L-Isoleucyl-L-phenyl­alanine dihydrate

The structure of the title compound, C₁₅H₂₂N₂O₃·2H₂O, was derived from data collected on a very thin twinned needle. The peptide mol­ecule is in a rare conformation normally associated with hydro­phobic dipeptides that form nanotubes. Nevertheless, the present structure is divided into hydro­phobic and hydro­philic layers.

S1. Comment

L-Ile-L-Phe (IF) has been investigated as part of a systematic survey of dipeptides constructed from the five hydrophobic amino acid residues L-Ala, L-Val, L-Ile, L-Leu and L-Phe (Görbitz, 2003, and references therein). The peptide was crystallized as a dihydrate; the molecular structure is shown in Fig. 1. While the vast majority of dipeptides have main-chain conformations that bring one side chain above the peptide plane and one below, the opposite situation is observed for IF. The property of having both side chains on the same side of the peptide plane gives absolute values for the C₁^β—C₁^α···C₂^α—C₂^β (θ) torsion angle of less than 90°. For IF, the C2—C1···C7—C8 angle is 16.0 (5)°. The C1–C4 and C1/C6/O1/N2/C7 chains are both planar and form a dihedral angle [69.0 (3)°] that is not significantly different from that formed by the latter chain and the phenyl ring [69.6 (1)°]. The dihedral angle formed by the C1–C4 chain and the phenyl ring is 29.5 (3)°.

The limited number of dipeptides with conformations similar to IF usually have two large hydrophobic side chains (Phe, Leu or Ile) and form nanotubular structures with hydrophilic channels. This group has been called the FF class after L-Phe-L-Phe and includes L-Leu-L-Leu, L-Leu-L-Phe (LF), L-Phe-L-Leu (Görbitz, 2001) and L-Ile-L-Leu (Görbitz, 2004). L-Trp-Gly (Emge et al., 2000; Birkedal et al., 2002) is an unexpected last member of the FF class. The distinctly hydrophobic title compound does not form channels, however, but rather hydrophobic and hydrophilic layers in exactly the same manner as observed previously for L-Val-L-Phe dihydrate (VF, orthorhombic modification; Görbitz, 2002; Fig. 2). Similar hydrophilic layers were also found for L-Ala-L-Trp (AW; θ = 37.5°; Emge et al., 2000), while L-Phe-L-Pro hydrate (Panneerselvam & Chacko, 1989) has a different crystal packing arrangement despite having a low θ value (42.3°).

The –NH₃⁺···⁻OOC– hydrogen bond is the signature intermolecular interaction of crystal structures of linear unblocked peptides, where it generates the familiar head-to-tail peptide chains. The most special feature of the hydrogen-bond network of IF is the lack of such direct interactions between the charged terminal groups (Table 1). All amino H atoms are instead accepted by water molecules. In comparison, the hydrophilic region of AW is slightly contracted, as reflected by the shrinkage of the unit-cell lengths from a = 5.6350 (14)/5.6595 (4) Å and b = 8.2897 (18)/8.3306 (6) Å for IF/VF to a = 4.9475 (5) Å and b = 8.2059 (12) Å for AW. Water molecule 2 (O2W in Fig. 1) is then eliminated, with concomitant formation of two traditional –NH₃⁺···⁻OOC– hydrogen bonds.

While hydrophilic layers are identical for IF and VF, the additional terminal methyl group of the Ile residue modifies the contact interface at the center of the hydrophobic region in such a way as to shift the space group from P2₁2₁2₁2₁ for VF to P2₁ for IF (Fig. 2).

A schematic illustration of the transition from the layered IF and VF structures to members of the FF class is given in Fig. 3. In the process, the water content is reduced from two water molecules per peptide molecule (dihydrate) to just one (monohydrate). At the same time, the number of peptide molecules in the asymmetric unit is increased from one to two. LF is shown in Fig. 4 as an example of an FF-class structure. The water-filled channels are of rectangular shape, with van der Waals dimensions of 2.5 × 6.0 Å. The molecular conformations of VF, IF and LF are compared in Table 2, which lists relevant torsion angles in the three structures. VF and IF are very similar, but it is also clear that the special folded conformation is retained by LF in the FF class.

FF itself has hexagonal symmetry, a single molecule in the asymmetric unit, and a channel with a 10 Å van der Waals diameter (Görbitz, 2001).

S2. Experimental

Very thin needles of the title compound were obtained by fast evaporation of an aqueous solution at elevated temperature (333 K). The same technique is used for crystallizing compounds in the FF class (Görbitz, 2001).

S3. Refinement

The very thin needle used for data collection proved to be a merohedral twin. Twinning was handled in the refinement by a SHELXTL TWIN 1 0 0 0 − 1 0 − 1 0 − 1 command. The fractional contribution was 0.50 for each component. Heavy atoms were refined anisotropically and positional parameters for H atoms were refined only for the two water molecules. Restraints were applied to give O—H distances close to 0.90 Å and H—O—H angles close to 105°. Peptide H atoms were placed geometrically and included in the refinement with constraints. Free rotation was permitted for amino and methyl groups. U_iso values for H atoms were set at 1.2U_eq of the carrier atom, or 1.5U_eq for water, methyl and amino groups. In the absence of signinficant anomalous scattering effects, 1103 Friedel pairs were merged. The absolute configuration was known for the purchased material.

Computing details

Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Bruker, 2000); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. : The molecular structure of IF. Displacement ellipsoids are shown at the 50% probability level and H atoms are drawn as spheres of arbitrary size.
	Fig. 2. : The unit cell and crystal packing of (a) IF and (b) VF (Görbitz, 2002). Both structures are viewed along the a axes. Hydrogen bonds are shown as dashed lines.
	Fig. 3. : A schematic illustration of the difference between the crystal structures of VF/IF and the FF class (Görbitz, 2001). Starting with VF/IF (top), every second peptide facing a water layer can undergo a rotation of about 60°, as indicated by the small arrows, to yield the tubular patterns of LL/LF with water molecules inside hydrophilic channels.
	Fig. 4. : The unit cell and crystal packing of LF (Görbitz, 2001). C atoms in molecules that have been rotated as described in Fig. 3 are shown in a darker tone.

L-Isoleucyl-L-phenylalanine

Crystal data

C15H26N2O5	F(000) = 340
Mr = 314.38	Dx = 1.303 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
a = 5.6350 (14) Å	Cell parameters from 3020 reflections
b = 8.2897 (18) Å	θ = 2.4–26.4°
c = 17.382 (4) Å	µ = 0.10 mm^−1
β = 99.256 (9)°	T = 105 K
V = 801.4 (3) Å^3	Needle, colourless
Z = 2	1.05 × 0.01 × 0.01 mm

Data collection

Siemens SMART CCD diffractometer	1741 independent reflections
Radiation source: fine-focus sealed tube	1425 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.064
Detector resolution: 8.3 pixels mm^-1	θmax = 26.4°, θmin = 2.4°
Sets of exposures each taken over 0.3° ω rotation scans	h = −7→7
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	k = −8→10
Tmin = 0.790, Tmax = 0.999	l = −21→20
6941 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.039	H-atom parameters constrained
wR(F^2) = 0.082	w = 1/[σ^2(Fo^2) + (0.0398P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.08	(Δ/σ)max = 0.005
1741 reflections	Δρmax = 0.31 e Å^−3
230 parameters	Δρmin = −0.26 e Å^−3
7 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.283 (15)

Special details

Experimental. Data were collected by measuring three sets of exposures with the detector set at 2θ = 28°, crystal-to-detector distance 5.00 cm.

Refinement. Refinement of F² against ALL reflections.

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

	x	y	z	Uiso*/Ueq
O1	0.5186 (6)	0.5156 (3)	0.64137 (17)	0.0221 (8)
O2	0.4907 (6)	0.8750 (3)	0.58758 (15)	0.0206 (7)
O3	0.8168 (6)	0.8606 (4)	0.67888 (16)	0.0217 (7)
N1	0.1632 (7)	0.3180 (4)	0.57261 (19)	0.0200 (9)
H1	0.082	0.216	0.5720	0.030*
H2	0.333	0.301	0.5750	0.030*
H3	0.102	0.377	0.5259	0.030*
N2	0.2585 (8)	0.6790 (4)	0.68836 (19)	0.0157 (9)
H4	0.105	0.696	0.6933	0.019*
C1	0.1200 (10)	0.4131 (5)	0.6425 (2)	0.0195 (11)
H11	−0.054	0.470	0.6313	0.023*
C2	0.1341 (9)	0.2977 (5)	0.7126 (2)	0.0189 (10)
H21	0.033	0.199	0.6944	0.023*
C3	0.0214 (10)	0.3772 (6)	0.7768 (2)	0.0226 (11)
H31	−0.152	0.422	0.7529	0.027*
H32	0.130	0.477	0.7999	0.027*
C4	−0.0026 (11)	0.2598 (6)	0.8425 (3)	0.0313 (13)
H41	−0.105	0.309	0.8783	0.047*
H42	0.161	0.235	0.8723	0.047*
H43	−0.079	0.158	0.8200	0.047*
C5	0.3887 (10)	0.2385 (6)	0.7427 (3)	0.0225 (11)
H51	0.382	0.148	0.7808	0.034*
H52	0.487	0.330	0.7693	0.034*
H53	0.465	0.199	0.6978	0.034*
C6	0.3172 (9)	0.5411 (5)	0.6563 (2)	0.0155 (10)
C7	0.4371 (9)	0.8028 (5)	0.7157 (2)	0.0175 (10)
H71	0.343	0.903	0.7236	0.021*
C8	0.5874 (9)	0.7639 (6)	0.7955 (2)	0.0210 (10)
H81	0.698	0.674	0.7886	0.025*
H82	0.688	0.859	0.8131	0.025*
C9	0.4484 (10)	0.7186 (5)	0.8582 (2)	0.0208 (11)
C10	0.5299 (10)	0.5915 (6)	0.9090 (3)	0.0255 (12)
H101	0.679	0.531	0.9022	0.031*
C11	0.4057 (10)	0.5494 (6)	0.9681 (3)	0.0298 (13)
H111	0.462	0.460	1.0027	0.036*
C12	0.2042 (10)	0.6321 (6)	0.9786 (3)	0.0285 (13)
H121	0.129	0.606	1.0159	0.034*
C13	0.1202 (10)	0.7590 (6)	0.9286 (3)	0.0246 (12)
H131	−0.033	0.821	0.9359	0.030*
C14	0.2455 (10)	0.8006 (6)	0.8693 (2)	0.0225 (11)
H141	0.187	0.892	0.8339	0.027*
C15	0.5968 (8)	0.8465 (5)	0.6559 (2)	0.0149 (9)
O1W	0.0399 (6)	0.9787 (4)	0.56290 (16)	0.0196 (8)
H11W	−0.039	0.949	0.6018	0.029*
H12W	0.194	0.946	0.5744	0.029*
O2W	0.6089 (7)	0.1956 (4)	0.54772 (17)	0.0258 (8)
H22W	0.549	0.224	0.4987	0.039*
H21W	0.619	0.088	0.5482	0.039*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.022 (2)	0.0154 (17)	0.0291 (17)	−0.0012 (16)	0.0055 (16)	0.0001 (13)
O2	0.030 (2)	0.0156 (15)	0.0160 (14)	−0.0020 (16)	0.0039 (13)	0.0007 (13)
O3	0.0217 (18)	0.0207 (18)	0.0236 (14)	−0.0005 (15)	0.0068 (14)	0.0023 (13)
N1	0.028 (2)	0.0148 (19)	0.0174 (16)	−0.0013 (18)	0.0034 (17)	−0.0009 (15)
N2	0.019 (2)	0.0095 (18)	0.0199 (17)	0.0008 (17)	0.0063 (17)	0.0004 (14)
C1	0.026 (3)	0.012 (2)	0.021 (2)	−0.002 (2)	0.007 (2)	−0.0042 (16)
C2	0.025 (3)	0.0097 (19)	0.023 (2)	−0.004 (2)	0.007 (2)	0.0011 (18)
C3	0.033 (3)	0.016 (2)	0.020 (2)	−0.001 (2)	0.010 (2)	0.000 (2)
C4	0.041 (3)	0.027 (3)	0.029 (3)	−0.002 (2)	0.012 (2)	0.003 (2)
C5	0.030 (3)	0.017 (2)	0.021 (2)	0.005 (2)	0.005 (2)	0.0047 (18)
C6	0.022 (3)	0.010 (2)	0.0146 (19)	−0.001 (2)	0.0038 (19)	0.0012 (16)
C7	0.023 (3)	0.010 (2)	0.019 (2)	−0.001 (2)	0.0026 (19)	−0.0024 (18)
C8	0.021 (3)	0.023 (2)	0.019 (2)	−0.003 (2)	0.002 (2)	−0.0026 (19)
C9	0.025 (3)	0.018 (3)	0.020 (2)	0.000 (2)	0.004 (2)	−0.0020 (18)
C10	0.031 (3)	0.024 (3)	0.021 (2)	0.001 (2)	0.002 (2)	0.001 (2)
C11	0.042 (4)	0.027 (3)	0.019 (2)	−0.001 (3)	0.002 (2)	0.008 (2)
C12	0.044 (4)	0.025 (3)	0.019 (2)	−0.006 (2)	0.011 (2)	−0.0007 (19)
C13	0.030 (3)	0.022 (2)	0.023 (2)	0.003 (2)	0.007 (2)	−0.0066 (19)
C14	0.033 (3)	0.016 (2)	0.018 (2)	−0.004 (2)	0.005 (2)	−0.0005 (19)
C15	0.014 (3)	0.006 (2)	0.024 (2)	−0.0017 (18)	0.0035 (19)	−0.0005 (16)
O1W	0.0211 (19)	0.0167 (17)	0.0220 (15)	0.0006 (15)	0.0062 (15)	0.0020 (13)
O2W	0.039 (2)	0.0159 (16)	0.0228 (15)	0.0035 (17)	0.0050 (16)	0.0028 (13)

Geometric parameters (Å, º)

O1—C6	1.222 (6)	C5—H52	1.0040
O2—C15	1.263 (5)	C5—H53	1.0040
O3—C15	1.245 (5)	C7—C15	1.524 (6)
N1—C1	1.501 (5)	C7—C8	1.538 (5)
N1—H1	0.9620	C7—H71	1.0070
N1—H2	0.9620	C8—C9	1.489 (7)
N1—H3	0.9620	C8—H81	0.9919
N2—C6	1.337 (6)	C8—H82	0.9919
N2—C7	1.462 (6)	C9—C14	1.370 (7)
N2—H4	0.8952	C9—C10	1.403 (6)
C1—C6	1.528 (6)	C10—C11	1.378 (7)
C1—C2	1.540 (6)	C10—H101	1.0021
C1—H11	1.0731	C11—C12	1.363 (7)
C2—C3	1.521 (6)	C11—H111	0.9768
C2—C5	1.527 (6)	C12—C13	1.397 (7)
C2—H21	1.0148	C12—H121	0.8585
C3—C4	1.522 (6)	C13—C14	1.385 (6)
C3—H31	1.0684	C13—H131	1.0280
C3—H32	1.0684	C14—H141	0.9998
C4—H41	1.0017	O1W—H11W	0.899
C4—H42	1.0017	O1W—H12W	0.898
C4—H43	1.0017	O2W—H22W	0.896
C5—H51	1.0040	O2W—H21W	0.897
C1—N1—H1	109.5	O1—C6—N2	122.5 (4)
C1—N1—H2	109.5	O1—C6—C1	121.6 (4)
H1—N1—H2	109.5	N2—C6—C1	115.9 (4)
C1—N1—H3	109.5	N2—C7—C15	113.3 (3)
H1—N1—H3	109.5	N2—C7—C8	113.3 (3)
H2—N1—H3	109.5	C15—C7—C8	111.4 (4)
C6—N2—C7	122.2 (4)	N2—C7—H71	106.0
C6—N2—H4	118.9	C15—C7—H71	106.0
C7—N2—H4	118.9	C8—C7—H71	106.0
N1—C1—C6	106.4 (3)	C9—C8—C7	115.8 (4)
N1—C1—C2	108.6 (3)	C9—C8—H81	108.3
C6—C1—C2	111.4 (4)	C7—C8—H81	108.3
N1—C1—H11	110.1	C9—C8—H82	108.3
C6—C1—H11	110.1	C7—C8—H82	108.3
C2—C1—H11	110.1	H81—C8—H82	107.4
C3—C2—C5	111.5 (4)	C14—C9—C10	118.7 (4)
C3—C2—C1	109.7 (4)	C14—C9—C8	121.8 (4)
C5—C2—C1	113.4 (4)	C10—C9—C8	119.5 (5)
C3—C2—H21	107.3	C11—C10—C9	120.3 (5)
C5—C2—H21	107.3	C11—C10—H101	119.8
C1—C2—H21	107.3	C9—C10—H101	119.8
C2—C3—C4	111.8 (4)	C12—C11—C10	120.4 (5)
C2—C3—H31	109.2	C12—C11—H111	119.8
C4—C3—H31	109.2	C10—C11—H111	119.8
C2—C3—H32	109.2	C11—C12—C13	120.1 (5)
C4—C3—H32	109.2	C11—C12—H121	119.9
H31—C3—H32	107.9	C13—C12—H121	119.9
C3—C4—H41	109.5	C14—C13—C12	119.2 (5)
C3—C4—H42	109.5	C14—C13—H131	120.4
H41—C4—H42	109.5	C12—C13—H131	120.4
C3—C4—H43	109.5	C9—C14—C13	121.2 (4)
H41—C4—H43	109.5	C9—C14—H141	119.4
H42—C4—H43	109.5	C13—C14—H141	119.4
C2—C5—H51	109.5	O3—C15—O2	125.5 (4)
C2—C5—H52	109.5	O3—C15—C7	118.0 (3)
H51—C5—H52	109.5	O2—C15—C7	116.3 (4)
C2—C5—H53	109.5	H11W—O1W—H12W	109
H51—C5—H53	109.5	H22W—O2W—H21W	107
H52—C5—H53	109.5
N1—C1—C6—N2	150.0 (4)	C2—C1—C6—O1	85.5 (5)
C1—C6—N2—C7	170.6 (3)	C2—C1—C6—N2	−91.8 (4)
C6—N2—C7—C15	49.4 (5)	C6—N2—C7—C8	−78.8 (5)
N2—C7—C15—O2	48.4 (5)	C15—C7—C8—C9	−179.7 (4)
N1—C1—C2—C5	70.9 (5)	C14—C9—C10—C11	0.8 (7)
N1—C1—C2—C3	−163.6 (4)	C8—C9—C10—C11	179.0 (4)
C1—C2—C3—C4	171.6 (4)	C9—C10—C11—C12	−0.9 (7)
N2—C7—C8—C9	−50.5 (5)	C10—C11—C12—C13	0.8 (7)
C7—C8—C9—C10	138.6 (4)	C11—C12—C13—C14	−0.8 (7)
C7—C8—C9—C14	−43.3 (6)	C10—C9—C14—C13	−0.8 (6)
C6—C1—C2—C3	79.5 (5)	C8—C9—C14—C13	−178.9 (4)
C6—C1—C2—C5	−45.9 (5)	C12—C13—C14—C9	0.7 (7)
C5—C2—C3—C4	−61.8 (5)	N2—C7—C15—O3	−135.8 (4)
C7—N2—C6—O1	−6.7 (6)	C8—C7—C15—O3	−6.6 (5)
N1—C1—C6—O1	−32.7 (5)	C8—C7—C15—O2	177.6 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1W^i	0.96	1.98	2.895 (5)	158
N1—H2···O2W	0.96	1.91	2.806 (5)	154
N1—H2···O1	0.96	2.28	2.711 (5)	106
N1—H3···O1W^ii	0.96	1.83	2.787 (5)	175
N2—H4···O3^iii	0.90	2.10	2.891 (5)	146
C1—H11···O1^iii	1.07	2.48	3.491 (6)	158
O1W—H11W···O3^iii	0.90	1.83	2.724 (4)	172
O1W—H12W···O2	0.90	1.75	2.651 (4)	174
O2W—H21W···O2^i	0.90	2.06	2.852 (4)	146
O2W—H22W···O2^iv	0.90	1.94	2.763 (4)	152

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