1

Synthesis and Spectroscopic Analysis

Of Hydroxamic Acid Ligands and their Complexes.

by

Saif Ullah

Program of Study: M.Phill

Supervisor: Dr. Naqeebullah

Co-Supervisor: Dr. Samiullah

Department of Chemistry
University of Balochistan
Session: 2017-2019
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Background
Hydroxamic acids are a special class of organic compounds that are naturally occurring or
synthetic. They are weak organic acids and generally hydrophilic organic compounds.
They have many important applications in industries and as well as in human life. These
acids react with variety of transition metals to form complexes which have wide spread
applications. Complexes of hydroxamic acids with transition metals have got
considerable attention because of their extensive applications. These acids are an
important and major class of organic compounds having a wide variety of
pharmacological actions in targeting cancers, Alzheimer’s disease, asthama,
inflammation, arthritis, cardiovascular diseases, HIV, Malaria, Allergic diseases ( EMF
Muri et al., 2002). Due to the fatal side effects of drugs and appearance of drug resistance
in pathogens, there is a need to synthesize new compound with fewer side effects and
greater activity. Due to the facile synthesis and wide applications of hydroxamic acid
complexes, we are interested to synthesize hydroxamic acid ligands, their metal
complexes and explore their in-vitro biological activity. The characterization of transition
metal complexes of hydroxamic acid ligands will be done by spectroscopic techniques.
Antibacterial and antifungal activities of the synthesized compound will also be assayed
(ACC Aguiar et al., 2012).
Objectives
1. To prepare hydroxamic acids and their metal complexes.
2. To characterize the ligand and its metal complexes via spectroscopic techniques.
3. To evaluate biological activities of synthesized ligand and its metal complexes.
1. Introduction
Hydroxamic acids are known as naturally occurring or synthetic weak organic acids and
can produce hydroxamate ion easily (S Sathiyavasan et al., 2017). These compounds
contain oxime (–N–OH) and the carbonyl (C=O) groups as well as shown in Figure 1.
They are generally synthesized by the reaction of hydroxylamine with acid chlorides or
esters (Y Farina et al., 2013).
Hydroxamic acids are organic compounds which have hydrophilic nature. The
deprotonation could be either from nitrogen or from oxygen atom, resulting in N-acids or
O-acids. These ligands are bidentate and form complexes with metals via both oxygen
donor sites (Codd, 2008). The most versatile and important application of N-
Oxidobenzamide is acting as good metal ion chelators (S Sathiyavasan et al., 2017).
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These acids and their byproducts contain multiple important properties and have got
especial attention in several research areas of chemistry. (Pavia, et al., 2007).
R'

R N H
O

O
Figure 1.The structure of Hydroxamic acid

These acids are generally represented by the following formula RCONHOH. The
hydroxamic acids are simply derived by substituting the Cl of carboxylic acid salts by
RNHOH. These compounds contain oxime N-OH and carbonyl group as shown in the
following Figure 2.
R O R OH

N N
H OH OH

(a) (b)
Figure 2. Keto and enol forms of hydroxamic acids
RC (O) NHOH (Hydroxamic acids) have found a very important class of organic
compounds in the recent era which can play a vast role in biology, medicine and in many
other fields. They show enzyme-inhibitory properties (Marmion, et al., 2004).These acids
have the capability of hindering the growth of multiple biocatalysts such as ureases
matrix metalloprotienase and peroxidases. For the treatment of many diseases, varieties of
hydroxmate derivatives are used. These acids play an important role in pharmaceutical,
analytical and industrial fields.
Major biological utilization of hydroxamic acids is their ability of forming stable metal
complexes (Marmion, et al., 2004; Codd, 2008), and possibly their NO-releasing
properties. (Murphy, et al., 2000). In addition, the hydroxamic acids (RCOHNO−) can
form salts with proteins in deprotonated form. Whereas in neutral (RCOHNOH) form,
they may involve in a versatile hydrogen-bonding interactions (Marmion, et al., 2004;
Beissel, et al., 1999).
The discovery of cisplatin has led to the clinical application of chemotherapeutic agent
for cancer treatment. Synthesis of transition metal complexes based drugs, is not an easy
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task, it needs extensive efforts. In spite of their side effects, we still use such complexes
as chemotherapeutic agent.
One of main role of hydroxamic acids is their utilization as siderophores. Typically,
hydroxamic acids form complex with Fe (III) in a bidentate way in order to form metal
chelates with particularly very good and high formation constants.
2. Literature Review
Saranya Sathiyavasan et al., 2017, revealed via the study of spectral electronic and
melting point examination that the metal center is connected with ligands through O, O
donor positions. IR analysis confirms the coordination of hydroxamate ions in the metal
center as O, O-bidentate mode through carbonyl oxygen and hydroxyl oxygen atoms of
the ligand.

K.P Srivastava et al., 2009, studied that the ligand acids α mercaptobenzaceto-
hydroxammico (MBAHA-H) and 2-amino-α-mercaptobenzacetohydroxamic acid
(AMBAHA-H) and its some new complexes of diverse ligands with Co (III) having
precise formulas have been prepared and also analyzed by elemental analysis, and
magnetic moments, conductivity measurements, electronic and IR spectral studies.

Swetlana Gez et al., 2005, studied that the reactions of Cr (VI) complexes with different
hydroxamic acids in aprotic polar solvents that leads to relatively stable Cr(V)
intermediate hydroxylates, which denotes a new family of compounds Cr(V). In above
mentioned reactions, hydroxamic acids act as reducing ligands.

Yang Farina et al., 2013, prepared a new ligand and its diorganotin(IV) hydroxamates,
that gave very précised melting points indicating that the compounds were pure and
characterized successfully via elemental analyses, IR, NMR techniques etc.

P. Nenortiene et al., 2002, studied that the hydroxamic acids are common in plant tissues,
also in fungi and bacteria metabolites, consisting complex compounds with metal ions.
These acids have a very vast spectrum of biological activity and are very important
potential reagents for the analysis of chemical elements.

Natalija Usachova et al., 2010, has shown the activation of carboxylic acids with N, N'-
carbonyldiimidazole that is followed by aqueous hydroxylamine hydrochloride. The
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reaction is a simple method to be used for the preparation of hydroxamic acids with very
good yield and great purity after aqueous treatment.

3. Material and methods

i) Synthesis of Hydroxamate acid Ligands,
Many of hydroxamic acid and their various derivatives have been prepared by replacing
the hydrogen atom bonded with nitrogen atom or by simply changing the alkyl or aryl
groups. The deprotonated form of hydroxamic acids are known as hydroxamates. These
are found almost everywhere in nature and related to iron transport bacteria. These acids
have wide biological application such as, antifungal, antibacterial etc.
The hydroxamic acids ligands are generally prepared by reacting aryl or alkyl
hydroxylamine with salts of carboxylicacids in the presence of a base such as sodium by
carbonate (NaHCO)3 ((Hauser., 1939).

O
O

O
+ N-RHOH.HCl N H
Cl

Benzoyl chloride N-alkylhydroxylamine N-alkylbenzohydroxamic acid

hydrochloride

Figure 3. Synthesis of hydroxamic acid.

The above method is the simplest and easiest way to prepare hydroxamic acid.
Hydroxamic acids can also prepared by other methods such as from acid chlorides or
esters by a reaction with hydroxylamine salts. The following equation shows the synthesis
of benzohydroxamic acid (Hauser.,1939).
C6H5CO2Me + NH2OH → C6H5C (O) NHOH + MeOH
ii) Synthesis of metal complexes of hydroxamic acid
Hydroxamic acids, RC(O)NHOHcoordinate with different type of transition metal ions
mainly as the monoanionic hydroxamato or dianionic (RN= H) hydroximato O, O′-
bidentate chelates ( R Codd, 2008).
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Transition metal complexes of hydroxamic acid ligands are very important owing to their
various oxidation states and coordination modes. Such type of transition metal complexes
may be positively, negatively and neutral charged species that are coordinated by ligands.
These metal complexes show great variety in mode of action as compared to non-metals.
The hydroxamic acid reacts with different transition metal to form complexes (Maiti et
al., 2016). Various metal complexes are used as therapeutic agents as anti-inflammatory
and anti-infective agents. Metal complexes are also important in photochemistry and
biological systems.
The metal complexes of hydroxamic acids are generally prepared by ligand and a metal
atom treating transition metals salts in MeOH with equivalent amount of KOH. The
solution is simply stirred at room temperature for 15-20 minutes (Brown et al., 2006). The
solids of metal complexes of hydroxamic acid are usually purified with a suitable solvent.

O
N
O
O Reflux
N H + MCl2
O M O

R O
N

N-arylbenzohydroxamic acid Metal hydroxamate

Figure 4: Scheme for synthesis of metal complexes of hydroxamic acids

iii) Characterization
The characterization hydroxamic acid ligand with transition metal complexes will be
done by IR and NMR spectroscopic techniques.
iv) Biological activities
Antibacterial and antifungal activities of the prepared ligands and its metal complexes
will be analyzed by using methods available conveniently.
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4. References
i. Muri, E. M., Nieto, M. J., Sindelar, R. D., & Williamson, J. S. (2002). Hydroxamic
acids as pharmacological agents. Current medicinal chemistry, 9(17), 1631-1653.
ii. Aguiar, A. C. C., da Rocha, E. M., de Souza, N. B., França, T. C., & Krettli, A. U.
(2012). New approaches in antimalarial drug discovery and development: a
review. Memorias do Instituto Oswaldo Cruz, 107(7), 831-845.
iii. Sathiyavasan, S., Sithambaresan, M., Gunasingham, P., & Srikaran, R. (2017).
Synthesis and Spectroscopic Analysis of the Nature of Coordination Modes of Ligands in
Copper (ll) and Cadmium (ll) Complexes of Two N-Oxidobenzamide Derivatives.
International Journal of Science, Technology and Society, 5(5), 179..
iv. Farina, Y., Chan, K. M., Mun, L. K., Rajab, N. F., & Ooi, T. C. (2013). Diorganotin
(IV) Derivatives of N-Methyl p-Fluorobenzo-Hydroxamic Acid: Preparation, Spectral
Characterization, X-ray Diffraction Studies and Antitumor Activity. Molecules, 18(7),
8696-8711.
v. Codd, R. (2008). Traversing the coordination chemistry and chemical biology of
hydroxamic acids. Coordination Chemistry Reviews, 252(12-14), 1387-1408..
vi. Marmion, C. J., Griffith, D., & Nolan, K. B. (2004). Hydroxamic Acids− An
Intriguing Family of Enzyme Inhibitors and Biomedical Ligands. European Journal of
Inorganic Chemistry, 2004(15), 3003-3016.
vii. Codd, R. (2008). Traversing the coordination chemistry and chemical biology of
hydroxamic acids. Coordination Chemistry Reviews, 252(12-14), 1387-1408.
viii. Marmion, C. J., Murphy, T., Docherty, J. R., & Nolan, K. B. (2000). Hydroxamic
acids are nitric oxide donors. Facile formation of ruthenium (II)-nitrosyls and NO-
mediated activation of guanylate cyclase by hydroxamic acids. Chemical
Communications, (13), 1153-1154.
ix. Griffith, D., Lyssenko, K., Jensen, P., Kruger, P. E., & Marmion, C. J. (2005). Novel
platinum (II) ammine hydroxamate and hydroximate complexes and the platinum-assisted
hydrolysis of hydroxamic acids. Dalton Transactions, (5), 956-961..
x. Hariprasath, K., Deepthi, B., Babu, I. S., Venkatesh, P., Sharfudeen, S., & Soumya,
V. (2010). Journal of Chemical and Pharmaceutical Research. J. Chem, 2(4), 496-499.
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xi. Nwabueze, J. N. (1996). Complexes of iron (III) with cyclopropanecarbo-and

cyclohexyl-acetohydroxamic acids. Transition Metal Chemistry, 21(3), 258-261.
xii. Sarina, E. A., Olmstead, M. M., Nguyen, D. N., & Groziak, M. P. (2013). 1-Hydroxy-
1H-benzo [d][1, 2, 6] oxazaborinin-4 (3H)-one. Acta Crystallographica Section C:
Crystal Structure Communications, 69(2), 183-185.
xiii. Beissel, T., Powers, R. E., Parac, T. N., & Raymond, K. N. (1999). Dynamic
Isomerization of a Supramolecular Tetrahedral M4L6 Cluster1. Journal of the American
Chemical Society, 121(17), 4200-4206.
xiv. Sathiyavasan, S., Sithambaresan, M., Gunasingham, P., & Srikaran, R. (2017).
Synthesis and Spectroscopic Analysis of the Nature of Coordination Modes of Ligands in
Copper (ll) and Cadmium (ll) Complexes of Two N-Oxidobenzamide
Derivatives. International Journal of Science, Technology and Society, 5(5), 179.
xv. Srivastava, K. P., Singh, B., & Akbar, A. (2009). Synthesis and Characterisation of
Co II Complexes of Dibasic Tetradentate (OO’NO donor) Ligand. International Journal
of ChemTech Research, 1(1), 71-79.
xvi. Gez, S., Luxenhofer, R., Levina, A., Codd, R., & Lay, P. A. (2005). Chromium (V)
complexes of hydroxamic acids: formation, structures, and reactivities. Inorganic
chemistry, 44(8), 2934-2943.
xvii. Kakkar, R. (2013). Theoretical Studies on Hydroxamic Acids. In Hydroxamic
Acids (pp. 19-53). Springer, Berlin, Heidelberg.
xviii. Farina, Y., Chan, K. M., Mun, L. K., Rajab, N. F., & Ooi, T. C. (2013). Diorganotin
(IV) Derivatives of N-Methyl p-Fluorobenzo-Hydroxamic Acid: Preparation, Spectral
Characterization, X-ray Diffraction Studies and Antitumor Activity. Molecules, 18(7),
8696-8711.
xix. Nenortiene, P., Sapragoniene, M., & Stankevicius, A. (2002). Synthesis of
hydroxamic acids and study of their complexes with iron (II) and (III) ions. Medicina
(Kaunas, Lithuania), 38(7), 744-751.
xx. Yang, K. H. (2014). Synthesis, crystal structures, and catalytic oxidation properties of
oxidovanadium (V) complexes with Schiff base ligands. Transition Metal
Chemistry, 39(4), 469-475.
xxi. Usachova, N., Leitis, G., Jirgensons, A., & Kalvinsh, I. (2010). Synthesis of
hydroxamic acids by activation of carboxylic acids with N, N′-carbonyldiimidazole:
exploring the efficiency of the method. Synthetic Communications®, 40(6), 927-935.
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xxii. Bright, R. D., & Hauser, C. R. (1939). The influence of substituents on the rates of
decomposition of the potassium salts of dihydroxamic acids. The Lossen
rearrangement. Journal of the American Chemical Society, 61(3), 618-629.
xxiii. Sarina, E. A., Olmstead, M. M., Nguyen, D. N., & Groziak, M. P. (2013). 1-Hydroxy-
1H-benzo [d][1, 2, 6] oxazaborinin-4 (3H)-one. Acta Crystallographica Section C:
Crystal Structure Communications, 69(2), 183-185..
xxiv. Maiti, S. K., Malik, K. A., Gupta, S., Chakraborty, S., Ganguli, A. K., Mukherjee, A.
K., & Bhattacharyya, R. (2006). Oxo-and oxoperoxo-molybdenum (VI) complexes with
aryl hydroxamates: Synthesis, structure, and catalytic uses in highly efficient, selective,
and ecologically benign peroxidic epoxidation of olefins. Inorganic chemistry, 45(24),
9843-9857.
xxv. Farkas, E., Bátka, D., Csapó, E., Buglyó, P., Haase, W., & Sanna, D. (2007).
Synthesis and characterization of Cu2+, Ni2+ and Zn2+ binding capability of some
amino-and imidazole hydroxamic acids: Effects of substitution of side chain amino-N for
imidazole-N or hydroxamic-NH for-N-CH3 on metal complexation. Polyhedron, 26(3),
543-554.
xxvi. Brown, D. A., Fitzpatrick, N. J., Müller-Bunz, H., & Ryan, Á. T. (2006). Di-, tri-, and
tetranuclear zinc hydroxamate complexes as structural models for the inhibition of zinc
hydrolases by hydroxamic acids. Inorganic chemistry, 45(11), 4497-4507.