See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/323536185

DFT studies of temperature effect on coordination chemistry of Cu(II)-

trimethoprim complexes

Article  in  Journal of Coordination Chemistry · March 2018

DOI: 10.1080/00958972.2018.1447667

CITATIONS READS

2 515

2 authors, including:

Uzma Habib
National University of Sciences and Technology
12 PUBLICATIONS   44 CITATIONS   

SEE PROFILE

All content following this page was uploaded by Uzma Habib on 07 October 2018.

The user has requested enhancement of the downloaded file.

 Journal of Coordination Chemistry

ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20

DFT studies of temperature effect on coordination

chemistry of Cu(II)-trimethoprim complexes

Malik Zaheer Ahmed & Uzma Habib

To cite this article: Malik Zaheer Ahmed & Uzma Habib (2018) DFT studies of temperature effect
on coordination chemistry of Cu(II)-trimethoprim complexes, Journal of Coordination Chemistry,
71:8, 1102-1113, DOI: 10.1080/00958972.2018.1447667

To link to this article: https://doi.org/10.1080/00958972.2018.1447667

View supplementary material

Accepted author version posted online: 02

Mar 2018.
Published online: 15 Mar 2018.

Submit your article to this journal

Article views: 23

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=gcoo20
Journal of Coordination Chemistry, 2018
VOL. 71, NO. 8, 1102–1113
https://doi.org/10.1080/00958972.2018.1447667

DFT studies of temperature effect on coordination chemistry

of Cu(II)-trimethoprim complexes
Malik Zaheer Ahmed and Uzma Habib 
Research Center for Modeling and Simulations (RCMS), National University of Sciences and Technology
(NUST), Islamabad, Pakistan

ABSTRACT ARTICLE HISTORY

The computational analysis of geometrically different copper- Received 17 August 2017
trimethoprim complexes, experimentally formed at two different Accepted 3 February 2018
temperatures, was performed using Density Functional Theory
KEYWORDS
(DFT) method. Initial geometries of copper-trimethoprim complexes Copper; trimethoprim;
1, 2, and 3 were obtained from crystallographic data. These three metallic complexes;
geometries of complexes 1, 2, and 3 were fully optimized using coordination chemistry;
B3LYP/BLYP hybrid density functional methods along with 6-31G and density functional theory
LANL2DZ basis sets at two temperatures, 298 and 352 K. The results (DFT) method
obtained were compared with the experimental data and show that
complex 1 is the most stable geometry while complex 3 is unstable/
intermediate geometry and can be converted to stable form after
the recrystallization process. Moreover, LANL2DZ basis set gives more
accurate (with respect to experimental) results as compared to 6-31G.

1. Introduction
Trimethoprim {(2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, TMP} belongs to a syn-
thetic antibacterial agent and diaminopyrimidine (pyridine-3,4-diamine) compound group.
Dihydrofolate reductase (DHFR) is the target enzyme of trimethoprim. This enzyme catalyzes
the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate in the presence of NADPH.
Trimethoprim is a good inhibitor of bacterial dihydrofolate reductase and is used to prevent
the conversion of dihydrofolic acid to tetrahydrofolic acid [1, 2] (Figure 1).
It is effective against most of the common bacterial species and is used in combination
with sulfamethoxazole for the treatment of pneumocystis pneumonia infections in AIDS’s

CONTACT  Uzma Habib  uzma.habib@rcms.nust.edu.pk

 Supplemental data for this article can be accessed at https://doi.org/10.1080/00958972.2018.1447667.
© 2018 Informa UK Limited, trading as Taylor & Francis Group
 JOURNAL OF COORDINATION CHEMISTRY   1103

Figure 1. (a) 2D structure of trimethoprim; (b) 3D structure of trimethoprim.

patients [3], infections caused by Gram-positive and Gram-negative bacteria [4]. However,
trimethoprim alone is used for the prophylaxis and treatment of uncomplicated urinary tract
infections [5].
Trimethoprim is a well-known biological agent among such kind of ligands which contains
pyrimidine ring system. Many compounds which contain pyrimidine ring system are impor-
tant therapeutically. In nucleic acids, several vitamins, co-enzymes and antibiotics contain
pyrimidine ring which provides potential binding sites for metal ions. Substituted 2,4-diami-
nopyrimidine compounds are extensively used as metabolic inhibitors of the pathways
leading to the synthesis of proteins and nucleic acids [6].
Complexes and Schiff bases of trimethoprim have also been investigated for their coor-
dination chemistry and applications. Many metal complexes when present in body fluids or
tissue cells show higher activity on many micro-organisms, even on those which have high
resistance to antibiotic itself, e.g. 1,10-phenanthroline exhibits higher bacteriostatic effect
compared to the ligand on rumen bacteria [7], acid fast bacteria [8] and many gram-positive
bacteria [9]. The metal complexes of sulfa-drugs have been found to be more bacteriostatic
than the drug itself [10, 11]. For metal ions, although trimethoprim has seven potential
binding sites, it interacts as a monodentate ligand, e.g. trimethoprim complexes with metal(II/
III), like Cu(II), Zn(II), Pt(II), Ru(II), Fe(III), Cd(III), Co(III), and Co(II).
Organometallic complexes of trimethoprim have an important role in coordination chem-
istry. It forms stable complexes with most of the transition metals and show higher antibac-
terial and antimicrobial activities. The trimethoprim complexes with transition metal ions
form square planar, tetrahedral and octahedral geometries [6, 12–14]. Copper, as copper
acetate monohydrate, formed different geometrical complexes with trimethoprim at differ-
ent temperatures [12, 15], e.g. olive-green crystals of Cu(II)-trimethoprim complexes (com-
plex 1 and complex 2) having distorted octahedral geometry were formed when the same
1:1 ratio of ethanolic solutions of trimethoprim and copper acetate monohydrate were mixed
and refluxed for 2 h [12] (Figures 2 and 3). Light-blue crystals of Cu(II)-trimethoprim complex
(complex 3) having distorted square planar geometry were formed by mixing 1:1 ratio
of ethanolic solutions of trimethoprim and copper acetate monohydrate at 20–25 °C [15]
(Figure 4).
Different types of copper-trimethoprim complexes were formed from the same concen-
tration of reactants but at two different temperatures. Three copper atoms with different
oxidation states linked with each other in complex formed at 20–25 °C (complex 3) [15]. In
1104   M. Z. AHMED AND U. HABIB

Figure 2. Crystal structure of copper trimethoprim complex 1 at 75–80 °C [12].

Figure 3. Crystal structure of copper trimethoprim complex 2 at 75–80 °C [12].

complex 3, each metal (Cu) center exhibits distorted tetrahedral geometry and show +1
and +2 oxidation states.
When the ethanolic solutions of copper acetate monohydrate and trimethoprim were
mixed at boiling temperature and refluxed for 2 h, dirty olive-green amorphous Cu-TMP
complex is formed. On crystallization, dirty olive-green amorphous form is converted into
two geometrical isomeric forms of olive-green crystals (complex 1 and complex 2); both
isomers show Cu–Cu linkage where each Cu shows +2 oxidation states [12].
The purpose of this study is to describe the coordination chemistry of different geomet-
rical complexes of Cu(II)-trimethoprim at different temperatures [12, 15] with the help of
density functional theory (DFT). Molecular geometries and optimization energies were cal-
culated with the help of DFT and the results obtained were compared with the experimental
data. The electronic and structural properties of the complexes at their ground states in gas
phase as well as in solvent are also studied.
 JOURNAL OF COORDINATION CHEMISTRY   1105

Figure 4. Crystal structure of copper trimethoprim complex 3 at 20–25 °C [15].

2.  Computational details

All geometries of complexes 1, 2 and 3 obtained from crystallographic data (CCDC Nos.
619488 and 619490) are fully optimized using Gaussian G09 [16] with B3LYP and BLYP [17,
18] hybrid DFT methods. 6-31G and LANL2DZ are used as basis sets for this study.
Optimizations of geometries were carried out at 298 and 352 K. B3LYP and BLYP hybrid
density functions were also used for single-point energy calculations in the gas and solvent
phase. Single-point energies were calculated using Stuttgart-Dresden (SDD) effective core
potential basis set augmented by polarization functions for all atoms except Cu, H (ζ = 0.600,
1.154, and 0.864 for C, O, and N, respectively). Self-consistence reaction field (SCRF) calcu-
lations [19] were performed on optimized geometries using water and ethanol solvents by
a conductor-like polarizable continuum method (CPCM) [20].

3.  Results and discussion

Trimethoprim (TMP) itself is used as an antibiotic for uncomplicated urinary tract infections
(UTI). It is distributed into the body fluid and tissues through oral rout absorption and active
against a wide range of Gram-positive and Gram-negative aerobic bacteria [21]. Trimethoprim
is also used along with sulfamethoxazole as co-trimoxazole for a long time.
Experimentally, metal complexes of trimethoprim were produced many times.
Trimethoprim forms complexes with Pd(II) and Pt(II) as square planar [14]. With Mn(II), tri-
methoprim forms low-spin octahedral complex while high-spin octahedral complexes are
reported by Co(II), Ni(II), Fe(II) and Zn(II) [13]. Zn(II) also exhibited tetrahedral complex with
trimethoprim [6]. Cu(II) trimethoprim complexes show high activity constant value [22].
1106   M. Z. AHMED AND U. HABIB

Complexes of Zn(II) and Cu(II) with Schiff bases of trimethoprim and sulphamethoxazole
were also synthesized [23], however, Cu(II) is the most studied metal. Copper shows beneficial
effects in different diseases such as gastric ulcer, rheumatoid arthritis and cancer. It also acts
as an oxygen carrier [12].
The DFT study presented in this article is mainly focused on the (a) formation of trimeth-
oprim complexes with copper acetate as reported in the literature and (b) coordination
chemistry of trimethoprim complexes 1, 2 and 3. Literature shows that, at 352 K temperature,
two different geometrical complexes (olive-green colored) are formed. It shows that just by
changing the temperature, different geometrical complexes were obtained with different
number of atoms and of different colors. These complexes obtained also show different
antibacterial activities while distorted square planar complex (light-blue colored) is formed
at 298 K in which three copper atoms are involved in complex formation. These three copper
atoms are linked with each other through acetate and hydroxide bridging.
For this purpose, DFT studies are carried out using two different hybrid density functional
methods (B3LYP and BLYP) and each hybrid DFT method with two different basis sets (6-31G
and LANL2DZ). To get reliability, computational results obtained at two different DFT meth-
ods and basis sets were compared within themselves as well as with the experimental results.

3.1.  Geometry optimization of copper-trimethoprim complexes

All geometries of copper acetate, trimethoprim and copper-trimethoprim complexes (com-
plexes 1, 2, and 3) were optimized at B3LYP/LANL2DZ, B3LYP/6-31G, BLYP/LANL2DZ and
BLYP/6-31G DFT levels in the gas phase (Figures 5–8). Relative energies were calculated for
the formation of copper-trimethoprim complexes (Tables 1–3). Structural parameters of
optimized and calculated geometries are also shown in Tables 4–9.

3.1.1. Complex 1
Computational results of complex 1 show that the relative energies calculated at 298 and
354 K using B3LYP/LANL2DZ, B3LYP/6-31G, BLYP/LANL2DZ, and BLYP/6-31G levels of hybrid
DFT are comparable with relative energies ranges from −19.9 to −21.1 kcal/mol (Table 1).
The results show that the maximum relative energy of −19.9 kcal/mol was obtained from

Figure 5. Optimized geometry of complex 1.

 JOURNAL OF COORDINATION CHEMISTRY   1107

Figure 6. Optimized geometry of complex 2.

Figure 7. Disrupted optimized geometry of complex 3 at LANL2DZ basis set.

BLYP/6-31G at both 298 and 352 K whereas the acceptable minimum energy of −21.1 kcal/
mol was obtained from B3LYP/LANL2DZ at both 298 and 352 K. Also, the calculated and
experimental copper-trimethoprim complexes show similarity in average bond lengths with
the deviation of ± 0.1 Å (Tables 1, 4, 5, and Figure 5).

3.1.2. Complex 2
Computational results of complex 2 show significant difference of 9.9 kcal/mol (−7.4 to
−17.3 kcal/mol) in the relative energies calculated at 298 and 352 K using the same hybrid
density functional theory levels, as used for complex 1, however the trend that B3LYP/
LANL2DZ provides the minimum relative energy is the same as for complex 1 (Table 1).
1108   M. Z. AHMED AND U. HABIB

Figure 8. Optimized geometry of complex 3 at 6-31G basis set.

Table 1. Relative energy values (kcal/mol) of complex 1.

Complex 1
298 K 352 K
B3LYP BLYP B3LYP BLYP
6-31G LANL2DZ 6-31G LANL2DZ 6-31G LANL2DZ 6-31G LANL2DZ
Opt. −11.85 −12.79 −10.40 −12.84 −11.83 −12.79 −10.40 −12.35
SDD −12.80 −12.87 −11.59 −14.21 −12.78 −12.89 −11.59 −12.72
CPCM-Water −21.44 −21.24 −20.20 −22.05 −21.44 −21.13 −20.20 −24.11
CPCM-Ethanol −21.15 −20.95 −19.90 −21.77 −21.14 −20.84 −19.90 −20.08

Table 2. Relative energy values (kcal/mol) of complex 2.

Complex 2
298 K 352 K
B3LYP BLYP B3LYP BLYP
6-31G LANL2DZ 6-31G LANL2DZ 6-31G LANL2DZ 6-31G LANL2DZ
Opt. −7.41 −7.98 −5.58 −6.06 −7.38 −7.98 −5.59 −6.06
SDD −7.38 −7.79 −4.60 −0.57 −7.37 −7.81 −4.61 −6.40
CPCM-Water −16.39 −17.67 −14.60 −9.07 −16.38 −17.55 −14.60 −20.04
CPCM-Ethanol −16.06 −17.31 −14.24 −8.76 −16.05 −17.2 −14.24 −15.91

Table 3. Relative energy values (kcal/mol) of complex 3.

Complex 3
298 K 352 K
Jobs B3LYP BLYP B3LYP BLYP
6-31G LANL2DZ 6-31G LANL2DZ 6-31G LANL2DZ 6-31G LANL2DZ
Opt. 81.22 29.56 52.09 19.53 81.23 28.72 52.09 19.53
SDD 76.87 47.28 64.97 33.16 76.86 47.28 61.67 34.65
CPCM-Water 68.69 41.56 56.92 25.21 68.71 41.56 52.18 23.15
CPCM-Ethanol 69.03 41.81 57.25 25.54 69.04 41.81 52.57 27.23
 JOURNAL OF COORDINATION CHEMISTRY   1109

Table 4. Bond lengths of Cu-trimethoprim complex 1.

Complex 1 at 352 K Complex 1 at 298 K
Bond
lengths B3LY- BLY- B3LYP/ BLYP/ B3LY- BLY- B3LYP/ BLYP/
(Å) Exp. P/6-31G P/6-31G LANL2DZ LANL2DZ P/6-31G P/6-31G LANL2DZ LANL2DZ
Cu1–Cu55 2.7052 2.7048 2.8214 2.8715 2.8861 2.7999 2.8214 2.8717 2.886
Cu1–O1 1.9846 1.9788 2.0051 2.0426 2.0491 1.9764 2.0051 2.0426 2.049
Cu1–O3 1.9666 2.0227 2.0227 2.0207 2.0736 2.0251 2.0227 2.0209 2.0736
Cu1–O58 1.9792 2.0137 2.0166 2.0446 2.0705 2.016 2.0166 2.0444 2.0705
Cu1–O59 1.9846 1.9739 2.0051 2.0223 2.0498 1.9718 2.005 2.0224 2.0498
Cu1–N9 2.2079 2.1616 2.1872 2.1901 2.2084 2.1608 2.1872 2.19 2.2084

Table 5. Bond angles of Cu-trimethoprim complex 1.

Complex 1 at 298 K Complex 1 at 352 K
B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/
Bond angles (°) Exp. 6-31G 6-31G LANL2DZ LANL2DZ 6-31G 6-31G LANL2DZ LANL2DZ
O(2)–Cu(1)–Cu(55) 79.71 82.57 83.16 81.79 82.06 79.61 82.35 82.35 82.01
C(17)–O(2)–Cu(1) 128.55 124.74 124.46 125.46 124.83 122.57 123.89 124.43 124.69
N(9)–Cu(1)–Cu(55) 172.75 178.13 178.13 177.63 177.79 179.27 179.47 177.63 177.36

Table 6. Bond lengths of Cu-trimethoprim complex 2.

Complex 2 at 352 K Complex 2 at 298 K
Bond
lengths B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/
(Å) Exp. 6-31G 6-31G LANL2DZ LANL2DZ 6-31G 6-31G LANL2DZ LANL2DZ
Cu1–Cu55 2.7052 2.8012 2.7983 2.8427 2.89 2.8012 2.7979 2.8426 2.89
Cu1–O1 1.9846 1.9555 2.0242 2.0484 2.0497 2.0529 2.0109 2.0483 2.0497
Cu1–O3 1.9666 1.9514 1.9979 2.0062 2.0779 1.9557 2.0237 2.0063 2.0779
Cu1–O58 1.9792 2.042 2.0075 2.063 2.0623 2.0415 2.0099 2.0079 2.0623
Cu1–O59 1.9846 2.0535 2.0365 2.0079 2.0499 1.9516 2.0119 2.0609 2.0499
Cu1–N9 2.2079 2.1552 2.1799 2.1758 2.2087 2.1719 2.1794 2.1758 2.2087

Table 7. Bond angles of Cu-trimethoprim complex 2.

Complex 2 at 298 K Complex 2 at 352 K
B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/
Bond angles (°) Exp. 6-31G 6-31G LANL2DZ LANL2DZ 6-31G 6-31G LANL2DZ LANL2DZ
O(4)–Cu(1)–Cu(55) 79.7 82.6 83.2 81.8 82.1 79.6 82.4 80.3 82.0
C(17)–O(4)–Cu(1) 128.6 124.7 124.5 125.5 124.8 122.6 123.9 124.2 124.7
N(9)–Cu(1)–Cu(55) 172.8 178.1 178.1 177.6 177.8 179.3 179.5 177.4 177.4

Maximum −7.4 kcal/mol and the minimum −17.3 kcal/mol relative energies were produced
by B3LYP/6-31G and B3LYP/LANL2DZ levels of DFT, respectively. However, the calculated
and experimental copper-trimethoprim complexes 2 show similarity in average bond lengths
with deviation of ±0.1 Å (Tables 2, 6, 7, and Figure 6).
1110   M. Z. AHMED AND U. HABIB

Table 8. Bond lengths of Cu-trimethoprim complex 3.

Complex 3 at 298 K Complex 3 at 352 K
Bond
lengths B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/
(Å) Exp. 6-31G 6-31G LANL2DZ LANL2DZ 6-31G 6-31G LANL2DZ LANL2DZ
Cu1–N(10) 2.0228 1.93407 1.93584 3.41813 3.4442 1.9341 1.93548 3.4181 3.4436
Cu1–O8 1.9416 2.03838 2.01749 2.24771 2.1180 2.0384 2.01479 2.2475 2.1180
Cu1–O5 1.9496 2.02091 2.01754 1.94411 1.9615 2.0209 2.01754 1.9441 1.9615
Cu1–O7 1.9518 2.14419 2.11748 1.93110 1.9457 1.1442 2.11748 1.9311 1.9457
Cu56–O6 1.9544 1.95843 1.97732 1.99978 2.1032 1.9584 1.97732 1.9997 2.1033
Cu56–O8 1.9110 1.91100 1.94273 1.93237 1.9859 1.9256 1.94273 1.9323 1.9860

Table 9. Bond angles of Cu-trimethoprim complex 3.

Complex 3 at 298 K Complex 3 at 352 K
B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/ B3LYP/ BLYP/
Bond angles (°) Exp. 6-31G 6-31G LANL2DZ LANL2DZ 6-31G 6-31G LANL2DZ LANL2DZ
O(8)–Cu(1)–O(5) 90.21 106.79 109.12 58.91 104.32 106.79 109.12 97.43 104.32
O(5)–Cu(1)–O(7) 177.11 100.23 98.38 155.58 151.03 100.23 98.37 159.85 151.03
O(8)–Cu(1)–N(10) 174.35 113.75 113.00 75.65 78.92 113.75 113.00 75.66 78.93
O(5)–Cu(1)–N(10) 86.71 111.69 109.32 91.90 92.49 111.68 109.32 91.91 92.43
Cu(1)–O(8)–Cu(56) 122.2 118.48 116.59 100.7 109.86 118.48 116.59 100.70 109.84
C(46)–O(5)–Cu(1) 136.41 126.97 126.63 128.86 127.79 126.97 126.63 128.86 127.78
C(18)–O(2)–Cu(1) 180 19.87 19.92 25.86 26.11 19.87 19.92 25.86 26.11

3.1.3. Complex 3
Computational analysis of complex 3 shows a drastic shift from the experimentally repre-
sented structure. Although the relative energy obtained from B3LYP/LANL2DZ is much lower
compared to the others, trimethoprim bond with copper has been broken while optimizing
with the LANL2DZ basis set and form bond with the N(10) of trimethoprim with acetate
oxygen (112) through hydrogen (114) while nitrogen (11) of the trimethoprim attached with
hydroxyl oxygen (8) through hydrogen (13). Same pattern of attachment is observed at the
second trimethoprim molecule on the other side of the molecule (Figures 7 and 8).
The computational results show that complex 3 has some intermediate geometry but
not the product. There are two main reasons for this conclusion: (1) relative energies are
much higher ranging from 19.5 to 81.2 kcal/mol, as compared to complexes 1 and 2, and
(2) geometry of complex 3 distort/break-down during optimization at B3LYP/LANL2DZ and
BLYP/LANL2DZ levels of DFT. Therefore, it is proposed that complex 3 is an unstable geometry
as compared to complexes 1 and 2 and it may be an intermediate which can be converted
to complexes 1 or 2, if the complex solution would be refluxed. The computational and
experimental results of copper-trimethoprim complex 3 shows deviation of ±0.78 Å in aver-
age bond lengths (Tables 3, 8 and 9).
The relative energies calculated at B3LYP/BLYP hybrid DFT with 6-31G/LANL2DZ as basis
sets for the two geometries of complexes 1 and 2 show that the optimization energies of
complex 2 are comparatively high as compared with complex 1. This means that complex
1 is more stable and hence was produced more as compared with 2 (Tables 1 and 2). The
computational result shows that complex 1 is a more stable and dominant structure as
compared with other geometries. Experimental results also verified that complex 1 was
formed in greater amount.
 JOURNAL OF COORDINATION CHEMISTRY   1111

Comparing the geometry optimization of complexes 1 and 2, it is assumed that single

stable geometry can be obtained on repetition of crystallization process.

3.2.  Comparison of the hybrid density functional methods

When comparing the hybrid density functional methods, it has been observed from the
computational analysis that relative energies obtained from BLYP hybrid DFT method are
by ±0.1 kcal/mol lower in energy than the results obtained from B3LYP DFT method for
complex 1 geometry which is a negligible difference. Same trend is observed in other geom-
etries (complex 2 and complex 3) in which BLYP hybrid DFT method produce ±0.1 kcal/mol
lower energy as compared to B3LYP hybrid DFT method.

3.3.  Comparison of the basis sets

On comparing the basis sets, it has been revealed that LANL2DZ basis set gives more accurate
(comparable to experimental) results as compared to 6-31G for the computational analysis of
transition metal complexes. The same trend i.e. B3LYP/LANL2DZ gives more acceptable results
than B3LYP/6-31G and similarly BLYP/LANL2DZ produce more acceptable results than BLYP/6-
31G, has been observed in the results obtained at two different temperatures, 298 and 352 K.

3.4.  Effect of temperature

As described earlier, all geometries were optimized at two different temperatures, 298 and
352 K. Computational result shows the similarity between the relative energies produced at
B3LYP/LANL2DZ, B3LYP/6-31G, BLYP/LANL2DZ and BLYP/6-31G levels of hybrid DFT. It has
been observed that the difference between the results obtained is 2.4 kcal/mol which is less
than 5 kcal/mol at both temperatures and hence not significantly different.

3.5.  Effect of solvent

SCRF (Self-consistent reaction field) calculations were performed on optimized geometries
of complexes 1, 2 and 3 by using default solvent, water and ethanol as solvent through
Gaussian-09 by conductor-like polarizable continuum model (CPCM). The comparison of
computational results obtained for complexes 1 and 2 shows that B3LYP/6-31G for 1 has
lower relative energy values in default (−21.44 kcal/mol), water (−21.44 kcal/mol), and eth-
anol solvent (−21.15 kcal/mol) as compared to 2 (−16.39, −16.39, and −16.06 kcal/mol,
respectively). Similarly, B3LYP/LANL2DZ shows lower relative energy values in complex 1
(−21.13, −21.13, and −20.84 kcal/mol, respectively) as compared in complex 2 (−17.55, −17.55
and −17.2 kcal/mol, respectively). The same has been observed when BLYP hybrid density
functional method is used instead of B3LYP.
In complex 3, at 298 K CPCM results show higher relative energy values at all above
mentioned conditions when compared with complexes 1 and 2. The relative energy values
at B3LYP/LANL2DZ give 41.56, 41.56 and 41.81 kcal/mol at default, water and ethanol as
solvent, respectively, are lower than the relative energies obtained at B3LYP/6-31G i.e.,
68.69 kcal/mol for default solvent, 68.69 kcal/mol for water and 69.03 kcal/mol for ethanol
as solvent. Similarly, BLYP/LANL2DZ gives lower relative energy values in solvent as compared
1112   M. Z. AHMED AND U. HABIB

with BLYP/6-31G level of DFT method (25.21 kcal/mol in default solvent, 25.21 kcal/mol in

water and 25.54 kcal/mol in ethanol with 56.92, 56.92, and 57.25 kcal/mol, respectively).
The relative energy values obtained from the computational analysis of complexes 1, 2
and 3 in SCRF using CPCM as default solvent and CPCM as ethanol solvent shows that when
we change solvent from ethanol to water no significant change has been observed in relative
energy; moreover it is noted that 1 has lower relative energy values at all conditions, hence
it is assumed that 1 is more stable compared with 2 and will be produced in higher amount.
Experimental results also showed that 1 was produced in higher amount as compared with
2 at 352 K. The higher relative energy values of complex 3 at 298 K show that this is an inter-
mediate geometry and not the product. According to computational results, it is assumed
that if the temperature is increased and recrystallization process may be repeated twice or
thrice then we can get a single stable geometry.

4. Conclusion
DFT calculations were performed on three geometries of copper-trimethoprim complexes
(1, 2, and 3) using B3LYP/BLYP methods along with 6-31G/LANL2DZ basis sets. A good agree-
ment found as a result of comparison of experimental results with computational analysis.
All geometries were fully optimized at 298 K as well as 352 K and no significant difference
in energy values obtained at two different temperatures was found. Hence, there is no sig-
nificant temperature effect found. The comparison of complex 1 with complex 2 shows that
1 is the most stable geometry with low energy value and experimental results also showed
the formation of 1 is in higher amounts. The energy value of complex 3 is much higher which
shows that this is an unstable geometry and can be converted to a stable geometry after
recrystallization process. The stability order was found as 1 > 2 > 3. Moreover, computational
results also show that B3LYP/LANL2DZ and BLYP/LANL2DZ produces more reliable/compa-
rable results as compared to B3LYP/6-31G and BLYP/6-31G.

Acknowledgements
Authors acknowledge the Super Computing Lab of National University of Sciences and Technology
for providing facilities to complete this project. Authors also acknowledge the Metro and Ambrosia
Pharmaceuticals for their support during this study.

Disclosure statement
No potential conflict of interest was reported by the authors.

ORCID
Uzma Habib   http://orcid.org/0000-0001-6592-6419

References
  [1] S. Bhattacharya, A.S.P. Ray. Pharmacology, Elsevier, 2, 406, (2009).
  [2] E.P. Quinlivan, J. McPartlin, D.G. Weir. FASEB J., 14, 2519 (2000).
  [3] L. Huang, A. Cattamanchi, J.L. Davis, S.D. Boon, J. Kovacs, S. Meshnick, R.F. Miller, P.D. Walzer, W.
Worodria, H. Masur. Proc. Am. Thoracic Soc. ATS J., 8, 294 (2011).
 JOURNAL OF COORDINATION CHEMISTRY   1113

 [4] A.V.M. Franco. Best Practice Res. Clin. Obst. Gyn., 19, 861 (2005).
 [5] M. Mashkovskii. Drugs [in Russian], Vol. 1, pp. 275, Novaya Volna, Moscow (2000).
  [6] N. Demirezen, D. Tarınc, D. Polat, M. Cesme. Spectrochim. Acta, Part A, 129, 52 (2014).
  [7] W.W. Brandt, F.P. Dwyer, E.D. Gyarfas. Chem. Rev., 54, 959 (1954).
  [8] I. Georgieva, N. Trendafilova. J. Phys. Chem. A, 111, 13075 (2007).
  [9] L. Chen, T. Liu, C. Ma. J. Phys. Chem. A, 114, 443 (2009).
[10] Y. Niu, S. Feng, R. Qu, Y. Ding, D. Wang. Int. J. Quantum Chem., 111, 991 (2011).
[11] S.I. Gorelsky, L. Basumallick, J. Vura-Weis, R. Sarangi, K.O. Hodgson, B. Hedman, K. Fujisawa,
E.I. Solomon. Inorg. Chem., 44, 4947 (2005).
[12] U. Habib, A. Badshah, U. Flörke, R.A. Qureshi, B. Mirza, N. Islam, A. Khan. J. Chem. Cryst., 39, 730
(2009).
[13] A. Aderoju, S.M.W. Osowole, K. Alao Olaoluwa. World Appl. Sci. J., 33, 336 (2015).
[14]  P.A. Ajibade, O.G. Idemudia. Bioinorg. Chem. Appl., 2013, 8 p. Article ID: 549549 (2013).
doi:10.1155/2013/549549.
[15] U. Habib, A. Badshah, U. Flörke, R.A. Qureshi, B. Mirza, N. Nazar-ul-Islam, A. Khan. J. Chem.
Crystallogr., 39, 607 (2009).
[16] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani,
V. Barone, B. Mennucci, G.A. Petersson. Gaussian09, Gaussian Inc., Rev. A.2, Wallingford, CT (2009).
[17] A.D. Becke. Phys. Rev. A, 38, 3098 (1988).
[18] C. Lee, W. Yang, R.G. Parr. Phys. Rev. B, 37, 785 (1988).
[19] B. Marten, K. Kim, C. Cortis, R.A. Friesner, R.B. Murphy, M.N. Ringnalda, D. Sitkoff, B. Honig. J. Phys.
Chem., 100, 11775 (1996).
[20] M.D. Liptak, G.C. Shields. J. Am. Chem. Soc., 123, 7314 (2001).
[21] R.N. Brogden, A.A. Carmine, R.C. Heel, T.M. Speight, G.S. Avery. Drugs, 23, 405 (1982).
[22] A.C. Tella, J.A. Obaleye. Int. J. Chem. Sci., 8, 1675 (2010).
[23] M.S. Iqbal, A.H. Khan, B.A. Loothar, I.H. Bukhari. Med. Chem. Res., 18, 31 (2009).

View publication stats