Hydrolysis of Letrozole catalyzed by macrocyclic Rhodium (I) Schiff-base complexes

Article abstract of DOI:10.1016/j.saa.2014.12.033

Ten mononuclear Rhodium (I) complexes were synthesized by macrocyclic ligands having N₄ and N₂O₂ donor sites. Square planar geometry is assigned based on the analytical and spectral properties for all complexes. Rh(I) comp

Full text of DOI:10.1016/j.saa.2014.12.033

Accepted Manuscript
Hydrolysis of Letrozole Catalyzed by Macrocyclic Rhodium (I) Schiff-base
Complexes
P. Muralidhar Reddy, K. Shanker, V. Srinivas, E. Ravi Krishna, R. Rohini, G.
Srikanth, Anren Hu, V. Ravinder
PII:
S1386-1425(14)01804-6
http://dx.doi.org/10.1016/j.saa.2014.12.033
SAA 13074
DOI:
Reference:
To appear in:
Spectrochimica Acta Part A: Molecular and Biomo-
lecular Spectroscopy
Received Date:
Revised Date:
Accepted Date:
30 March 2014
23 July 2014
9 December 2014
Please cite this article as: P. Muralidhar Reddy, K. Shanker, V. Srinivas, E. Ravi Krishna, R. Rohini, G. Srikanth,
A. Hu, V. Ravinder, Hydrolysis of Letrozole Catalyzed by Macrocyclic Rhodium (I) Schiff-base Complexes,
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), doi: http://dx.doi.org/10.1016/j.saa.
2
014.12.033
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Hydrolysis of Letrozole Catalyzed by Macrocyclic Rhodium (I)
Schiff-base Complexes
1
P. Muralidhar Reddy , K. Shanker , V. Srinivas , E. Ravi Krishna , R. Rohini
†
2,†
2
2
2, 3
, G.
2
Srikanth , Anren Hu * and V. Ravinder *
4
2,
1
Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
2
Department of Chemistry, Kakatiya University, Warangal-506 009, A.P, India
3
Department of Chemistry, National Dong Hwa University, Hualien-974, Taiwan
4
Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualien, Taiwan
†
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed; E-Mails:
ravichemku@rediffmail.com; anren@mail.tcu.edu.tw; Tel.: +886-3-8565301 (ext. 2334 or
335); +91-9390100594; Fax: +886-3-8571917 (A.H.).
2

Abstract
Ten mononuclear Rhodium (I) complexes were synthesized by macrocyclic ligands
having N and N donor sites. Square planar geometry is assigned based on the analytical and
4
2 2
O
spectral properties for all complexes. Rh(I) complexes were investigated as catalysts in
hydrolysis of nitrile group containing pharmaceutical drug Letrozole. A comparative study
showed that all the complexes are efficient in the catalysis. The percent yields of all the catalytic
reaction products viz. drug impurities were determined by spectrophotometric procedures and
characterized by spectral studies.
Keywords: rhodium (I) complexes, hydrolysis, Letrozole, spectrophotometry, spectral studies

1
. Introduction
The macrocyclic metal complexes have attracted a great deal of attention because they
can be used as models for more complex biological macrocyclic systems such as hemoglobin,
myoglobin, cytochromes, chlorophylls, vitamin B12, valinomycin, and nonactin etc. These
breakthroughs have created supramolecular chemistry and its tremendous diversity [1].
Generally, macrocycles can be synthesized by template and non-template methods [2-6]. Most of
the synthetic routes of macrocycles involve templation, but the products are not easily scaled up.
However, Schiff base condensation is preferred to overcome this problem [7-9]. Ortho-
phthalaldehyde (OPA) serves as a good starting material for the synthesis of macrocycles [10].
Literature study discloses that a little bit of work was done to synthesize Schiff bases from OPA
by either template or non-template methods [10-18]. In previous work, we have reported the non-
,
template synthesis of N- O-, donor macrocycles, benzimidazo/indolo [1,2-c] quinazolines[19-25]
and their metal complexes [14-16, 26-30]. Still, the many of the existing OPA based macrocyclic
metal compounds were synthesized by the direct treatment of OPA, diamine and metal salts [11,
1
2]. Since, macrocyclic Rhodium (I) complexes are not synthesized by the initial preparation of
macrocycle followed by its treatment with [Rh(COD)Cl]2.
In recent years, research towards the catalytic applications of macrocyclic metal
complexes is rapidly increasing [26, 27]. It bids attractive chances for industry, which attempts
to develop more environmentally benign manufacturing methods. Governing authorities are now
giving critical attention on impurity profiling of active pharmaceutical ingredients (APIs) and
demanding for the identification and quantization of impurities in APIs in order to protect the
patient against the undesirable side effects [31-33]. Hence, International Conference on
Harmonization (ICH) guideline [34] set a threshold of 0.1 percentage impurities in APIs, above

which the identification of the impurity is compulsory. Forced degradation (stress) studies [34,
5] are also to be executed to produce and detect these impurities and the recommended
3
conditions include oxidation, hydrolysis at high and low pH, elevated temperature, photolysis of
APIs. A number of recent reports have described a designed approach and guidance for isolating,
detecting and synthesizing process related impurities [36, 37] and degradation products [38, 39].
Rhodium complexes are versatile catalysts and can be used for several organic reactions, like
oxidation [40], reduction [41], carbonylation [42], addition [43], hydroformylation [44],
3 3
hydroboration [45] etc. The Wilkinson catalyst, RhCl(PPh ) is the classic example of a
homogeneous hydrogenation catalyst [46]. In the present study, we synthesized mononuclear
macrocyclic Rh(I) complexes (Scheme 1) and utilized in the hydrolysis of Letrozole drug
molecule to develop its impurities.
2
. Experimental Section
2
.1. Materials
The macrocyclic ligands (MLs) namely 7,8,17,18-tetrahydrodibenzo [f,n][1,4,9,12]
tetraazacyclohexadecine[HBACHD] (L1), Tetrabenzo[b,f,j,n][1,4,9,12]tetraazacyclo hexadecane
[
(
BACHD] (L2),Dibenzo[f,n]dipyrido[2,3-b:3,2-j][1,4,9,12]-tetraazacyclohexadecine [BPACHD]
L3),Dibenzo[g,p]dinaphtho-[1,8-bc:1,8-kl][1,5,10,14]-tetraazacyclooctadecine[BNACOD](L4),
6
,7-dihydrotribenzo-[e,i,m][1,4,7,12]-ioxadiazacyclotetradecine [HBOACTD] (L5), 13,14-
dihydro-12H-tribenzo[b,f,j][1,12,4,9]dioxadiazacyclopentadecine[HBOACPD](L6),6,7-di hydro
benzo [i]dipyrido[3,2-e:2,3-m][1,4,7,12]dioxadiazacyclotetradecine [HBPOACTD] (L7), 13,14-
dihydro-12H-benzo-[f]-dipyrido-[3,2-b:2,3-j][1,12,4,9]-dioxadiazacyclopentadecine [HBPOAC
PD](L8),21,22-dihydrobenzo[i]dinaphtho[2,3-e:2,3-m][1,4,7,12]dioxadiazacyclotetradecine [HB

NOACTD](L9) and 15,16-dihydro-14H-benzo[f]binaphthol[2,3-b:2,3-j] [1,12,4,9] dioxa
diazacyclopentadecine [HBNOACPD] (L10) were synthesized according to literature procedures
[
2
10, 47]. [Rh(COD)Cl] was obtained from Aldrich, USA, and all other compounds were
analytical grade products from Merck. Aromatic amines, o-phthalaldehyde (OPA), and
substituted aromatic amino alcohols were acquired from Aldrich, USA. The melting points of all
the macrocyclic Rh(I) complexes were obtained on a Buchi- 510 melting point apparatus. The
percentages of carbon, hydrogen, nitrogen were determined by using a Perkin-Elmer CHN
analyzer at 240C. Rhodium was determined calorimetrically by treating with 2-mercapto-
benzoxazole [48]. The IR spectra were recorded in KBr pellets on a Perkin Elmer-283
spectrophotometer. Brucker WH 300 (200 MHz) and Brucker WH 270 (67.93 MHz)
1
13
spectrometers were used for H NMR and C NMR measurements. ESI and MALDI MS were
used to obtain mass spectra. UV-Visible spectra were recorded with Shimadzu UV-160A double
beam spectrophotometer with matched quartz cells of path length of 1 cm. Conductance
-
3
measurements were done on 10 M solution of compounds in dichloromethane at room
temperature using Digisun Digital conductivity meter model DL-909. Gouy balance calibrated
4
with Hg[Co(NCS) ] was used for the determination of magnetic susceptibilities of complexes in
solid state at room temperature. The solvents were dried by standard procedures, distilled and
stored over molecular sieves. The purity of the compounds was checked by TLC using Merck
6
0F254 silica gel plates.
2
.2. Typical procedure for preparation of macrocyclic Rh(I) complexes
2
A methanolic solution of [Rh(COD)Cl] (1.47 g, 0.003 mol.) was added to the solution of
ML component (0.003 mol.) in methanol and the solution was stirred magnetically for about 2h.
The solution became thick in due course of the reaction. Then, solution volume was reduced to

half of its original volume and 15 ml diethyl ether was added drop-wise to initiate the
crystallization of the product. It was filtered and washed with ether to give pure crystalline solid,
which was dried under vacuo. Synthetic route of macrocyclic Rh(I) complexes are shown in
Scheme 1
2
.3. Drug solution and Reagents
Letrozole solution (200 µg/ml) was prepared by dissolving 20 mg of pure LTZ in 100 ml
of double distilled water. 0.1 N NaOH solution (Merck) was prepared by dissolving 4 g in 1000
ml of double distilled water. Ferric chloride solution (Sd-Fine, 0.2 M) was prepared by
dissolving 5.40 g in 0.1 M hydrochloric acid solution.
2
.4. Hydrolysis of Letrozole
In a 100 ml round bottom (RB) flask, 3 ml of LTZ solution (200 µg/ml), 3 ml of NaOH
and [Rh(HBACHD)]Cl (Comp.1, 0.02 mmol) were taken and refluxed for 15 min. The contents
of RB flask were cooled for 10 min and transferred to 20 ml calibrated tubes. Now, 5 ml of ferric
chloride was added to each tube and the total volumes were made up to 20 ml with double
distilled water and kept aside for 5 min. The absorbance of the yellow colored solutions was
measured at 380 nm against a similar reagent blank (Fig. S1). The amount of HLTZ was assayed
from the calibration curve (Fig. S1). The procedure was repeated by changing the rhodium
catalysts.
Insert Scheme 1
3
. Results and Discussion
In the present investigations, ten new tetra coordinated Schiff base macrocyclic Rh(I)
2
complexes were synthesized by treating [Rh(COD)Cl] with the ten MLs separately (see Scheme

1
). The percentages of carbon, hydrogen and nitrogen were determined experimentally using
CHN analyzer. The percentage of rhodium in these macrocyclic Rh(I) complexes were
determined by literature method [49]. The physical and analytical data (Table 1) for the newly
synthesized macrocyclic Rh(I) complexes is in good agreement with the proposed molecular
formulae viz. [Rh(I)(L)]Cl (where L= tetra dentate macrocyclic ligand).
Insert Table 1
3
.1. Infrared spectral analysis
The infrared spectra of the MLs are compared with the macrocyclic Rh(I) complexes to
elucidate the binding mode of the MLs to Rh(I) ion. In the IR spectra of the MLs, a medium
-
1
intensity υC=N band was observed in the range of 1630-1608 cm [10]. This band was shifted
-1
-1
towards lower side about 19-38 cm which was in the range of 1601-1573 cm [15, 16] in case
of macrocyclic Rh(I) complexes. This supports the fact that the MLs coordinate to the metal ions
through the nitrogen of the C=N group in all the macrocyclic Rh(I) complexes. This fact is
-
1
further proved by the presence of a medium intensity band in the region of 502-537 cm
assignable to υM-N vibration [15, 16]. On the other hand, in MLs, υC-O-C band was observed in the
-1
-1
range of 1208-1141 cm [10, 47], which was shifted towards lower side about 19-43 cm and
-
1
found in the range of 1187-1116 cm [16] for corresponding macrocyclic Rh(I) complexes. This
supports the fact that the MLs coordinate to the metal ions through an oxygen of the C-O-C
group in addition to the nitrogens of the C=N group in these complexes. This is further
-1
confirmed by the appearance of a medium intensity band in the region of 432-408 cm
assignable to υM-O vibration [15, 16]. The characteristic bands due to pyridine υC=N and aromatic
stretching vibrations in the spectra of respective macrocyclic Rh(I) complexes were remain
almost upshifted (Table 2).

Insert Table 2
1
.2. H NMR spectral analysis
3
1
H NMR spectral comparison between MLs and Rh(I) complexes was made to confirm
1
the binding nature of MLs to Rh(I) ion. The integral intensities of each signal in the H NMR
spectra of ligands/Rh(I) complexes were found to agree with the number of different types of
protons present. In all the MLs signals corresponding to CH=N protons were observed in the
range of 8.02-8.83 δ [10, 47] and in the spectra of Rh(I) complexes these signals were observed
slightly in the down field regions of 8.15-8.98 δ confirming the coordination of nitrogen atom of
this group to Rh(I) ion. In the spectra of MLs (L5-10), a signal is appeared in the range of 3.90-
4
.37 δ corresponding to O-CH
complex this signal was observed with a little down field in the range of 3.97-4.42 δ. The above
fact supports the coordination of these MLs through an oxygen atom of O-CH group in addition
2
protons. However, in the spectra of the corresponding Rh(I)
2
to the nitrogen atom of CH=N group. There is no major change in the peak positions
corresponding to aromatic protons.
1
3C
3
.3.
NMR spectral analysis
1
The C NMR spectra of all the MLs contain signals in the range of 150.4-179.0 δ due to
3
the presence of carbon which is doubly bonded to nitrogen [10]. Though, in the spectra of Rh(I)
complexes, an up field shift in peak position was observed in the range of 156.3-178.6 δ. This
fact confirms that all the MLs coordinate by the nitrogen atoms. However, the MLs L5-10
contain peaks in the range of 60.0-67.4 δ corresponding to carbon atoms adjacent to oxygens.
This range was shifted to up field region to 61.8-72.1 δ in the Rh(I) complexes, representing the
2
coordination of the oxygen atoms of O-CH group to Rh(I) ion in addition to the two nitrogen
atoms of CH=N group[14, 26, 27]. Significant changes in peak positions were not observed with

1
respect to aryl carbons and carbons adjacent to ring nitrogen atom [28]. The specific H peak
1
positions of selected protons and C peak positions of carbon atoms of all the macrocyclic Rh(I)
3
complexes are given in Table 3.
Insert Table 3
3
.4. Molar conductance, magnetic properties, electronic and thermal data
-
3
The molar conductance values for all the Rh(I) complexes (10 M) were determined in
-1
2
-1
DCM. These values were found between 36.2-52.7 ohm cm mol signifying 1:1 electrolytic
nature (see Table 1). The electrolytic nature of the complexes is owing to the presence of one
chloride ion outside the coordination sphere [50]. This was confirmed by the addition of AgNO
3
reagent leading to the formation of a white precipitate [26]. The magnetic susceptibility
measurements have been carried out by a Gouy balance for Rh(I) complexes and were found to
be diamagnetic and hence, Rh(I) ion is in the low spin configuration. The diamagnetic nature of
1
complexes was further confirmed by the sharp, well-defined signals in the H NMR spectra. The
electronic spectra recorded for all the Rh(I) complexes in acetone exhibited mainly two bands of
comparable intensity in the range of 520-240 nm (see Table 1). The bands in the visible region
may be assigned to metal-ligand charge-transfer transaction [51]. Whereas the bands observed in
the UV region are assigned to intra-ligand transitions. No d-d transitions were detected. The
Rh(I) species are a strong reducing in character that their d-d transitions are usually obscured by
charge-transfer transitions. The thermograms of TGA and DTA of Rh(I) complexes with all the
o
MLs exhibit decomposition in only one stages around 250 C, corresponding to the loss of
organic moiety, demonstrating that, there are no water molecules of both types (lattice
held/coordinated) in all the complexes[26]. The nonexistence of water molecules in the Rh(I)
complexes were further evidenced by their DTA curves which contain only one exothermic peak

o
in the temperature range around 250 C corresponding to the loss of organic moiety. Above 540
o
C, the organic moieties in Rh(I) complexes were decomposed leading to the formation of their
oxide.
3
.5. Mass spectral analysis
The molecular ion peaks of Rh(I) complexes shows different m/z values with different
+
intensities. The mass spectra contain molecular ion peaks at m/z 454 (M , Comp.1), 573
+
M +Na, Comp. 2), 552 (M , Comp.3), 650 (M , Comp.4), 503 (M +Na, Comp.5), 494 (M ,
+
+
+
+
(
+
Comp.6), 482 (M , Comp.7), 496 (M , Comp.8), 580 (M , Comp.9), and 594 (M , Comp.10).
+
+
+
This data is in good agreement with the corresponding molecular formulae.
4
. Drug catalysis
Letrozole (LTZ), chemically known as 4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]
benzonitrile is an oral non-steroidal aromatase inhibitor that has been introduced for the adjuvant
treatment of hormonally-responsive breast cancer [52]. It contains two Nitrile groups and able to
produce carboxylic acid derivative by hydrolysis.
4
.1. Hydrolysis of Letrozole
Hydrolysis of Nitrile compounds is an area of great synthetic significance for the
preparation of amides and carboxylic acids in view of the industrial applications and
pharmacological interest of both the classes of these compounds. However, amides can be
obtained by the selective hydrolysis of Nitrile compounds. Nitrile groups vary greatly in their
ease of hydrolysis depending on the substrates and conditions. Hence, in order to activate Nitrile
groups, strong inorganic acid or base and high temperatures are normally needed. Base catalyzed

reactions are generally preferred because these reactions are faster than the acid catalyzed
reactions and the application of strong acidic solutions requires a careful control of the
temperature due to the exothermic behavior. Pombeiro et. al. reviewed metal mediated and metal
catalyzed hydrolysis of nitriles [53]. Wang reported the enantioselective biotransformations of
nitriles in organic synthesis [54]. One of the main goal of the present studies is the hydrolysis of
Nitrile group containing Letrozole by Rh (I) catalysts to prepare its hydrolysis derivatives, which
can be considered as a potential impurity of LTZ. The percent yield of hydrolyzed Letrozole
(
HLTZ) was determined spectrophotometrically [55] using acidified ferric chloride reagent.
.2. Optimum conditions
The hydrolysis of LTZ was investigated by using [Rh(HBACHD)]Cl (Comp.1) by
4
optimizing the volume of sodium hydroxide. Three mL of sodium hydroxide was found to be
adequate for the hydrolysis of LTZ, below which the percent yield of HLTZ was low and above
it was constant. To investigate the optimum heating time for hydrolysis of LTZ, 3 ml of LTZ
solution was mixed with 3 mL of sodium hydroxide in the presence of rhodium catalyst and
heated in an interval of 5-120 min in a water bath at 70 °C. HLTZ was treated with acidified
ferric chloride. Maximum color intensity was obtained at 15 min heating time and remained
constant on further heating. Therefore, 15 min of heating time was maintained throughout the
experiment. 0.02 mmol of rhodium catalyst was found to be sufficient for the reaction. The
highest absorbance was obtained with 5 ml of acidified ferric chloride, which remain unchanged
with higher volume. The λmax value of the colored product was found to be 380 nm and was up
to 30 min at room temperature (Figure S1). Similar tendencies were observed with the remaining
nine Rh(I) complexes.
4
.3. Product analysis

-
1
The IR spectrum of LTZ shows a peak around 2200 cm due to the stretching of C≡N
-
1
group. It does not show any signals around 1700 cm corresponding to the carbonyl stretching
-
1
vibrations of acid group. The disappearance of a peak around 2200 cm and the appearance of a
-
1
new peak at 1724 cm in HLTZ are indicating the hydrolysis of a Cyano group of LTZ to the
1
carboxylic acid group (Figure S2). The H NMR spectrum of LTZ doesn’t contain any peak
above 9.0δ. But in the spectrum of HLTZ a peak is appears at 10.07 (corresponding to the –
COOH proton confirming the hydrolysis of a Nitrile group of LTZ to its acid derivative (Figure
1
3
S3). The C-NMR spectrum of LTZ shows a peak at 118 (corresponding to the carbon belonging
to Nitrile group. But, in the spectrum of HLTZ, this peak was not appeared. Instead of this, a
new peak appeared at 176.3 δ belonging to carboxylic acid carbon indicating the conversion of -
CN group to COOH group (Figure S4). The mass spectrum of HLTZ was shown molecular ion
+
peak at a m/z value of 324.5 (M ).
4
.4. Mechanism of catalytic cycle
A probable mechanism has been proposed for Rh(I) catalyzed hydrolysis of LTZ
(
Scheme S1) in the presence of sodium hydroxide. Initially, two hydroxyl ions attack the two
Nitrile carbons of LTZ, which in turn hydrolyses to produce carboxylic acid groups with the
release of two ammonia gas molecules. Now, two hydroxyl ions from two water molecule
attacks the two catalyst molecules, replace two chlorine atoms which in turn combine with two
sodium ions and forms two sodium chloride molecules. The regeneration of Rh(I) catalyst takes
places finally by the addition of two hydrochloric acid.
Insert Scheme 2 and 3
4
.5. Chemistry of colored species

The Nitrile groups in LTZ are hydrolyzed with Rh(I) catalysts leading to the formation of
carboxylic acid groups. These groups react with ferric chloride and form a yellow colored
product (Scheme S2). The percent yields of HLTZ with all the ten macrocyclic Rh(I) complexes
were determined spectrophotometrically (Table 4).
Insert Table 4
5
. Conclusions
2
Macrocyclic Rh(I) complexes were synthesized by treating [Rh(COD)Cl] precursor with
the ten MLs separately. In all Rh(I) complexes the MLs L1-L4 coordinate through four nitrogen
atoms of C=N group, and the MLs L5-L10 coordinates through two nitrogen atoms of C=N
2
group and two oxygen atoms of O-CH group to Rh(I) ion. These compounds were found to have
mono-electrolytic nature. Square-planar structures were assigned to these complexes based on
elemental and spectral data. All these Rh(I) catalysts were applied for the catalytic hydrolysis of
LTZ. The catalytic procedure involves mild reaction condition and easy to work-up. The
spectrophotometric determination method is simple and the chemistry involved in this is
familiar. Hence, this approach can be effectively used for the hydrolysis of APIs containing
Nitrile group to produce their impurities with carboxylic acid groups.
Acknowledgments
The authors thank the University Grant Commission (UGC, F. No. 34-363/2008(SR)), New
Delhi, India for financially supporting this research.
Electronic supporting information is available

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X
NH2
NH2
NH2
OH
CHO
CHO
or
+
Y
MeOH:H O (1:1) CH COONa
2
3
X
X
Y
Y
N
N
N
N
N
N
OH
OH
Y= -C H -; Z= -(CH ) - for HBOACTD
6
Y= -C H -; Z= -(CH ) - for HBOACPD
4
2 2
6
Y= -C H N-; Z= -(CH ) - for HBPOACTD
4
2 3
5
3
2 2
Z
Y= -C H N-; Z= -(CH ) - for HBPOACPD
5 3 2 3
Y= -C10H -; Z= -(CH ) - for HBNOACTD
Y= -C10H -; Z= -(CH ) - for HBNOACPD
6 2 3
MeOH
NaOH
Br
Br
6
2 2
X= -CH -CH for HBACHD
2
X= -C H - for BACHD
2
6
X= -C H N- for BPACHD
4
5
X= -C10H - for BNACOD
3
Y
6
O
O
N
N
Z
Y
X
X
N
N
N
N
N
N
N
N
Cl
Rh
X
X
[
Rh(COD)Cl]2
or
Y
MeOH
Y
N
O
O
O
Rh
Z Cl
N
Z
N
N
O
Y
Y
4 2 2
Scheme 1. Synthetic route of N and N O donor macrocyclic ligands and their Rh(I) metal
complexes

Table1
Analytical and electronic spectral data of macrocyclic Rh(I) complexes
Comp. Mac. Rh(I) complex/
No.
λmax (nm)
512, 254
510, 240
520, 290
483, 269
512, 282
490, 247
517, 280
491, 260
504, 272
482, 265
Λ
M
Analyses (%) Found (Calculated)
Molecular formula
C
H
N
Rh
1.
2.
3.
4.
5.
6.
7.
8.
9.
[Rh(HBACHD)]Cl
51.0
48.5
43.6
50.1
38.8
47.3
39.1
52.7
36.2
45.9
52.47
4.51
12.40
22.67
C
20
H
20ClN
20ClN
18ClN
24ClN
18ClN
20ClN
16ClN
18ClN
22ClN
24ClN
4
Rh
[Rh(BACHD)]Cl
Rh
[Rh(BPACHD)]Cl
Rh
[Rh(BNACOD)]Cl
Rh
[Rh(HBOACTD)]Cl
Rh
[Rh(HBOACPD)]Cl
Rh
[Rh(HBPOACTD)]Cl
Rh
[Rh(HBPOACPD)]Cl
Rh
[Rh(HBNOACTD)]Cl
Rh
[Rh(HBNOACPD)]Cl
Rh
(52.82) (4.43) (12.32) (22.63)
60.96 3.72 10.12 18.73
(61.05) (3.66) (10.17) (18.68)
56.23 3.37 15.29 18.53
(56.49) (3.28) (15.20) (18.61)
66.59 3.61 8.78 15.92
(66.42) (3.72) (8.61) (15.81)
55.07 3.81 5.70 21.38
(54.96) (3.77) (5.83) (21.41)
55.89 3.98 5.60 20.92
(55.83) (4.07) (5.66) (20.80)
49.83 3.21 11.77 21.20
(49.76) (3.34) (11.61) (21.32)
50.87 3.72 11.12 20.64
(50.77) (3.65) (11.28) (20.72)
61.93 3.74 4.97 17.83
(62.03) (3.82) (4.82) (17.72)
62.62 3.94 4.83 17.52
(62.59) (4.07) (4.71) (17.30)
C
28
H
4
C
26
H
6
C
36
H
4
C
22
H
2 2
O
C
23
H
2 2
O
C
20
H
4 2
O
C
21
H
4 2
O
C
30
H
2 2
O
1
0.
C
31
H
2 2
O

Table 2
Infrared spectral data of macrocyclic Rh(I) complexes
-1
Selected IR bands (cm )
Comp.
No.
Mac. Rh(I) complexes
υ
C=N
υ
C-O-C
υ
Rh-N
υ
Rh-O
1
2
3
4
5
6
.
.
.
.
.
.
[Rh(HBACHD)]Cl
[Rh(BACHD)]Cl
1586
1591
1600
1578
1593
1582
1593
-
-
-
-
523
510
537
529
502
525
518
-
-
-
-
[Rh(BPACHD)]Cl
[Rh(BNACOD)]Cl
[Rh(HBOACTD)]Cl
[Rh(HBOACPD)]Cl
1116
1152
1163
1181
1139
1187
414
408
427
432
418
430
7
8
9
.
.
.
[Rh(HBPOACTD)]Cl
[Rh(HBPOACPD)]Cl
[Rh(HBNOACTD)]Cl
[Rh(HBNOACPD)]Cl
1601
1573
509
518
532
1
0.
1
589

Table 3
1
13
H NMR and C NMR spectral data of Rh(I) complexes
1
13
Comp. Mac. Rh(I) complex
No.
H NMR peak position
C NMR peak position
(δ ppm)
(δ ppm)
1
2
3
.
.
.
[Rh(HBACHD)]Cl
[Rh(BACHD)]Cl
[Rh(BPACHD)]Cl
3.74 (8H, s, CH
2
-CH
2 2 2
), 6.91- 52.5 (4C, CH -CH ), 129.0,
7
s, CH=N)
.53 (8H, m, Ar-H), 8.15 (4H, 134.3, 136.6 (12C, Ar-C), 167.5
(4C, CH=N)
6.78-7.49 (16H, m, Ar-H), 123.4, 128.0, 132.0, 133.4,
.51 (4H, s, CH=N) 137.0, 142.1 (24C, Ar-C), 160.4
4C, CH=N)
6.32-7.52 (12H, m, Ar-H), 119.3, 131.7, 133.1, 133.5,
.22 (2H, s, CH=N in 137.8, 137.9, 145.4, 155.4
8
(
8
pyridine), 8.84 (4H, s, CH=N) (20C, Ar-C) 170.6 (2H, Ar-
CH=N), 171.1 (4C, CH=N)
7.00-8.03 (20H, m. Ar-H), 121.5, 129.3, 130.2, 132.0,
4
5
.
.
[Rh(BNACOD)]Cl
[Rh(HBOACTD)]Cl
8
.98 (4H, s, CH=N)
133.4, 135.3, 137.4, 137.9 (32C,
Ar-C), 162.1 (4C, CH=N)
), 6.60- 69.8 (2C, O-CH -
CH -O), 110.3,
2
2 2
4.29 (4H, s, O–CH
.83 (12H, m, Ar-H), 8.64
7
1
1
28.2, 129.4, 133.0, 138.1,
53.6 (18C, Ar-C), 175.0 (2C,
(
2H, s, CH=N)
CH=N)
–C), 30.4 (1C, C-CH -C), 72.1 (2C,
2
6
.
[Rh(HBOACPD)]Cl
2.31-2.52 (2H, m, C–CH
2
3
7
.97 (4H, t, O–CH
2
), 6.78-
O-CH ), 127.2, 128.0, 129.5,
2
.82 (12H, m, Ar-H), 8.64
1
38.8, 151.7 (18C, Ar-C), 158.0
2C, CH=N)
), 6.02- 67.3 (2C, O-CH
.04 (8H, m, Ar-H), 7.78 (2H, 133.0, 136.6, 142.0, 143.2 (16C,
s, CH=N in pyridine ), 8.88 Ar-C), 151.5 (2C, Ar-CH=N),
2H, s, CH=N) 176.4 (2C, CH=N)
[Rh(HBPOACPD)]Cl 2.20-2.31 (2H, m, C–CH –C), 30.4 (1C, C-CH -C), 62.3 (2C,
.98 (4H, t, O–CH ), 7.81 O-CH ), 122.5, 123.4, 133.8,
2H, s, CH=N in pyridine), 142.2(16C, Ar-C), 155.7 (2C,
.42-7.41 (8H, m, Ar-H), 8.74 Ar-CH=N), 178.6 (2C, CH=N)
2H, s, CH=N)
[Rh(HBNOACTD)]Cl 4.42 (4H, s, O–CH
.54 (16H, m, Ar-H), 8.54 125.7, 126.2, 127.0, 133.3,
2H, s, CH=N) 134.0, 140.5, 150.1 (26C, Ar-C),
74.8 (2C, CH=N)
–C), 30.5 (1C, C-CH -C), 61.8 (2C,
), 125.7, 126.0, 126.0,
.92 (16H, m Ar-H), 8.58 126.7, 133.6, 148.1 (26C, Ar-C),
156.3 (2C, CH=N)
(
2H, s, CH=N)
(
7
8
.
.
[Rh(HBPOACTD)]Cl 4.15 (4H, s, O–CH
2
2
), 119.7, 121.2,
7
(
2
2
3
2
2
(
6
(
9
.
2 2
), 7.01- 68.2 (2C, O-CH ), 109.5, 124.1,
7
(
1
1
0.
[Rh(HBNOACPD)]Cl 2.30-2.41 (2H, m, C–CH
2
2
3
7
2 2
.99 (4H, t, O–CH ), 7.21- O-CH
(
2H, s, CH=N)

Table-4
Percent yields of HLTZ formed with macrocyclic Rh(I) complexes
Comp. No. Macrocyclic Rh(I) Complex
Yield(%)
1
2
3
4
5
6
7
8
9
.
.
.
.
.
.
.
.
.
[Rh(HBACHD)]Cl
[Rh(BACHD)]Cl
96.66
89.24
91.00
90.37
97.43
88.50
89.31
92.22
94.06
93.98
[Rh(BPACHD)]Cl
[Rh(BNACOD)]Cl
[Rh(HBOACTD)]Cl
[Rh(HBOACPD)]Cl
[Rh(HBPOACTD)]Cl
[Rh(HBPOACPD)]Cl
[Rh(HBNOACTD)]Cl
[Rh(HBNOACPD)]Cl
1
0.

Graphical Abstract
X
X
N
N
N
N
N
N
N
N
Cl
Rh
X
X
[Rh(COD)Cl]2
or
Y
Y
N
N
O
O
Cl
Z
O
O
Rh
N
N
Z
Y
Y

Highlights
ꢀ
ꢀ
Mononuclear Rhodium (I) complexes with macrocyclic ligands having N
4 2 2
and N O
donor sites were reported
Investigated as effective catalysts in hydrolysis of Nitrile group containing
pharmaceutical drug Letrozole
ꢀ
ꢀ
Catalytic procedure involves mild reaction condition and easy to work-up
This approach can be effectively used for the hydrolysis of Nitrile group containing APIs.