Characteristic conformation of Mosher's amide elucidated using the cambridge structural database.

Conformations of the crystalline 3,3,3-trifluoro-2-methoxy-2-phenylpropanamide derivatives (MTPA amides) deposited in the Cambridge Structural Database (CSD) were examined statistically as Racid-enantiomers. The majority of dihedral angles (48/58, ca. 83%) of the amide carbonyl groups and the trifluoromethyl groups ranged from -30° to 0° with an average angle θ1 of -13°. The other conformational properties were also clarified: (1) one of the fluorine atoms was antiperiplanar (ap) to the amide carbonyl group, forming a staggered conformation; (2) the MTPA amides prepared from primary amines showed a Z form in amide moieties; (3) in the case of the MTPA amide prepared from a primary amine possessing secondary alkyl groups (i.e., Mosher-type MTPA amide), the dihedral angles between the methine groups and the carbonyl groups were syn and indicative of a moderate conformational flexibility; (4) the phenyl plane was inclined from the O-Cchiral bond of the methoxy moiety with an average dihedral angle θ2 of +21°; (5) the methyl group of the methoxy moiety was ap to the ipso-carbon atom of the phenyl group.

1. Introduction

NMR using chiral resolving agents is a powerful technique, along with X-ray crystallog<n class="Chemical">span class="Gene">raphy and circular dichroism, for assignment of the absolute configuration of organic compounds [1]. <spn>an class="Chemical">Mosher et al. developed 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (MTPA, 1, Figure 1) and constructed the conformational model of the MTPA amide and the MTPA ester derived from a primary amine and a secondary alcohol, respectively (Figure 2a) [2,3,4]. Considering the shielding effect of the phenyl ring, the relative stereochemistry of the MTPA amide and the MTPA ester could be elucidated based on a mutual comparison of the 1H-NMR chemical shifts of their diastereomers; namely, upfield shifts are observed in substituent L2. Therefore, the absolute configuration of the amine moieties and the alcohol moieties could be clarified using stereochemistry of the MTPA moiety as an internal standard. Kusumi et al. modified this method using two-dimensional NMR spectroscopy [5,6,7,8].

Figure 1

Structures of chiral resolving agents.

Figure 2

Major conformation of (Racid)-MTPA amide proposed in (a) previous studies and (b) this study. The Newman-like projection originally proposed by Mosher et al. [3] was modified in (b). Three covalent bonds separate the two chiral centers C1′ and C2; therefore, L3–C1′–L2 moiety is more flat in this projection. The MTPA ester exhibited the equivalent conformation with substitution of NH for O [9].

Major conformation of (<span class="Chemical">Racidn>)-<span class="Gene">MTPA <span class="Chemical">amide proposed in (a) previous studies and (b) this study. The Newman-like projection originally proposed by Mosher et al. [3] was modified in (b). Three covalent bonds separate the two chiral centers C1′ and C2; therefore, L3–C1′–L2 moiety is more flat in this projection. The MTPA ester exhibited the equivalent conformation with substitution of NH for O [9].

We studied on three chiral resolving agents [i.e., MαNP acid (2), Mβn class="Chemical">NP acid (3), and M9PP acid (4)] based on their enantioresolution of chiral alcohols and elucidation of absolute configurations [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. The resolving ability of 2 is superior to that of 1 in normal phase HPLC. The diastereomeric MαNP esters also exhibit large chemical shift differences (Δδ values) in 1H-NMR spectroscopy [12,18].

In 2013, we elucidated the crystal structure of <span class="Chemical">Moshern>’s <span class="Chemical">salt prepared from <span class="Chemical">(R)-1 and (R)-1-phenylethylamine using X-ray crystallography [9]; Mosher et al. prepared this compound via the enantioresolution of rac-1 in ethanol as a less soluble salt [2]. In the course of this study, we found that a number of crystal structures of MTPA amides and MTPA esters were deposited in the CSD.

Each molecular structure is influenced by packing force in crystal [25]. However, statistical analyses of the crystal structures elucidated the relative stability of each conformer [25]. Therefore, we reported statistical analyses of the crystal structures of <span class="Gene">MTPAn> <span class="Chemical">esters [9].

The properties of the major conformation of the crystalline <span class="Gene">MTPAn> <span class="Chemical">ester are as follows [9]: (1) the <span class="Chemical">ester carbonyl group is synperiplanar (sp, dihedral angle 0° to ±30°) [26] to the trifluoromethyl group; (2) the trifluoromethyl group is in the staggered conformation; (3) the methine group of the alcohol moiety is syn to the carbonyl group; (4) the phenyl plane is inclined from the O–Cchiral bond of the methoxy moiety; (5) the methyl group of the methoxy moiety is antiperiplanar (ap, dihedral angle ±150° to 180°) [26] to the ipso‑carbon atom of the phenyl group. Thus, our database study proposed a modified conformational model of the MTPA ester.

In this report, we perform the statistical analyses of the crystal conformations of <span class="Chemical">MTPA amidesn> deposited in the <span class="Disease">CSD [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. The conformational data of the crystalline <span class="Gene">MTPA amide moiety (a total of 58), which had been prepared from: (i) primary amines; (ii) secondary amines; (iii) aniline derivatives [tetrakis-MTPA amides of ruthenium(II) porphyrin complexes]; (iv) diethyl 1-aminoalkylphosphonate derivatives; (v) benzotriazole; (vi) an oxazolidine-2-selone derivative; (vii) a thiocarbamide derivative; and (viii) a p-toluenesulfonamide derivative, were statistically analyzed as Racid-enantiomers.

Conformational features of the <span class="Gene">MTPAn> <span class="Chemical">amide moiety were similar to those of the <span class="Gene">MTPA esters, with less diversity (Figure 2b). The features of the major conformation of crystalline MTPA amides are as follows: (1) the amide carbonyl group is sp to the trifluoromethyl group with an average dihedral angle θ1 of −13°; (2) the trifluoromethyl group is in the staggered conformation; (3) the amide moiety of the secondary MTPA amide is in the Z form (i.e., R = H, R = alkyl group); (4) H1′ of the amine moiety is syn to the carbonyl carbon atom C1; (5) the phenyl plane is inclined from the O2–C2 bond with an average dihedral angle θ2 of +21°; (6) the methyl group of the methoxy moiety is ap to C5 of the phenyl group.

Structural elucidation of chiral <span class="Chemical">aminesn> is important, because a considerable number of biologically active natural products and pharmaceuticals contain key chiral <span class="Chemical">amine moieties [67,68,69]. The number of entries in the <span class="Disease">CSD is increasing rapidly; therefore, the crystal database is important for structural chemistry. The statistical analyses of crystal data have increased our understanding on the properties of acid 1 and have established valuable insights for Mosher’s method and crystal engineering [70,71] of MTPA derivatives.

2. Results and Discussion

2.1. Crystal Structures of MTPA Amides Deposited in the CSD

The crystal structures of the <span class="Gene">MTPAn> <span class="Chemical">amide moieties were searched in the <span class="Disease">CSD using ConQuest software. Table 1 shows the original dihedral angles of (Racid)- and (Sacid)-MTPA amides [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64].

Table 1

Dihedral angles of crystalline MTPA amides (a).

No.	CCDC Number (b)	Reference	Chirality of MTPA (a)	Amine Moiety	R sp	R ap	O1–C1–C2–C3 (θ1)	C1–C2–C3–F3	C1'–N–C1–O1	X1′′–N–C1–O1 (c)	H1′–C1′–N–C1	O2–C2–C5–C10 (θ2)	C1–C2–O2–C4
1 (d)	199868	[27]	R	Primary amine	Secondary alkyl group	H	−13.1(2)	−172.0(1)	7.1(2)	−172.9	−47.4	23.3(2)	54.2(2)
2 (d)	199868	[27]	R	Primary amine	Secondary alkyl group	H	−7.3(2)	−174.6(1)	6.3(2)	−173.7	−51.5	29.4(2)	50.4(2)
3 (d)	222942	[28]	R	Primary amine	Secondary alkyl group	H	30.3(3) (e)	175.6(2)	−4.2(5)	169(4)	47.0	11.2(7)	−44.4(4)
4 (d)	603055	[29]	S	Primary amine	Secondary alkyl group	H	35.0(4) (e)	165.9(3)	0.5(5)	−179.5	15.2	−43.7(4)	−72.0(3)
5	651954	[30]	R	Primary amine	Primary alkyl group	H	−26(2)	−168(1)	−6(2)	173	–	24(2)	72(1)
6	651954	[30]	R	Primary amine	Primary alkyl group	H	−25(2)	−166(1)	8(2)	−172	–	22(2)	60(2)
7 (d)	678252	[31]	R	Primary amine	Secondary alkyl group	H	−22.6(4)	−171.7(3)	9.5(5)	−170.6	29.6	19.7(4)	58.4(3)
8 (d)	678252	[31]	R	Primary amine	Secondary alkyl group	H	−14.4(5)	−173.2(3)	5.2(6)	−174.8	28.3	22.5(4)	54.2(4)
9 (d,f)	703912	[32]	R	Primary amine	Secondary alkyl group	H	−67.7(6) (e)	−174.6(5)	3.7(9)	170(5)	−22.5	−58.9(7)	−162.7(5)
10	734247	[33]	R	Primary amine	Primary alkyl group	H	−29.1(5)	−168.3(3)	−2.9(6)	177.0	–	24.2(5)	62.9(4)
11	739753	[34]	R	Primary amine	Primary alkyl group	H	−36.0(2) (e)	−164.7(2)	7.1(3)	−172.9	–	49.8(2)	64.5(2)
12 (d)	1218697	[35]	R	Primary amine	Secondary alkyl group	H	−9.8(3)	−176.9(2)	−3.0(4)	171(2)	1.3	12.0(3)	55.5(3)
13 (d)	1229820	[36]	R	Primary amine	Secondary alkyl group	H	−31(1) (e)	−169.2(8)	15(2)	136	−7	21	64
14 (d)	1277744	[37]	R	Primary amine	Secondary alkyl group	H	−28.4(3)	−170.3(2)	3.9(4)	−176.0	−14.4	26.9(3)	65.2(3)
15 (g)	140352	[38]	R	Secondary amine	Secondary alkyl group	Primary Alkyl group	−4.7(5)	−175.4(3)	5.3(6)	−174.7(4)	20.4(6)	27.5(5)	53.4(4)
16 (g)	167289	[39]	S	Secondary amine	Secondary alkyl group	Primary alkyl group	5.2(2)	177.7(1)	−0.5(2)	−177.4(2)	10(2)	−11.7(2)	−45.0(2)
17 (g)	241708	[40]	S	Secondary amine	Secondary alkyl group	Primary alkyl group	6.9(2)	176.0(1)	−1.7(2)	169.5(1)	48.1	−15.4(2)	−45.1(2)
18 (g)	251663	[41]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−12.4(2)	−172.3(1)	1.8(2)	−168.2(1)	24.3	24.5(2)	56.7(2)
19	288331	[42]	S	Secondary amine	Secondary alkyl group	Secondary alkyl group	7.7(3)	176.5(2)	8.7(3)	174.0(2)	−1.3	−14.0(3)	−50.1(3)
20	296547	[43]	R	Secondary amine	Primary alkyl group	Primary alkyl group	–13.4(8)	−171.7(5)	−0.9(9)	−170.9(6)	–	12.6(7)	47.4(7)
21 (g)	604432	[44]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−4.1(5)	−176.3(3)	8.7(5)	−170.3(3)	17.1	15.3(4)	51.7(4)
22 (g)	605818	[45]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−15.6(2)	−174.1(1)	5.8(2)	−164.3(1)	−58.3	6.9(2)	52.1(1)
23	638938	[46]	R	Secondary amine	Primary alkyl group	Primary alkyl group	−6.2(5)	−173.8(3)	−1.8(5)	−173.7(3)	–	27.7(4)	51.2(4)
24 (g)	675390	[47]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−14.6(2)	−174.7(1)	10.1(3)	−164.8(2)	−56.5	9.2(2)	50.4(2)
25 (g)	706349	[48]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−13.7(4)	−172.3(3)	5.9(5)	−168.6(3)	19(2)	19.3(4)	59.4(4)
26 (h)	707825	[49]	S	Secondary amine	Me	Secondary alkyl group	8.6(3)	173.1(2)	0.1(3)	173.6(2)	–	−12.7(3)	−50.0(3)
27 (h)	707825	[49]	S	Secondary amine	Me	Secondary alkyl group	4.0(3)	176.7(2)	0.3(3)	−174.7(2)	–	−14.1(3)	−51.0(2)
28 (h)	707825	[49]	S	Secondary amine	Me	Secondary alkyl group	1.1(3)	178.0(2)	1.3(3)	−176.7(2)	–	–18.4(3)	−48.3(3)
29 (h)	707825	[49]	S	Secondary amine	Me	Secondary alkyl group	3.6(3)	177.1(2)	1.2(3)	–179.7(2)	–	−9.4(3)	−46.0(3)
30	766837	[50]	S	Secondary amine	Primary alkyl group	Primary alkyl group	9.4(2)	175.1(1)	2.0(2)	177.8(1)	–	−14.7(2)	−44.7(1)
31 (g)	830079	[51]	R	Secondary amine	Tertiary alkyl group	Primary alkyl group	−18(1)	−173.1(6)	−1(1)	−178.3(7)	–	20(1)	55.8(9)
32	1104875	[52]	R	Secondary amine	Primary alkyl group	Primary alkyl group	−2.2(2)	−176.5(2)	−5.2(3)	−176.7(2)	–	27.1(2)	45.2(2)
33	1105464	[53]	R	Secondary amine	Primary alkyl group	Primary alkyl group	−8.2(8)	178.4(5)	−0.7(9)	−172.4(6)	–	12.0(8)	46.6(8)
34	1105464	[53]	R	Secondary amine	Primary alkyl group	Primary alkyl group	–9.0(8)	–175.6(5)	–6.1(9)	–168.0(6)	–	13.7(8)	45.8(7)
35 (g)	1267150	[54]	S	Secondary amine	Secondary alkyl group	Primary alkyl group	7.1(6)	176.2(4)	−3.0(7)	−179.1(4)	19.5	−15.3(6)	−42.6(5)
36 (g)	1267151	[54]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−14.0(7)	−170.3(4)	8.4(7)	−163.3(5)	24.4	29.7(7)	59.7(6)
37 (g)	1280861	[55]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−15.6(6)	−170.9(4)	11.4(7)	−174.1(4)	−15.1	28.5(7)	50.1(6)
38 (g)	1280861	[55]	R	Secondary amine	Secondary alkyl group	Primary alkyl group	−5.5(6)	−177.6(4)	7.8(7)	−177.4(4)	−17.0	25.0(6)	41.3(6)
39	1294281	[56]	R	Secondary amine	Primary alkyl group	Primary alkyl group	−6(1)	−175.0(7)	1(1)	−172.0(7)	–	26(1)	44.0(9)
40	1294281	[56]	R	Secondary amine	Primary alkyl group	Primary alkyl group	−15(1)	−172.9(7)	1(1)	−163.7(8)	–	14(1)	47(1)
41 (i)	113953	[57]	R	Aniline derivative	ortho-Substituted phenyl group	H	−17(1)	−174.9(6)	−11(1)	178.6	–	8(1)	54.6(8)
42 (i)	113953	[57]	R	Aniline derivative	ortho-Substituted phenyl group	H	−28(1)	−168.0(7)	−1(1)	−170.3	–	47.7(9)	65.9(8)
43 (f,i)	113953	[57]	R	Aniline derivative	ortho-Substituted phenyl group	H	−58.4(9) (e)	−175.1(6)	−1(1)	176.4	–	−56.4(9)	−153.6(6)
44 (i)	113953	[57]	R	Aniline derivative	ortho-Substituted phenyl group	H	−15(1)	−170.8(6)	6(1)	175.4	–	36.1(9)	57.7(8)
45 (i)	1310848	[58]	R	Aniline derivative	ortho-Substituted phenyl group	H	−2(2)	−172(1)	−5(3)	–	–	35(2)	51(2)
46 (f,i)	1310848	[58]	R	Aniline derivative	ortho-Substituted phenyl group	H	−60(2) (e)	179(2)	3(3)	–	–	−34(2)	−172(2)
47 (i)	1310848	[58]	R	Aniline derivative	ortho-Substituted phenyl group	H	−41(2) (e)	−169(2)	0(3)	–	–	13(2)	71(2)
48 (f,i)	1310848	[58]	R	Aniline derivative	ortho-Substituted phenyl group	H	−51(2) (e)	−165(2)	−1(3)	–	–	85(2)	−154(2)
49	655554	[59]	R	Benzotriazole	ortho-Substituted phenyl group	N	−9.3(1)	−175.21(7)	−2.8(1)	178.81(8)	–	25.7(1)	46.6(1)
50 (f)	1142231	[60]	S	Diethyl 1-aminoalkylphos-phonate derivative	1-(Diethoxy-phophoryl)alkyl group	H	57(3) (e)	169(2)	9(4)	–	−14	77(2)	148(2)
51	1142231	[60]	S	Diethyl 1-aminoalkylphos-phonate derivative	1-(Diethoxy-phophoryl)alkyl group	H	24(3)	172(2)	4(3)	–	−12	−35(2)	−65(2)
52	1236701	[61]	R	Diethyl 1-aminoalkylphos-phonate derivative	1-(Diethoxy-phophoryl)alkyl group	H	−23.1(5)	−171.5(3)	−3.1(6)	176.6	19.2	7.3(5)	59.3(4)
53	1236702	[61]	R	Diethyl 1-aminoalkylphos-phonate derivative	1-(Diethoxy-phophoryl)alkyl group	H	−19.4(6)	−174.3(4)	−3.2(7)	177.2	18.8	5.8(6)	55.8(5)
54	1236703	[61]	R	Diethyl 1-aminoalkylphos-phonate derivative	1-(Diethoxy-phophoryl)alkyl group	H	−24(2)	−166(1)	4(2)	−173	11	31(2)	59(2)
55	1236703	[61]	R	Diethyl 1-aminoalkylphos-phonate derivative	1-(Diethoxy-phophoryl)alkyl group	H	−24(2)	−166(1)	9(2)	−171	−14	35(2)	57(1)
56	1216345	[62]	R	Oxazolidine-2-selone derivative	Selenoxo group	Secondary alkyl group	−15.9(4)	−172.9(2)	24.5(4)	−147.8(3)	–	18.5(4)	56.6(3)
57	630372	[63]	R	Thiocarbamide derivative	N-Substituted thiocarbamoyl group	Secondary alkyl group	−16.7(3)	−174.1(2)	11.2(4)	−152.6(2)	–	24.8(3)	57.7(3)
58	143886	[64]	R	p-Toluene-sulfonamide derivative	p-Toluene-sulfonyl group	Primary alkyl group	−5.4(6)	−177.4(3)	7.4(5) (j)	−177.6(4)	–	18.2(6)	37.8(5)

(a) The original dihedral angles were cited for both (Racid)- and (Sacid)-MTPA amides. In the following sections, (Sacid)-MTPA amides were processed as (Racid)-MTPA amides with plus/minus sign reversal. (b) The same CCDC numbers stand for multiple conformers in a lattice or bis- and tetrakis-MTPA amides. (c) X1′′ stands for the atom at the α-position of substituent R in the amine moiety. (d) Mosher‑type MTPA amides prepared from primary amines possessing secondary alkyl groups. (e) These ten entries were omitted from the calculation of the average dihedral angle θ1. (f) The minor conformer in which the amide carbonyl group and the methoxy group were anti. (g) The tertiary amides exhibiting Z forms (R > R). All precursors of these Z amides were the cyclic secondary amines. We refer to Z and E as the forms in which the larger N-substituent is sp and ap to the carbonyl oxygen atom, respectively [72]. (h) The four conformers of CCDC 707825 (N-methylamide derivative) only exhibited E forms (R < R) in the amide moieties [49]. (i) The tetrakis-MTPA amides of ruthenium(II) porphyrin complexes. (j) The dihedral angle of S–N–C1–O1 was cited.

Dihedral angles of crystalline <span class="Chemical">MTPA amidesn> (a).

(a) The original dihedral angles were cited for both (<span class="Chemical">Racidn>)- and (Sacid)-<span class="Chemical">MTPA amides. In the following sections, (Sacid)-<span class="Chemical">MTPA amides were processed as (Racid)-MTPA amides with plus/minus sign reversal. (b) The same CCDC numbers stand for multiple conformers in a lattice or bis- and tetrakis-MTPA amides. (c) X1′′ stands for the atom at the α-position of substituent R in the amine moiety. (d) Mosher‑type MTPA amides prepared from primary amines possessing secondary alkyl groups. (e) These ten entries were omitted from the calculation of the average dihedral angle θ1. (f) The minor conformer in which the amide carbonyl group and the methoxy group were anti. (g) The tertiary amides exhibiting Z forms (R > R). All precursors of these Z amides were the cyclic secondary amines. We refer to Z and E as the forms in which the larger N-substituent is sp and ap to the carbonyl oxygen atom, respectively [72]. (h) The four conformers of CCDC 707825 (N-methylamide derivative) only exhibited E forms (R < R) in the amide moieties [49]. (i) The tetrakis-MTPA amides of ruthenium(II) porphyrin complexes. (j) The dihedral angle of S–N–C1–O1 was cited.

All obtained <span class="Gene">MTPAn> <span class="Chemical">amide moieties (a total of 58) were processed as <span class="Chemical">Racid-enantiomers in the following sections; that is, the dihedral angles of (Sacid)-MTPA amides cited in Table 1 were substituted by those of the mirror images (i.e., Racid-enantiomers) with plus/minus sign reversal. Despite the various structures of the amine moiety, the MTPA amide moieties showed little conformational diversity. Therefore, the conformations of all MTPA amide moieties were processed together, excluding the dihedral angle H1′–C1′–N–C1, which was specific to the MTPA amides prepared from amines possessing a secondary alkyl group (see Section 2.6).

2.2. Dihedral Angles of Amide Carbonyl Group and Trifluoromethyl Group: O1–C1–C2–C3

The distribution of the dihedral angles O1–C1–C2–C3 (θ1) exhibited a concentration of entries between −30° and 0° (Figure 3). All dihedral angles ranged from −70° to +40°; the median angle was −14.5°. These data confirmed <n class="Chemical">span class="Chemical">Mosher’s hypothesis that the <spn>an class="Chemical">carbonyl and trifluoromethyl groups of the MTPA amide are syn [3]. In addition, the majority of dihedral angles θ1 (48/58, ca. 83%) ranged from −30° to 0° with the average angle θ1 of −13°. That is, the carbonyl group was close to the phenyl group. This phenomenon was also observed for the MTPA esters and MTPA salt; we observed the short contacts between the two oxygen atoms and the ortho‑hydrogen atoms of phenyl group in the MTPA anion [9].

Figure 3

Histogram for dihedral angles between the amide carbonyl and trifluoromethyl groups of all MTPA amides. (a) The bar indicates the frequency of −10 < θ1 ≤ 0; and the same is true for the others.

Histogram for dihedral angles between the <span class="Chemical">amiden> <span class="Chemical">carbonyl and trifluoromethyl groups of all <span class="Chemical">MTPA amides. (a) The bar indicates the frequency of −10 < θ1 ≤ 0; and the same is true for the others.

All the outliers were the dihedral angles θ1 of the secondary <span class="Chemical">amidesn>. An irregular θ1 of +30.3(3)° represents <span class="Chemical">CCDC 222942 [28] in which the intramolecular aromatic C–H···π interactions and N–H···O <span class="Chemical">hydrogen bond were observed.

The five entries around −60° were indicative of a minor conformer in which the <span class="Chemical">amiden> <span class="Chemical">carbonyl group and the methoxy group were anti [i.e., <span class="Chemical">CCDC 703912 [32], −67.7 (6)°; CCDC 1142231 [60], −57(3)° as Racid-enantiomer; CCDC 113953 [57], −58.4(9)°; CCDC 1310848 [58], −60(2)° and −51(2)°] (see Section 2.7 and Section 2.8). The amine moiety of CCDC 703912 has a linear conjugated diene structure. In the case of CCDC 1142231, the phenyl group of the MTPA moiety formed an intramolecular C–H···O hydrogen bond [73] with the oxygen atom of the amine moiety. The other minor anti conformers (i.e., CCDC 113953 and CCDC 1310848) were the tetrakis-MTPA amide derivatives of ruthenium(II) porphyrin complexes.

The tetrakis-<span class="Gene">MTPAn> <span class="Chemical">amide derivative <span class="Chemical">CCDC 1310848 also exhibited another irregular θ1 of −41(2)°. CCDC 739753 [34] showed an irregular θ1 of −36.0(2)°; the methoxy group of the MTPA moiety formed an intramolecular aromatic C–H···π interaction with the phenyl group of the amine moiety. CCDC 122980 [36] also exhibited an irregular θ1 of −31(1)°; the methoxy group of the MTPA moiety formed an intramolecular C–H···O hydrogen bond with the oxygen atom of the amine moiety. In addition, CCDC 603055 [29] showed an irregular θ1 of −35.0(4)° as Racid-enantiomer; the amine moiety possessed a sulfonamide moiety and a phenyl group.

Previously, the dihedral angle θ1 was discussed in relation to the steric repulsion between the phenyl group and L2 or L3 substituents of the <span class="Chemical">aminen> moiety; it was estimated that the larger repulsion resulted in a lager dihedral angle θ1, and a smaller deshielding of the <span class="Chemical">fluorine atoms by the <span class="Chemical">amide or ester carbonyl groups [4]. However, Kusumi et al. observed the inaccuracies of the MTPA method using 19F-NMR spectroscopy [5,8]. In 2007, Brand et al. reported that the origin of the sp conformation is the hyperconjugative interactions between the carbonyl group and the electronegative trifluoromethyl group [74].

2.3. Staggered Conformation of Trifluoromethyl Group: C1–C2–C3–F3

The distribution of the dihedral angle C1–C2–C3–F3 showed a concentration of entries around −180° (Figure 4). The median angle was −174°. This was suggestive of the staggered conformation of the trifluoromethyl group [9]; that is, the two <span class="Chemical">oxygenn> atoms O1 and <span class="Chemical">O2 were as far as possible from the <span class="Chemical">fluorine atoms.

Figure 4

Histogram for dihedral angles C1–C2–C3–F3 of all MTPA amides. F3 is the fluorine atom ap to C1. The possible range of the dihedral angle C1–C2–C3–F3 is from −180° to −120° and from +120° to +180°.

Histogram for dihedral angles C1–C2–C3–F3 of all <span class="Chemical">MTPA amidesn>. F3 is the <span class="Chemical">fluorine atom ap to C1. The possible range of the dihedral angle C1–C2–C3–F3 is from −180° to −120° and from +120° to +180°.

Khan et al. reported the nonequivalence of three <span class="Chemical">fluorinen> atoms of the <span class="Gene">MTPA <span class="Chemical">amide prepared from secondary amines on the 19F-NMR spectra at low temperatures [75]. They also reported that barriers to the hindered rotation on the C2–C3 bonds were in the range of 36–46 kJ/mol. This suggested the severe steric crowding of the MTPA moiety.

2.4. Resonance Effects of Amide Bond: C1′–N–C1–O1

The distribution of the dihedral angle C1′–N–C1–n class="Chemical">O1 exhibited a concentration of entries around 0° (Figure 5). The average angle and the median angle were +2° and +0.8°, respectively. This represents the resonance effects of the amide bond (Figure 6). Similar planarity was observed in the ester moieties of the crystalline MTPA esters [9].

Figure 5

Histogram for the dihedral angles C1′–N–C1–O1 of all MTPA amides. The α-carbon atom of substituent R, which is sp to the amide carbonyl group, was defined as C1′. The possible range of the dihedral angle C1′–N–C1–O1 is from −90° to +90°.

Figure 6

Z/E forms and their resonance hybrids of MTPA amides. R1 indicates the substituents with higher Cahn–Ingold–Prelog (CIP) priority (e.g., secondary alkyl group); R2 indicates the substituents with lower CIP priority (e.g., hydrogen atom and methyl group).

Histogram for the dihedral angles C1′–N–C1–n class="Chemical">O1 of all MTPA amides. The α-carbon atom of substituent R, which is sp to the amide carbonyl group, was defined as C1′. The possible range of the dihedral angle C1′–N–C1–O1 is from −90° to +90°.

Z/E forms and their resonance hybrids of <span class="Chemical">MTPA amidesn>. R1 indicates the substituents with higher Cahn–Ingold–Prelog (<span class="Disease">CIP) priority (e.g., secondary alkyl group); R2 indicates the substituents with lower <span class="Disease">CIP priority (e.g., hydrogen atom and methyl group).

The trivalent <span class="Chemical">nitrogenn> atom afforded the Z and E forms in the <span class="Chemical">amide moiety (Figure 6). All crystalline secondary <span class="Chemical">MTPA amides prepared from primary amines exhibited the Z form, in which the N-substituent was sp to the amide carbonyl group (Figure 2 and Table 1).

In the case of tertiary <span class="Gene">MTPAn> <span class="Chemical">amide moieties prepared from secondary <span class="Chemical">amines, the ratio of Z/E forms was 13:4 (Table 1). The MTPA amide moieties prepared from cyclic secondary amines exhibited the Z forms (i.e., CCDC 140352 [38], CCDC 167289 [39], CCDC 241708 [40], CCDC 251663 [41], CCDC 604432 [44], CCDC 605818 [45], CCDC 675390 [47], CCDC 706349 [48], CCDC 830079 [51], CCDC 1267150 [54], CCDC 1267151 [54], and the two conformers of CCDC 1280861 [55]).

The four conformers of an N-methyl <n class="Chemical">span class="Gene">MTPA <spn>an class="Chemical">amide exhibited the E forms (i.e., CCDC 707825 [49]). It is noteworthy that the two aromatic rings of the larger secondary alkyl group R1 were bound to the MTPA’s phenyl groups via the aromatic C–H···π and π···π interactions [73,76], respectively. By contrast, Nakagawa and Somei reported the Z form of a crystalline N-methyl MTPA amide in the course of the total synthesis of ergot alkaloids [65].

It is possible that the application of <span class="Chemical">Moshern>’s method using <span class="Chemical">1H-NMR could be expanded to the <span class="Chemical">cyclic secondary amines [77,78]. In 1996, Hoye and Renner applied the MTPA method for assignment of the absolute configuration in chiral cyclic amines; they observed equilibrium mixtures of the Z and E forms of amide moieties in the 1H-NMR spectra [77]. Similar peptidyl-prolyl isomerization is a key issue in protein chemistry [79]. In 2001, Azumaya reported the E‑preference of aromatic N-methylamides (e.g., N-methylbenzanilide) [80].

2.5. Resonance Effects of Amide Bond: X1′′–N–C1–O1

The distribution of the dihedral angle X1′′–N–C1–n class="Chemical">O1 also exhibited a concentration of entries around −180° (Figure 7). The median angle was −174°. This also represents for the resonance effects of the <span class="Chemical">amide bond (see above).

Figure 7

Histogram for dihedral angles X1′′–N–C1–O1 of all MTPA amides. X1′′ is the α-atom of R, which is ap to the amide carbonyl group. The possible range of the dihedral angle X1′′–N–C1–O1 is from −180° to −90° and from +90° to +180°.

Histogram for dihedral angles X1′′–N–C1–n class="Chemical">O1 of all <span class="Chemical">MTPA amides. X1′′ is the α-atom of R, which is ap to the <span class="Chemical">amide carbonyl group. The possible range of the dihedral angle X1′′–N–C1–O1 is from −180° to −90° and from +90° to +180°.

2.6. Conformation of the Amine Moiety: H1′–C1′–N–C1

The distribution of the dihedral angle H1′–C1′–N–C1 was ex<n class="Chemical">span class="Chemical">amined in the case of the ten crystalline <spn>an class="Chemical">MTPA amides prepared from the primary amines possessing secondary alkyl groups (i.e., Mosher‑type MTPA amides). All dihedral angles were distributed between −60° and +50° with an average angle of −5° (Figure 8). Besides, the median angle was −11°. These data agree with Mosher’s hypothesis of the MTPA plane [3,5]. In addition, the broad distribution of dihedral angles was indicative of a moderate conformational flexibility of the C1′–N bond. The same is true for the C1′–O bond of the crystalline MTPA esters prepared from secondary alcohols [9].

Figure 8

Histogram for dihedral angles H1′–C1′–N–C1 of the MTPA amides prepared from primary amines possessing a secondary alkyl group.

Histogram for dihedral angles H1′–C1′–N–C1 of the <n class="Chemical">span class="Chemical">MTPA amides prepared from primary <spn>an class="Chemical">amines possessing a secondary alkyl group.

Rzepa analyzed the relationship between the dihedral angle H–N–C=O and the distance from H1’ of the <n class="Chemical">span class="Chemical">amine moiety to the <spn>an class="Chemical">carbonyl oxygen atom in the crystalline secondary amides (a total of 619); that is, the major conformer exhibited a syn-co-planar alignment of the C–H bond with the plane of the C=O bond in the Z form [81].

2.7. Dihedral Angle between the Methoxy Group and Phenyl Group: O2–C2–C5–C10

The distribution of the dihedral angles <span class="Chemical">O2n>–C2–C5–<span class="Gene">C10 (θ2) exhibited a concentration of entries around +20° (Figure 9). The majority of dihedral angles (53/58, ca. 91%) ranged from 0° to +50°; the average angle of these major 53 conformers was +21°. Besides, the median angle for all 58 conformers was +20°.

Figure 9

Histogram for dihedral angles O2–C2–C5–C10 (θ2) of all MTPA amides. C10 is the ortho‑carbon atom that provides a smaller absolute value. The possible range of the dihedral angle O2–C2–C5–C10 (θ2) is from −90° to +90°.

These data confirmed <span class="Chemical">Moshern>’s hypothesis of <span class="Gene">MTPA <span class="Chemical">amide, in which the (Racid)-MTPA’s phenyl group shields the amine’s substituent L2 (Figure 2a) [3]. Figure 9 also suggested that the substituent L2 is not just above the phenyl ring. We reported that the phenyl group was inclined by +19° in the MTPA ester [9].

The other five entries exhibited the minor conformer in which the <span class="Chemical">amiden> <span class="Chemical">carbonyl group and the methoxy group were anti (see Section 2.2 and Section 2.8). The crowded tetrakis-<span class="Chemical">MTPA amides of ruthenium(II) porphyrin complexes (CCDC 113953 [57] and CCDC 1310848 [58]) exhibited the irregular dihedral angles θ2 [i.e., −56.4(9)°, −34(2)°, and +85(2)°]. One of the conformer of CCDC 1142231 [60], in which the MTPA’s phenyl group forms the C–H···O hydrogen bond with the ethoxy oxygen atom of amine moiety, also exhibited an irregular dihedral angle θ2 [i.e., −77(2)° as Racid-enantiomer]. The rest was CCDC 703912 [32] [i.e., −58.9(7)°], which contains the linear conjugated diene in the amine moiety.

Histogram for dihedral angles <span class="Chemical">O2n>–C2–C5–<span class="Gene">C10 (θ2) of all <span class="Chemical">MTPA amides. C10 is the ortho‑carbon atom that provides a smaller absolute value. The possible range of the dihedral angle O2–C2–C5–C10 (θ2) is from −90° to +90°.

The dihedral angle θ2 has a significant influence on shielding by the phenyl group according to <span class="Chemical">1Hn>-NMR spectroscopy. The dihedral angle θ2 also influenced the crystallization, because the intramolecular interactions (e.g., C–H···π and π···π interactions) are crucial for chiral recognition by the resolving agents [71].

2.8. Conformation of the Methoxy Group: C1–C2–O2–C4

The distribution of the dihedral angles C1–C2–<span class="Chemical">O2n>–C4 exhibited a concentration of entries around +50° (Figure 10). The majority of dihedral angles (52/58, ca. 90%) ranged between +30° and +80°; the average dihedral angle for the major 52 conformers was +54°. Besides, the median angle for all 58 conformers was +51°. That is, the methyl group of the methoxy moiety was ap to the phenyl group. This extended form was also observed as the major conformer in the <span class="Gene">MTPA <span class="Chemical">esters, along with the other minor conformers [9]. Khan et al. reported that θ2 was relaxed to +50° using the MNDO method in the case of (R)-N,N′-dimethyl-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide [75].

Figure 10

Histogram for dihedral angles between the methoxy and phenyl groups of all MTPA amides.

Histogram for dihedral angles between the methoxy and phenyl groups of all <span class="Chemical">MTPA amidesn>.

An irregular dihedral angle −44.4(4)° was observed in the conformer of <span class="Chemical">CCDCn> 222942 [28], in which the phenyl group of the <span class="Chemical">amine moiety formed the C–H···π interactions with the <span class="Gene">MTPA’s methoxy moiety (see Section 2.2.). Similar C–H···π interactions were observed in CCDC 739753 [34] and CCDC 1104875 [52]. It is possible that the methoxy moiety could interact with the amine moieties through weak intramolecular interactions (e.g., C–H···π interaction and C–H···O hydrogen bond) [9,73,76].

The tetrakis-<span class="Chemical">MTPA amidesn> of <span class="Chemical">ruthenium(II) porphyrin complexes again yielded the irregular dihedral angles (i.e., <span class="Chemical">CCDC 113953 [57], −153.6(6)°; CCDC 1310848 [58], −172(2)°, and −154(2)°). The MTPA amide of CCDC 703912 [32], which has a linear conjugated diene moiety in the amine’s substituent L2, exhibited another irregular dihedral angle of −162.7(5)°. One of the conformers of CCDC 1142231 [60] also exhibited the irregular dihedral angle (i.e., −148(2)° as Racid-enantiomer); these represent the minor conformer in which the amide carbonyl group and the methoxy group were anti.

It is noteworthy that Saigo reported that agreement of the molecular lengths is important for the successful resolution via the diastereomeric <span class="Chemical">saltn> formation method [71]. We reported that the agreement of the molecular lengths of acid/<span class="Chemical">alcohol moieties is important for the crystallization of MαNP <span class="Chemical">esters [16].

The crystal structures of <span class="Chemical">CCDCn> 199868 [27] and <span class="Chemical">CCDC 678252 [31] contain the typical conformations of <span class="Chemical">Mosher-type MTPA amides.

3. Experimental Section

3.1. Database Study of MTPA Amide

The accessible 41 crystal structures of <span class="Chemical">MTPA amidesn> reported from 1985 to 2011 [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66] were ex<span class="Chemical">amined. The original dihedral angles of (<span class="Chemical">Racid)- and (Sacid)-MTPA amides were shown in Table 1. In this study, all MTPA amides were processed as (Racid)-MTPA amides; that is, the dihedral angles of (Sacid)-MTPA amides cited in Table 1 were substituted by those of the mirror images (i.e., Racid-enantiomers) with plus/minus sign reversal [82]. Each of bis- and tetrakis-MTPA amides (i.e., CCDC 1280861 [55], CCDC 113953 [57], and CCDC 1310848 [58]), as well as the different conformers in a lattice (i.e., CCDC 199868 [27], CCDC 651954 [30], CCDC 678252 [31], CCDC 707825 [49], CCDC 1105464 [53], CCDC 1142231 [60], CCDC 1236703 [61], and CCDC 1294281 [56]), was processed individually. This procedure yielded 58 of (Racid)-MTPA amide moieties. These MTPA amide moieties were prepared from various amine moieties; that is, primary amines (a subtotal of 14), secondary amines (26), aniline derivatives [tetrakis-MTPA amides of ruthenium(II) porphyrin complexes] (8), benzotriazole (1), diethyl 1-aminoalkylphosphonate derivatives (6), an oxazolidine-2-selone derivative (1), a thiocarbamide derivative (1), and a p-toluenesulfonamide derivative (1). The dihedral angles were obtained using Mercury software (Ver. 3.5.1) [83] from the CIF files. The CIF files listed in Table 1 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).

3.2. Caution

Acylation of an <span class="Chemical">aminen> with (S)-<span class="Gene">MTPA chloride yields (<span class="Chemical">Racid)-MTPA amide. In the same way, acylation of an amine with (R)-MTPA chloride yields (Sacid)-MTPA amide. This nominal change in the absolute configuration has often caused confusion. The same is true for MTPA esters.

4. Conclusions

We conducted a database study of the crystal structures of <span class="Chemical">MTPA amidesn> deposited in the <span class="Disease">CSD. The properties of the major conformation of the <span class="Gene">MTPA amide elucidated from our database study confirmed Mosher’s empirical model on the conformation of MTPA amide; that is, the methine group of the amine moiety, the amide carbonyl group, and the trifluoromethyl group are on the MTPA plane. All secondary MTPA amides prepared from the primary amines exhibited the Z form in the amide moiety. The ratio of Z/E forms of amide moieties was 13:4 in the case of the tertiary MTPA amides prepared from the secondary amines; the cyclic secondary amines yielded the Z forms, whereas the N-methyl amines yielded the both Z and E forms. The amide carbonyl group was sp to the trifluoromethyl group with the average dihedral angle θ1 of −13°. The trifluoromethyl group was in the staggered conformation. In addition, the C1′–N bond of the amine moiety exhibited moderate conformational flexibility. The phenyl plane was inclined by θ2 = +21° from the O–Cchiral bond of the methoxy moiety. This dihedral angle θ2 was suggestive of the inefficient shielding of the phenyl ring. Finally, the methyl group of the methoxy moiety was ap to the ipso‑carbon atom of the phenyl group. These conformational properties were similar to those of the crystalline MTPA ester. Besides, the minor conformer of the crystalline MTPA amides was observed in which the amide carbonyl group and the methoxy group were anti. Mosher’s method using NMR spectroscopy is crucial for the structural elucidation of chiral amines in combination with X-ray crystallography. This report increases our understanding of Mosher’s method and acid 1 and can be used for crystal engineering of MTPA derivatives.