symmetrically disubstituted urea derivative may have different conformers320 (Figure 5.1).
rstand the effect of complexation to stabilize conformers of the
gand 3-phenyl-2-(3-phenyl-ureido) propionic acid (5.1) was prepared by two step procedure (Scheme 5.1). In the first step phenylalanine ethyl ester was reacted with phenyl (3-phenyl-ureido) propionic acid with an objective to prepare a series of carboxylate complexes and also to unde
urea derivative.
The li
isocyanate to form the corresponding ethyl ester.
O O
O R N
N R H H
R N
N H R H
H N
N H R R Syn-Syn Anti-Syn Anti-Anti
Figure 5.1
The hydrolysis of this ester by sodium hydroxide leads to the acid 5.1 in racemate form. The acid was crystallized from ethanol to get good diffraction quality crystals.
NH2 O O
+ N
C O
Dry DCM, RT
HN H N O
O O
1) NaOH, EtOH, RT 2) dil HCl
HN H N O
O OH
5.1(LH)
Scheme 5.1
In the crystal structure of the 3-phenyl-2-(3-phenyl-ureido) propionic acid (5.1), the carbonyl
group of the carboxylic h N−H of the urea part
rough N1−H····O2 [dN1····O2 3.009 Å, <D−H····A 159.7º], N2−H····O2 [dN2····O2 3.261 Å, D−H····A 160.8º] and N4−H····O6 [dN4····O6 3.182 Å, <D−H····A 145.3º] interactions. It is also observed that the carbonyl group of the urea part is participating in O3−H····O4 [dO3····O4 2.579 Å, <D−H····A 159.9º] and O5−H····O1 [dO5····O1 2.562 Å, <D−H····A 160.1º] hydrogen bonding with the hydrogen of carboxylic acid
acid is involved in hydrogen bonding wit th
<D−H····A 145.4º ], N3−H····O6 [dN3····O6 2.988 Å, <
group (Table 5.1). Thus, the hydrogen bonding pattern found in the structure of 5.1 is not usual as compared to the generally observed hydrogen bonding in urea derivatives. The carboxylic acid group of compound 5.1 also participates in intermolecular C24−H····O2 [dC24····O2 3.371 Å, <D−H····A 141.1º] interactions to make a self-assembled structure as illustrated in Figure 5.2B. The solid state structure is composed of two symmetrically non- equivalent molecules per unit cell (Figure 5.2A).
A B
Figure 5.2 A) Structure of 3-phenyl-2-(3-phenyl-ureido)-propionic acid (5.1), B) Hydrogen bonding interactions among the molecules of 5.1.
The symmetry non-equivalence arises due to the self-assembling of the two molecules in such
ea part, s of the two mmetry non equivalent molecules are so oriented that they are unable to form the usual urea
Table 5.1: Hydrogen bond geometry(Å, °) for 5.1
D−H···A d(D−H) d(H···A) d(D···A) <D−H···A
a way that they need two sets of symmetry elements for defining their positions in the unit cell. The compound 5.1 has syn-syn orientation around the carbonyl group of the ur
which is the most common conformation of urea group. The carbonyl group sy
tape motif generally seen in urea derivatives.
N1−H1····O2 [-x, 1-y, 1-z] 0.78(6) 2.27(6) 3.009(6) 159.7(5) N2−H2····O2 [-x, 1-y, 1-z] 0.86 2.52 3.261(5) 145.4
N3−H3····O6 [1-x, -y, 1-z] 0.91(6) 2.11(6) 2.988(5) 160.8(5) O3−H3····O4 [-1+x, y, z] 0.82 1.79 2.579(5) 159.9
N4−H4····O6 [1-x, -y, 1-z] 0.82(5) 2.47(5) 3.182(5) 145.3
H24····O2 [1+x, y, z] 0.98 2.55 3.371(5) 141.1
O5−H5····O1 0.82 1.78 2.562(5) 160.1
C24−
In the infra-red spectra of the compound there are two stro -1
-1
ng bands at 3403 cm and 3375 cm arising from N−H symmetrical stretching of amide. The carbonyl group of amide shows 1694 cm-1 and 1447 cm-1 respectively. 1H-NMR spectra of the complex 5.1 shows that the amide protons appear at 8.51 and 6.23 ppm as a singlet and doublet respectively. The -CH and -CH2 protons appeared at 5.55 ppm and 3.05 ppm, respectively (Figure 5.22).
absorption at 1648 cm-1. The C=O and C−O bands of the carboxylic acid appear at
When we have done the reaction of sodium hydroxide with the ligand 5.1(LH) we got the sodium complex having composition [Na(L)(H2O)3]2 (5.2) (Scheme 5.2). The complex 5.2 is dinuclear and the two sodium ions are in distorted octahedron geometry (Figure 5.3A). There are two bridging water molecules that hold the two sodium ions and the carboxylate groups attached to sodium ions in monodentate fashion.
5.1(LH) NaOH
MeOH/ H2O [Na(L)(H2O)3]2
5.2
HN H
N COOH O
MeOH/ H2O Mn(OAc)2
[Mn(L)2(H2O)2]n 5.3
Scheme 5.2
A chelate like structure is formed due to the coordination of both the carboxylate oxygen and the amide carbonyl oxygen to the sodium center. Two aqua ligands are coordinated to each sodium in trans orientation. The chelation makes the hydrogen bond pattern and the conformation of the ligand totally different from the parent LH. The urea part of the ligand in the sodium complex takes an anti-syn conformation.
Figure 5.3 A) crystal structure of complex 5.2, B) The hydrogen bonded self-assembly of dinuclear [NaL(H2O)3]2
Such anti-syn conformation occurs due to the puckering of the ligand on co-ordination to metal centers. The sodium complex in the solid state are self-assembled mainly through the O4−H····O3 [dO4····O3 2.907 Å, <D−H····A 174.0º], O4−H····O2 [dO4····O2 3.074 Å, <D−H····A 165.1º], O5−H····O6 [dO5····O6 2.853 Å, <D−H····A 176.3º], O5−H····O2 [dO5····O2 2.846 Å,
<D−H····A 175.8º], O6−H····O3 [dO6····O3 2.754 Å, <D−H····A 177.2º] and O6−H····O2 [dO6····O2 3.236 Å, <D−H····A 166.1º] interactions. There also exists N1−H····O2 [dN1····O2 3.013 Å,
<D−H····A 177.1º]interaction of the carboxylate group with N−H of urea part (Figure 5.3B).
Some important hydrogen bonding parameters are listed in Table 5.2. Similar type of anti-syn
in cadmium complex of N,N'-bis-4-methylpyridyl oxalamide323. There are many examples of sodium complexes that are bridged by water324, hydroxide325 or
ulphide326. However, the observation of a very stable [Na2(H2O)2] core is exceptional. The
N f
thi s
att f
the complex 5.2 has IR-absorpti -1. In UV it has two absorptions at appear at 242 nm and 206 nm due to n→π* and π→π* transitions respectively.
Table 5.2: Hydrogen bond geometry(Å, °) for complex 5.2 conformer is observed
s
a1−Na1 distance in the dinuclear core is 3.470Å. Few selected bond distances and angles o s complex are listed in Table 20 (Appendix). The stability of such [Na2(H2O)2] core i ributed to the hydrophobic confinement provided by the ligand. The carboxylate group o
ons at 1694 cm-1 and 1589 cm th
D−H···A d(D−H) d(H···A) d(D···A) <D−H···A N1−H1····O2 [x,−y, 1/2+z] 0.82(2) 2.20(2) 3.013(2) 177.1(3) O4−H4A····O3[x,1−y, 1/2+z] 0.88(4) 2.03(4) 2.907(3) 174.0(4) O4−H4B····O2 [x, y, 1+z] 0.80(5) 2.29(5) 3.074(3) 165.1(5) O5−H5A····O6 [x, −y, 1/2+z] 0.96(3) 1.90(3) 2.853(2) 176.3(3) O5−H5B····O2 [x, y, 1+z] 0.86(4) 1.99(4) 2.846(2) 175.8(3) O6−H6A····O3[1/2−x,1/2−y, −z] 0.88(4) 1.87(4) 2.754(3) 177.2(3)
O6−H6B····O2 0.92(4) 2.33(4) 3.236(3) 166.1(4)
Reaction of LH with manganese(II) acetate lead to an one dimensional co-ordination polymer having composition [Mn(L)2(H2O)2]n (5.3). In this complex each of the manganese centers have distorted octahedral geometry and the carboxylate groups coordinate in bridging
A B
Figure 5.4 A) Structure of the asymmetric unit of complex 5.3, B) The hydrogen bonded one- dimensional co-ordination polymer [MnL2(H2O)2]n (5.3)
akes a sheet like structure through R12(6) type hydrogen bond among the
º] interactions (Table 5.3). The polymeric hains are self-assembled through weak C−H····π interactions (dC13····π 3.780 Å, dC5····π 3.627Å).
Table 5.3: Hydrogen bond geometry(Å, °) for complex 5.3
D−H···A d(D−H) d(H···A) d(D···A) <D−H···A
bidentate mode. Structure of the asymmetric unit of complex 5.3 is shown in Figure 5.4A.
The organic part attached to the carboxylate group of the ligand are positioned parallel to each other and m
carbonyl and the N−H of urea functionality as shown in Figure 5.4B. Urea part of the ligand are hydrogen bonded through N1−H····O1 [dN1····O1 2.859 Å, <D−H····A 175.6º] and N2−H····O1 [dN2····O1 3.398 Å, <D−H····A 138.0
c
N1−H1····O1 [−1+x, y, z] 0.86 2.00 2.859 175.6
N2−H2····O1 0.86 2.70 3.398 138.0
of carbonyl group at 241 nm and the π → π* transition at 206 nm (Figure 5.6A).
The complex shows IR absorptions at 1640 cm-1 and 1545 cm-1 due to the bridging carboxylate groups. It has two UV absorptions due to the n → π* transition
Figure 5.5 Syn-syn and anti-syn geometry of sodium and manganese complexes
The sodium complex of the 3-phenyl-2-(3-phenyl-ureido)-propionic acid has anti-syn conformation around the urea moiety; whereas, in the manganese complex the urea part adopts the conventional syn-syn conformation. The study suggests that the complexation of metal to an urea derivative allows the ligand to stabilize a particular conformer (Figure 5.5).
The ESR spectra of complex 5.3 in dimethylsulfoxide has six hyperfine lines, these are observed due to a distorted octahedral manganese(II) center having d5 configuration in weak field (Figure 5.6B). Spectral analysis shows that the signals are uniformly spaced with a hyperfine coupling constant (aH) of 91.127G. The room temperature magnetic moment of the complex is found to be 5.12 BM corresponding to five unpaired electrons.
We have compared the UV-visible spectra of the complexes 5.2 and 5.3 with that of the parent ligand 5.1. In the UV-visible spectra of the complexes, each has absorptions of the
parent ligand but they are shifted from the original positions on complexation as shown in Figure 5.6A. The conformation change of the ligand occurring on complex formation is also reflected in the 1H NMR spectra of the complex 5.2 as illustrated in Figure 5.7.
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6
200 220 240 260 280 300 320 340
Wave length (nm)
Absorbance
5.1 Complex 5.2 Complex 5.3
A B
plexation through onyl. The amide protons in the sodium complex dose not appear in the spectra due to strong hydrogen b
center is not affected by
Figure 5.6 A) UV-Vis spectra of ligand 5.1 and complex 5.2-5.3, B) Solution state ESR spectra (in DMSO) of compound 5.3 at room temperature (g = 2.00116, center field=
3370.0G, Power= 0.99800 [mw], Frequency= 9449.994 [MHz], sweep time= 30 s)
The 1H NMR spectra of the complex 5.2 shows that the –CH2 group is drastically shifted as compared to in the parent ligand (5.1) due to puckering of the ligand on com
the urea carb
onding with solvent molecules. The proton attached to the chiral complex formation.
Figure 5.7 1H NMR spectra (400MHz) of 5.1 (in DMSO-d6) and complex 5.2 (in D2O)
oxylic acids commonly assemble through carboxylic groups in R22(8) type of geometry328. Polycarboxylic acids with flexible groups are self assembled in the lattice through weak interactions. These weak interactions play a major role in polymorphic properties of such compounds329. We have chosen two compounds namely (3-methoxycarbonylmethoxy-naphthalen-2-yloxy) acetic acid methyl ester (5.4) and (3-carboxymethoxynaphthalen-2-yloxy) aceti ) to study their structural aspects and
out the role of weak interactions in polymorphism.
loxy) acetic acid (5.5) in the second 5.2 Polymorphism and symmetry non-equivalence in (3-carboxymethoxy- naphthalen-2-yloxy) acetic acid and its derivative
Weak interactions provide elegant means in biological molecules to build assemblies of molecules327. It is a well known fact that carb
c acid (5.5 to find
We have synthesized (3-carboxymethoxynaphthalen-2-yloxy) acetic acid and its methyl ester using two-step synthetic procedure355(Scheme 5.3). In the first step, the reaction of naphthalene-2,3-diol with bromomethylacetate leads to (3-methoxycarbonylmethoxy- naphthalen-2-yloxy) acetic acid methyl ester (5.4). Base hydrolysis of the ester leads to the product (3-methoxycarbonylmethoxy-naphthalen-2-y
step.
OH OH
Br CO2Me K2CO3, Dry Acetone 60oC, 24h
O O
CO2Me
CO2Me
1. NaOH, MeOH/H2O Reflux 2. HCl, H2O
O O
COOH
COOH
5.4 5.5 (L1H2)
Scheme 5.3
two different polymorphs of the ester were btained. The two polymorphs are designated as 5.4A and 5.4B. The polymorphism arises On crystallization, (3-carboxymethoxynaphthalen-2-yloxy) acetic acid methyl ester from two different solvents namely methanol and THF,
o
due to the projection of the attached OCH2COOCH3 units across the rings. In the case of 5.4B both the OCH2COOCH3 units are placed in opposite direction (Figure 5.8B), whereas in 5.4A one OCH2COOCH3 unit is above and the other unit lies almost in the same plane of the aromatic ring as shown in Figure 5.8A.
Figure 5.8 Crystal structures of two po s o oxy eth len-
2 ster A) St f 5 truc B.
The torsion angles C4–O3–C3–C2 and –C in th ymorphs are -172.4°
, ° (5.4B ive the in th ngles
r orientation me r gr e la e two
p hs e rtho Pbc roup.
A polymorphs crystall sa gro iffer cking
atterns. The packing diagrams of the two polymorphs of (3-methoxycarbonylmethoxy-
Table 5.4: Hydrogen bond geometry(Å, °) in 5.4A
D−H···A d(D−H) d(H···A) d(D···A) <D−H···A A B
lymorph f (3-meth carbonylm oxy-naphtha .4A, B) S ture of 5.4
-yloxy) acetic acid methyl e ructure o
C13–O4 14–C15 e two pol
77.5° (5.4A) and -91.0°, -83.9 ) respect ly. Here, difference e torsion a efers to existence of two s of the thyl este oups in th ttice of th
olymorphs. Both the polymorp crystalliz in the o rhombic a space g lthough the two ize in the me space up they d in their pa p
naphthalen-2-yloxy) acetic acid methyl ester are shown in Figure 5.9. The prominent hydrogen bonding parameters of 5.4A and 5.4B are listed in Table 5.4 and 5.5 respectively.
C(1)–H(1A)····O(4) [-1/2+x, 1/2-y,-z] 0.96 2.57 3.374(6) 141.5 C(1)–H(1B)····O(2) [-1/2+x, 1/2-y,-z] 0.96 2.47 3.297(6) 144.6 C(14)–H(14A)····O(5) [3/2-x,-1/2+y, z] 0.97 2.53 3.496(5) 171.2 C(14)–H(14B)····O(2) [1/2+x, 1/2-y,-z] 0.97 2.45 3.411(4) 169.1
C(16)–H(16A)····O(5) 0.96 2.63 3.548 159.5
In the two polymorphs the hydrogen bond patterns are different, in case of 5.4A the methyl protons are involve H···O4 [d 3.374 Å, <D−H····A 141.5º], C1–H····O2 [dC1····O2
D−H····A 159.5º] hydrogen
2
C14····O5 dC14····O2 3.411 Å,
<D−H····A 169.1º] interactions (Table 5.4). Apart from the C–H····O interactions, the d in C1– C1····O4
3.297 Å, <D−H····A 144.6º] and C16–H····O5 [dC16····O5 3.548 Å, <
bonding interactions with carboxylate oxygen and the -CH - hydrogens are also involved in C14–H····O5 [d 3.496 Å, <D−H····A 171.2º] and C14–H····O2 [
polymorph 5.4A exhibits weak C16−H···π (dC16···π 3.367 Å) interaction leading to the self- assembly formation.
A