of diastereomeric salts (R-4-ClMA·R-PEA and S-4-ClMA·R-PEA) had significantly different solubilities and allowed optically pure crystals of the title complex, (R)-phenyl­ethyl­ammonium (R)-2-(4-chloro­phen­yl)-2-hydroxy­acetate, C₈H₁₂N⁺·C₈H₆ClO₃^- or [(R)-C₆H₅C(H)CH₃NH₃][(R)-4-ClC₆H₄C(H)(OH)CO₂], to be isolated. The crystal structure of the enanti­omeric S,S analogue has been published previously [Kinbara, Tagawa & Saigo (2001). Tetra­hedron Asymmetry, 12, 2927-2930]. In the title crystal structure, a two-dimensional network, perpendicular to the c axis, is formed via inter­molecular hydrogen bonds.

Key indicators

• Single-crystal X-ray study
• T = 296 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.038
• wR factor = 0.095
• Data-to-parameter ratio = 14.2

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for         C2
PLAT790_ALERT_4_C Centre of Gravity not Within Unit Cell: Resd.  #          2
              C8 H6 Cl O3

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           25.00
           From the CIF: _reflns_number_total               2731
           Count of symmetry unique reflns         1613
           Completeness (_total/calc)            169.31%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured      1118
           Fraction of Friedel pairs measured     0.693
           Are heavy atom types Z>Si present        yes
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C8     = .          R
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C15    = .          R

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   2 ALERT level C = Check and explain
   3 ALERT level G = General alerts; check

   2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Optically active (R)-4-Chloromandelic acid (R4-ClMA), being a significant chiral intermediate, has been widely used to synthesize many new pharmaceuticals (Adams et al., 2002). Huang et al. (2005) prepared (R)-4-ClMA by enantioselective degradation of racemates with newly isolated Pseudomonas putida. Yamaguchi et al. (2002) carried out the optical resolution of racemic organic acids using optically active 4-amino-2-methyl-butan-1-ol as a resolving agent in 2-propanol solvent. However, there are significant drawbacks among the above mentioned methods such as low yield and the high cost of resolving agents. Our lab is searching for economically feasible methods.

In the investigation of the optical resolution of racemic 4-Chloromandelic acid by (R)-Phenylethylamine, crystals of (R)-Phenylethylamine-(R)-4-Chloromandelic acid (R4-ClMA·R-PEA), were obtained from a methanol solution containing racemic 4-Chloromandelic acid and (R)-Phenylethylamine. Herein we present the structure of R4-ClMA·R-PEA showing the successful optical resolution. The crystal structure of the enantiomeric (S,S) analogue has previously been published (Kinbara et al., 2001).

The title complex consists of an ion pair; an amine cation and a carboxylate anion. The stereochemistry of each of the ions is successfully resolved (see: Flack parameter (Flack, 1983)) to be the R enantiomer. Three N—H atoms and a single O—H atom show close contacts to adjacent carboxylate O atoms. Thus, a two-dimensional network of H-bonding is observed. This presumably gives rise to the lower solubility of this product as compared to the S4-ClMA,R-PEA product. At present, we are attempting to grow single crystals of the S,R product.

Related literature

For background information, see: Adams et al. (2002); Huang et al. (2005); Yamaguchi et al. (2002); Langkilde et al. (2002); Hu et al. (2004). The crystal structure of the S,S enantiomer is isomorphous (Kinbara et al., 2001).

S2. Experimental

To a solution of racemic (+/-)-4-ClMA (8.4 g, 0.045 mol) in 72 ml me thanol, was gradually added (5.7 mL, 0.045 mol) R-PEA. A white crystalline solid appeared. The mixture was heated to 333 K using a water bath and the solid dissolved. The solution was then allowed to stand at 333 K for 30 minutes and subsequently cooled slowly to 295 K. After standing at 295 K for 60 minutes, the precipitate was collected and washed twice with methanol. The filtered precipitate was recrystallized in methanol to give the optically pure salt R-4-ClMA·R-PEA (3.1 g, 45% yield). X-ray quality crystals of R-4-ClMA·R-PEA were grown from iso-propanol solution by slow evaporation at room temperature.

S3. Refinement

All H atoms were positioned geometrically and constrained as riding atoms with C—H = 0.98 Å and U_iso(H) = 1.2U_eq(C) for methyne H atoms and C—H = 0.96 Å and U_iso(H) = 1.5U_eq(C) for methyl H atoms and C—H = 0.93 Å and U_iso(H) = 1.2U_eq(C) for aromatic H atoms and O—H = 0.82 Å and U_iso(H) = 1.5U_eq(C) for hydroxyl H atoms and N—H = 0.89 Å and U_iso(H) = 1.5U_eq(C) for amine H atoms.

Computing details

Data collection: COLLECT (Nonius, 2001); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC (Sheldrick, 2001); software used to prepare material for publication: SHELXTL/PC (Sheldrick, 2001).

Figures

Fig. 1. The molecular structure of the title compound with 30% probability displacement ellipsoids and the atom labelling scheme.

(R)-phenylethylaminium (R)-2-(4-chlorophenyl)-2-hydroxyacetate,

Crystal data

C8H12N^+·C8H6ClO3^−	F(000) = 648
Mr = 307.76	Dx = 1.312 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 23622 reflections
a = 6.8848 (3) Å	θ = 2.0–27.5°
b = 8.3979 (3) Å	µ = 0.25 mm^−1
c = 26.9433 (10) Å	T = 296 K
V = 1557.80 (11) Å^3	Rod, colourless
Z = 4	0.40 × 0.13 × 0.05 mm

Data collection

Nonius KappaCCD diffractometer	2731 independent reflections
Radiation source: fine-focus sealed tube	2086 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.055
φ scans, and ω scans with κ offsets	θmax = 25.0°, θmin = 2.9°
Absorption correction: multi-scan from symmetry-related measurements (SORTAV; Blessing, 1995)	h = −8→8
Tmin = 0.838, Tmax = 0.988	k = −9→9
18157 measured reflections	l = −32→20

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.038	w = 1/[σ^2(Fo^2) + (0.0425P)^2 + 0.2438P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.095	(Δ/σ)max < 0.001
S = 1.03	Δρmax = 0.15 e Å^−3
2731 reflections	Δρmin = −0.19 e Å^−3
193 parameters	Extinction correction: SHELXL97 (Sheldrick, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0116 (19)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983), 1121 Friedel pairs
Secondary atom site location: difference Fourier map	Absolute structure parameter: −0.07 (10)

Special details

Experimental. M·P. 469 K. The specific rotation was [α]²⁰_D = -48.5° (c=1, C₂H₅OH), determined using a WZZ-1S Digital Polarimeter; ¹H-NMR (d₆-DMSO/TMS): δ 1.41 (d, 3H, CH₃), 4.29 (m, 1H, CHNH₂), 4.53 (s, 1H, CHOH), 7.27–7.44 (m, 9H, C₆H₅ and C₆H₄Cl) measured using an AVANCE 500 MHz NMR (BRUKER). IR (KBr): 3301(m), 3036(s), 2535(m), 1610(s), 1576(s), 1531(s), 1383(s), 1193(m), 1072(s), 776(s), 705(s), 553(m), 478(m),446(m) measured using a NICOLET 5SXC. Elemental analysis: Calc'd for C₁₆H₁₈NO₃Cl (FW 307.8) C: 62.40, H: 5.85, N: 4.55; Found C: 62.71, H: 6.26, N: 4.48 using a Elementar Vario EL.

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Cl1	1.08733 (15)	1.26848 (13)	−0.22906 (3)	0.1093 (4)
C2	0.9516 (4)	1.2426 (3)	−0.17511 (10)	0.0619 (7)
C3	0.7898 (4)	1.1480 (3)	−0.17627 (10)	0.0661 (8)
H3A	0.7535	1.0971	−0.2055	0.079*
C4	0.6809 (4)	1.1287 (3)	−0.13362 (9)	0.0537 (6)
H4A	0.5702	1.0653	−0.1344	0.064*
C5	0.7339 (3)	1.2022 (2)	−0.08997 (8)	0.0403 (5)
C6	0.8988 (4)	1.2948 (3)	−0.08991 (10)	0.0530 (6)
H6A	0.9373	1.3442	−0.0606	0.064*
C7	1.0087 (4)	1.3160 (3)	−0.13242 (11)	0.0666 (8)
H7A	1.1195	1.3792	−0.1319	0.080*
C8	0.6149 (3)	1.1803 (3)	−0.04321 (8)	0.0427 (6)
H8A	0.6380	1.2723	−0.0216	0.051*
O9	0.4138 (2)	1.1733 (2)	−0.05381 (6)	0.0592 (5)
H9A	0.3595	1.2511	−0.0417	0.089*
C10	0.6798 (3)	1.0312 (3)	−0.01565 (8)	0.0392 (5)
O11	0.8499 (2)	1.03549 (18)	0.00208 (6)	0.0487 (4)
O12	0.5668 (2)	0.91601 (18)	−0.01150 (6)	0.0516 (4)
N13	0.6696 (3)	0.6352 (2)	0.04075 (7)	0.0461 (5)
H13A	0.6670	0.7336	0.0285	0.069*
H13B	0.5842	0.5749	0.0246	0.069*
H13C	0.7881	0.5946	0.0371	0.069*
C14	0.4278 (4)	0.7292 (3)	0.10083 (10)	0.0608 (7)
H14A	0.4446	0.8374	0.0902	0.091*
H14B	0.3895	0.7275	0.1351	0.091*
H14C	0.3292	0.6793	0.0810	0.091*
C15	0.6183 (3)	0.6394 (3)	0.09474 (8)	0.0455 (6)
H15A	0.5985	0.5297	0.1060	0.055*
C16	0.7750 (3)	0.7132 (3)	0.12610 (9)	0.0445 (6)
C17	0.8086 (4)	0.6529 (3)	0.17348 (9)	0.0606 (7)
H17A	0.7429	0.5622	0.1840	0.073*
C18	0.9392 (5)	0.7270 (4)	0.20491 (10)	0.0721 (8)
H18A	0.9602	0.6861	0.2365	0.087*
C19	1.0372 (4)	0.8594 (4)	0.18997 (11)	0.0664 (8)
H19A	1.1238	0.9094	0.2114	0.080*
C20	1.0075 (4)	0.9186 (3)	0.14321 (11)	0.0634 (8)
H20A	1.0755	1.0082	0.1328	0.076*
C21	0.8777 (4)	0.8465 (3)	0.11138 (9)	0.0530 (7)
H21A	0.8591	0.8880	0.0797	0.064*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.1089 (8)	0.1380 (9)	0.0811 (6)	0.0112 (7)	0.0429 (5)	0.0314 (6)
C2	0.0596 (18)	0.0677 (18)	0.0583 (17)	0.0094 (16)	0.0110 (14)	0.0151 (15)
C3	0.076 (2)	0.0736 (18)	0.0484 (16)	−0.0007 (17)	0.0007 (15)	−0.0050 (15)
C4	0.0510 (15)	0.0571 (15)	0.0531 (15)	−0.0083 (13)	−0.0019 (14)	−0.0021 (13)
C5	0.0368 (12)	0.0369 (12)	0.0471 (13)	0.0010 (10)	−0.0021 (11)	0.0029 (11)
C6	0.0498 (15)	0.0539 (14)	0.0552 (15)	−0.0087 (13)	−0.0040 (13)	0.0047 (12)
C7	0.0532 (16)	0.0677 (19)	0.079 (2)	−0.0111 (14)	0.0051 (16)	0.0172 (16)
C8	0.0373 (13)	0.0398 (13)	0.0509 (14)	0.0030 (10)	−0.0009 (11)	−0.0044 (10)
O9	0.0358 (9)	0.0656 (11)	0.0760 (12)	0.0102 (9)	0.0029 (9)	−0.0010 (9)
C10	0.0379 (14)	0.0408 (13)	0.0390 (12)	0.0012 (11)	0.0021 (11)	−0.0069 (10)
O11	0.0426 (10)	0.0503 (9)	0.0532 (10)	0.0008 (8)	−0.0060 (8)	0.0020 (7)
O12	0.0429 (9)	0.0430 (8)	0.0690 (11)	−0.0065 (8)	−0.0004 (9)	0.0057 (8)
N13	0.0381 (11)	0.0452 (11)	0.0551 (12)	0.0027 (9)	−0.0016 (9)	−0.0044 (9)
C14	0.0422 (14)	0.0654 (17)	0.0749 (18)	0.0017 (14)	0.0066 (13)	−0.0155 (14)
C15	0.0463 (14)	0.0388 (12)	0.0514 (14)	−0.0045 (11)	0.0062 (12)	−0.0013 (11)
C16	0.0396 (13)	0.0439 (12)	0.0501 (14)	0.0039 (11)	0.0051 (11)	−0.0029 (12)
C17	0.0684 (18)	0.0593 (15)	0.0541 (16)	−0.0036 (15)	0.0061 (14)	0.0066 (14)
C18	0.086 (2)	0.080 (2)	0.0507 (16)	0.008 (2)	−0.0072 (16)	−0.0019 (15)
C19	0.0624 (18)	0.0704 (18)	0.0664 (18)	0.0044 (16)	−0.0123 (15)	−0.0148 (16)
C20	0.0522 (17)	0.0576 (16)	0.080 (2)	−0.0091 (14)	−0.0056 (16)	−0.0010 (15)
C21	0.0511 (16)	0.0511 (14)	0.0568 (15)	−0.0078 (14)	−0.0065 (13)	0.0081 (12)

Geometric parameters (Å, º)

Cl1—C2	1.742 (3)	N13—H13B	0.8900
C2—C7	1.363 (4)	N13—H13C	0.8900
C2—C3	1.369 (4)	C14—C15	1.521 (3)
C3—C4	1.381 (4)	C14—H14A	0.9600
C3—H3A	0.9300	C14—H14B	0.9600
C4—C5	1.377 (3)	C14—H14C	0.9600
C4—H4A	0.9300	C15—C16	1.504 (3)
C5—C6	1.376 (3)	C15—H15A	0.9800
C5—C8	1.514 (3)	C16—C21	1.383 (3)
C6—C7	1.384 (4)	C16—C17	1.393 (3)
C6—H6A	0.9300	C17—C18	1.383 (4)
C7—H7A	0.9300	C17—H17A	0.9300
C8—O9	1.415 (3)	C18—C19	1.361 (4)
C8—C10	1.523 (3)	C18—H18A	0.9300
C8—H8A	0.9800	C19—C20	1.370 (4)
O9—H9A	0.8200	C19—H19A	0.9300
C10—O12	1.247 (3)	C20—C21	1.378 (3)
C10—O11	1.265 (3)	C20—H20A	0.9300
N13—C15	1.497 (3)	C21—H21A	0.9300
N13—H13A	0.8900
C7—C2—C3	121.1 (3)	H13A—N13—H13C	109.5
C7—C2—Cl1	119.6 (2)	H13B—N13—H13C	109.5
C3—C2—Cl1	119.3 (2)	C15—C14—H14A	109.5
C2—C3—C4	119.4 (3)	C15—C14—H14B	109.5
C2—C3—H3A	120.3	H14A—C14—H14B	109.5
C4—C3—H3A	120.3	C15—C14—H14C	109.5
C5—C4—C3	120.9 (2)	H14A—C14—H14C	109.5
C5—C4—H4A	119.5	H14B—C14—H14C	109.5
C3—C4—H4A	119.5	N13—C15—C16	112.72 (19)
C6—C5—C4	118.2 (2)	N13—C15—C14	108.7 (2)
C6—C5—C8	120.9 (2)	C16—C15—C14	110.69 (18)
C4—C5—C8	120.9 (2)	N13—C15—H15A	108.2
C5—C6—C7	121.5 (2)	C16—C15—H15A	108.2
C5—C6—H6A	119.2	C14—C15—H15A	108.2
C7—C6—H6A	119.2	C21—C16—C17	118.2 (2)
C2—C7—C6	118.9 (3)	C21—C16—C15	122.6 (2)
C2—C7—H7A	120.6	C17—C16—C15	119.0 (2)
C6—C7—H7A	120.6	C18—C17—C16	120.3 (3)
O9—C8—C5	111.52 (18)	C18—C17—H17A	119.8
O9—C8—C10	110.60 (18)	C16—C17—H17A	119.8
C5—C8—C10	110.28 (18)	C19—C18—C17	120.6 (3)
O9—C8—H8A	108.1	C19—C18—H18A	119.7
C5—C8—H8A	108.1	C17—C18—H18A	119.7
C10—C8—H8A	108.1	C18—C19—C20	119.6 (3)
C8—O9—H9A	109.5	C18—C19—H19A	120.2
O12—C10—O11	124.5 (2)	C20—C19—H19A	120.2
O12—C10—C8	119.9 (2)	C19—C20—C21	120.7 (3)
O11—C10—C8	115.61 (19)	C19—C20—H20A	119.7
C15—N13—H13A	109.5	C21—C20—H20A	119.7
C15—N13—H13B	109.5	C20—C21—C16	120.6 (2)
H13A—N13—H13B	109.5	C20—C21—H21A	119.7
C15—N13—H13C	109.5	C16—C21—H21A	119.7
C7—C2—C3—C4	1.1 (4)	C5—C8—C10—O12	−114.3 (2)
Cl1—C2—C3—C4	−179.3 (2)	O9—C8—C10—O11	−169.88 (19)
C2—C3—C4—C5	−0.6 (4)	C5—C8—C10—O11	66.3 (2)
C3—C4—C5—C6	−0.3 (4)	N13—C15—C16—C21	40.7 (3)
C3—C4—C5—C8	−179.7 (2)	C14—C15—C16—C21	−81.2 (3)
C4—C5—C6—C7	0.7 (3)	N13—C15—C16—C17	−144.3 (2)
C8—C5—C6—C7	−179.9 (2)	C14—C15—C16—C17	93.7 (3)
C3—C2—C7—C6	−0.7 (4)	C21—C16—C17—C18	1.1 (4)
Cl1—C2—C7—C6	179.7 (2)	C15—C16—C17—C18	−174.1 (2)
C5—C6—C7—C2	−0.2 (4)	C16—C17—C18—C19	−0.3 (4)
C6—C5—C8—O9	143.6 (2)	C17—C18—C19—C20	−0.7 (4)
C4—C5—C8—O9	−37.0 (3)	C18—C19—C20—C21	0.8 (4)
C6—C5—C8—C10	−93.1 (2)	C19—C20—C21—C16	0.1 (4)
C4—C5—C8—C10	86.3 (3)	C17—C16—C21—C20	−1.0 (4)
O9—C8—C10—O12	9.6 (3)	C15—C16—C21—C20	174.0 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O9—H9A···O11^i	0.82	2.09	2.848 (2)	154
N13—H13A···O12	0.89	2.00	2.836 (2)	157
N13—H13B···O11^ii	0.89	1.99	2.869 (3)	167
N13—H13C···O12^iii	0.89	2.04	2.878 (3)	156

Symmetry codes: (i) x−1/2, −y+5/2, −z; (ii) x−1/2, −y+3/2, −z; (iii) x+1/2, −y+3/2, −z.