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Home , Metal carbonyl, Molybdenum hexacarbonyl

CSJ 8(1): June, 2017 ISSN: 2276 – 707X Abubakar and Eke ChemSearch Journal 8(1): 29 – 33, June, 2017

Publication of Chemical Society of Nigeria, Kano Chapter

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R M Received: 10/02/2017 Accepted: 17/03/2017 E I C.S.N G C I A N http://dx.doi.org/10.4314/csj.v8i1.4 L F SO Y O CIET

Trimethylamine N-oxide Promoted Reactions of and Hexacarbonyls with Dimethylglyoxime

1*Abubakar A. T. and 2Eke U. B. 1Department of Chemistry, Sule Lamido University, Kafin Hausa, P. M. B. 048, K/Hausa, Nigeria. 2Department of Chemistry, University of Ilorin, P. M. B. 1515, Ilorin, Nigeria. Email: [email protected], [email protected]

ABSTRACT Decarbonylation of Mo and W hexacarbonyls in the presence of dimethylglyoxime was carried out under the control of trimethylamine N-oxide (TMNO). The two DMG substituted carbonyl complexes were prepared in a one pot synthesis using manipulated Schlenk techniques under dinitrogen in . The Mo complex system was successfully carried out by stirring the mixture of the molybdenum hexacarbonyl and DMG in tetrahydrofuran at room temperature for 18hrs. A similar procedure afforded the starting material for the W complex analogue. However, further refluxing for 6 h gave the desired W complex. The complexes were characterized using 1H NMR, IR, and CHN analyses. Results showed that the reactions produced analytically pure, mono-product dicarbonyl species; Mo(CO)2(DMG)2 I and W(CO)2(DMG)2 II where two DMG moieties were coordinated to the central metal atom through one N and O atoms respectively of each of the oxime groups.

Keywords: Bioorganometallic, , CO-RMs, Decarbonylation, Trimethylamine N-oxide

INTRODUCTION all come down to one and the same cellular target; Metal and metal containing compounds DNA seems most unlikely and organometallic are believed to be toxic in vivo because of their compounds do play vital roles in drug design and perceived interaction with biological substances, discovery (Gasser and Metzler-Nolte, 2012). hence organometallic compounds are rarely Preceding the period of the teaching considered as pharmaceutical agents (Gasser and paradigms that organometallics are unstable in air Metzler-Nolte, 2012). Generally, the development and water, they have played vital roles in biology. of metallodrugs have for a long time been Some organometallic compounds existed naturally hampered by their perceived undesired interactions as biomolecules, these include the cobalamines; with DNA and other biomolecules (Gasser and vitamin B12 and its derivatives (Gibaud and Jaouen, Metzler-Nolte, 2012). However, the discovery of 2010), the family (McGlynn, et al., the cancer drug, Cisplatin changed the fate of 2009) which catalyzes the useful process of the classical coordination compounds but reversible conversion of dihydrogen into protons bioorganometallic molecules continue to suffer and electrons in biological system. more due to the paradigm that ‘organometallics are Despite the issue of toxicity some unstable in air and water’ (Hartinger & Dyson, organometallics were used as drugs, the most 2009). popular being Paul Ehrlich’s Salversan and its Recent research findings, in several reviews; analogue, Neo-Salversan. They were the only have dealt comprehensively with founding remedy for syphilis at a time when syphilis ravaged principles and exciting medicinal applications like AIDS did at the present time (Gibaud and (Jaouen, 2006, Jaouen and Salmain, 2015, Jaouen Jaouen, 2010). For a very long time melasoprol, and Metzler-Nolte, 2010), challenges and prospects another organometallic drug remained the first-line in exploring organometallics as drug candidate treatment for patients with Trypanosoma brucei (Jaouen and Dyson, 2007, Metzler-Nolte, 2007) as gambiense trypanosomiasis and is still used in well as their roles in several novel pharmaceutical African countries even though it is toxic and screenings (Simonneaux, 2006, Fish and Jaouen, treatment result in the development of an extremely 2003). All of which have shown that certain severe reactive arsenic encephalopathy (RAE). The bioorganometallic compounds are stable in air and reality is; in the face of this unacceptable toxicity water and in some cases metals as well as their melasoprol will be in use as it is unlikely that any particular complexes have a diversity of chemical new drug will replace it anytime soon (Gasser and properties and hence ‘the notion that they should Metzler-Nolte, 2012, Gibaud and Jaouen, 2010) 29

CSJ 8(1): June, 2017 ISSN: 2276 – 707X Abubakar and Eke One particular class of organometallics that Purification of Tetrahydrofuran have caught the fancy of the Bioorganometallic The tetrahydrofuran (THF) tested negative Chemist is carbonyls. for peroxide when tested with chloride Appropriately substituted metal carbonyls have paper. The solvent was however passed through a been recognized as a potential drug candidate due column of activated silica gel. The silica gel was to its ability to slowly and systematically release predried in an oven at 100o C for 24 hours and monoxide (CO) molecule in biological thereafter allowed to cool to room temperature in a system, making it arguably the best class of the so desiccator before use. The solvent was then dried called CO-releasing molecules (CO-RMs) (Romao, by passing it over a column of the desiccant inside et al., 2012) the glove box (Armarego and Chai, 2003). There is Preclinical evidence that CO administration in animals have beneficial effects in PREPARATION OF SUBSTITUTED cardiovascular diseases, sepsis, shock, cancer, COMPLEXES acute lung, liver and kidney injury and etcetera Preparation of [Mo(CO)2(DMG)2] (I) (Nakatsu, et al, 2002, Abraham, et al, 2002, Wang, The preparation of the complexes by 2004). The technology for production and delivery decarbonylation of metal hexacarbonyls using (for inhalation) of pharmaceutical grade CO is TMNO as decarbonylating agent follow the method quite limited at the moment and only available in described in literature (Hor and Siti, 1988) with highly specialized hospitals. CO ingestion is minor modifications obviously challenging and can be carried out as pro In a one pot synthesis, TMNO.2H2O (0.339 drug and as CO-releasing molecules (CO-RMs), g, 3.06 mmol), Mo(CO)6 (0.792 g, 3.0 mmol), and with CO-RMs being the most effective. Five DMG (0.348 g, 3.0 mmol) were weighed and classes of CO-RMs have been identified and of dissolved in 20 mL THF in a flask equipped with a these, appropriately substituted transition metal magnetic stirrer. The mixture was vigorously carbonyls stand out as the most effective means of stirred under N2. An initial light yellow solution safe CO delivery to specific sites in biological changed to a red suspension after a few minutes. systems (Romao, et al., 2012). The stirring was continued for 24 hours at room For a full medicinal exploitation of this class temperature. The mixture was then reduced to very of compounds a detailed understanding of their low volume immediately with rotary evaporator, structural chemistry is required. Here we set out to washed with minimal quantity of CH2Cl2/n-hexane synthesize and characterise two DMG substituted (1:1) and left to crystallize. The brown crystals Mo and W carbonyl complexes. were washed with CH2Cl2/n-hexane under suction (Hor and Siti, 1988). (Yield 56%) MATERIALS AND METHOD Materials Preparation of [W(CO)2(DMG)2] (II) Molybdenum and tungsten hexacarbonyls, TMNO.2H2O (0.339 g, 3.06 mmol), trimethylamine N-oxide dehydrate (TMNO), W(CO)6 (1.056 g, 3.0 mmol), and DMG (0,348 g, dimethylglyoxime (DMG) and tetrahydrofuran 3.0 mmol) were weighed and dissolved in 20 mL (THF) were purchased from Sigma Aldrich. THF in a flask equipped with a magnetic stirrer. Tetrahydrofuran (THF) was purified prior to The mixture was vigorously stirred under N2. An use according to the method described in literature initial light yellow solution changed to a red (Armarego and Chai, 2003). All other solvents suspension after a few minutes. The stirring was were AR grade from Sigma Aldrich and were used continued for 24 hours at room temperature and without further purification. further refluxed for six hours. The mixture was then reduced to low volume immediately with METHODS rotary evaporator, washed with minimal quantity of All reactions involving metal carbonyls CH2Cl2/n-hexane (1:1) the mixture which turned were performed under pure dry gas using yellow was left to crystallize. The yellow crystals manipulated Schlenk techniques. Solvents were of (Yield 63%) were washed with CH2Cl2/n-hexane reagent grade and purified according to standard under suction (Hor and Siti, 1988). methods. Infrared spectra were obtained using SHIMADZU Fourier transform infrared RESULTS AND DISCUSSION spectrometer using KBr disc pellets technique. 1H The DMG Substituted Carbonyl NMR and Microanalysis were performed by Medac Complexes analytical and chemical consultancy services, UK, The reactions of molybdenum and tungsten using Bruker Avance III HD 500 spectrometer and hexacarbonyl with dimethylglyoxime under Thermo Flash 1112 elemental analyser nitrogen atmosphere in the presence of respectively. trimethylamine N-oxide yielded the dicarbonyl complexes as illustrated in scheme 1.

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CSJ 8(1): June, 2017 ISSN: 2276 – 707X Abubakar and Eke

slow [(CO) M C O] fast x "M(CO) " + NMe3 + 4CO2 M(CO)6 + Me3NO 2

O NMe3 DMG fast

M(CO)2(DMG)2

M = Mo, W Scheme 1: Route to the dimethylglyoxime stabilization of the TMANO decarbonylation of metal hexacarbonyl

The FTIR and elemental analysis result of the These bands are unambiguously assigned to complexes are presented in Tables 1 and 2 The terminal CO stretching vibrations. dimethylglyoxime was subjected to both infrared The three bands may not necessarily connote the and CHN analysis before use, the results were presence of three carbonyl , the weak bands positive. at 1840 cm-1 and 1892 cm-1 in both complexes can The FTIR spectra of the free DMG ligand shows be ascribed to coupling of CO ligands in trans stretching frequencies that are due to OH, NH and positions which is common with octahedral NO bands as shown in Table 2. A remarkable dicarbonyl complexes. The three peaks are usually feature of the oximato group is the splitting of the due to one symmetric and two asymmetric CO NO stretching vibrations at 1440 cm-1 and 1365 cm- vibrations (Socrates, 2001). The suggestion that the 1 in both complexes. Complexes I and II display complexes are likely to be dicarbonyls is further three peaks each at 2002 cm-1, 1921 cm-1, 1820 cm- established by the microelemental analysis results. 1 and 1998 cm-1, 1934 cm-1, 1892 cm-1 respectively.

Table 1: Elemental analysis data for the dimethylglyoxime complexes Compounds %C %H %N Calc Found Calc Found Calc Found DMG 41.34 40.71 6.94 6.80 24.12 22.89 I 31.24 31.33 4.20 5.17 14.59 15.00 II 25.42 24.93 3.39 3.20 11.86 12.13

Table 2: IR data for the ligand and metal DMG complexes in cm-1 Compounds νNH νOH νCO νCN νN-O νM-O νM-N DMG 3207 3340 1653 1440/1365 I 3213 3462 2002 1637 1440/1365 586 468 1921 1840 II 3302 3454 1998 1647 1440/1365 596 426 1934 1892

The mode of of the DMG complex to the molybdenum hexacarbonyl complex. This peak has metal centers can be instructive from the FTIR been ascribed to Mo-O vibration thereby results. Chelation of DMG to metal centers usually suggesting the involvement of at least one O atom occur through the N atoms of the oxime moieties in the oxime moiety in the coordination process. A but recently cases of chelation via N of one oxime similar band appearing very weak in the tungsten moiety and the O of the other in the same molecule complex at 596 cm-1 may also be due to W-O. The have been reported. The FTIR chart of the new peaks at 426 cm-1 and 468 cm1 in complexes I substituted molybdenum carbonyl complex and II are assigned to M-N coordination therefore exhibited a very strong and prominent peak at 586 leading to the proposed structures. cm-1 which is absent in both the free DMG and the

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CSJ 8(1): June, 2017 ISSN: 2276 – 707X Abubakar and Eke

OH CH 3 OH

H CH 3 H O O

N N CO N CO N

3 H C

H3C Mo CH 3 W CH 3

N N N N O CO O CO H H H3C OH H3C OH I II

Fig 1: the proposed structure of the substituted complexes, Mo(CO)2(DMG)2 I and W(CO)2(DMG)2 II

In the 1H NMR spectra, the resonance around 2.6 in diversity of organometallic complexes the two complexes are assigned to the 6 H of the with bioligands and molecular recognition two equivalent allylic CH3 groups on the studies of several supramolecular hoste dimethylglyoxime ligand, the singlets at 3.4 and with biomolecules, alkali ions and 11.3 are assigned to the proton of NH and OH organometallic pharmaceuticals. respectively which are consistent with NH of aryl Organometallics, 22, 2166-2177. amines and OH of oxime. Gasser, G., & Metzler-Nolte, N. (2012). The CONCLUSION potential of organometallic complexes in The successful decarbonylation of medicinal chemistry. Current Opinion in molybdenum and tungsten hexacarbonyls in the Chemical Biology, 16, 84-91. presence of DMG promoted by trimethylamine N- oxide is novel. Previous attempts via thermal and Gibaud, S., & Jaouen, G. (2010). Arsenic based photolytic pathways (Ramadan, et al., 1997, drugs: From Fowler's solution to modern Ramadan, 1998) in addition to the desired product anti-cancer chemotherapy. In Medicinal gave some undesired products and hence the , Top. cumbersome process of product separation and Organomet. Chem. (Vol. 32, pp. 1-20). purification. In this method the products were Berlin: Springer-Verlag. definite and analytically pure not requiring rigorous separation and purification processes. Hartinger, C. G., & Dyson, P. J. (2009). The resulting complexes with two CO Bioorganometallic chemistry - From ligands of decreased bond strength promises to be teaching paradigms to medicinal good candidates for CO release studies in application. Chemical Society Review, 38, biological system with the use of appropriate CO 391-401. release activating agent, thus offering some hope Hor, T. S., & Siti, R. B. (1988). Convenient for their use as CO-releasing molecules. The Syntheses and Characterizations of Group possible generation of a small CO molecule and 6 Metal Tricarbonyls with Ligating a- other biocompatible substrates by these compounds diimine and Triethyl phosphite. Journal of serves as encouragement for future studies using Organometallic Chemistry, 343-347. fragment based drug approach in screening these molecules as Pharmaceutical agents. Jaouen, G. (2006). Bioorganometallic: Biomolecule, Labelling, Medicine. REFRENCES Weiheim: Wilay-VCH. Abraham, N. G., Nath, K., & Alam, J. (Eds.). (2002). Heme Oxygenase in Biology and Jaouen, G., & Dyson, P. J. (2007). Medicinal Medicine. New York: Springer-Science. Organometallic Chemistry. In D. M. P. Mingos, & R. H. Crabtree, Comprehensive Armarego , W. L., & Chai, C. L. (2003). Organometallic Chemistry III (Vol. 12, Purification of Laboratory Chemicals (5th pp. 445-464). Amsterdam: Elsevier. ed., pp. 361). London: Butterworth Heinemann. Jaouen, G., & Metzler-Nolte, N. (2010). Medicinal Organometallic Chemistry, Top. Fish, R. H., & Jaouen, G. (2003). Organomet. Chem. (Vol. 32). Berlin: Bioorganometallic Chemistry: structural Springer-verlag. 32

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