Reactivity of M-C Bonds and Catalytic Formation of Heterocycles - Essay Example

? Reactivity of M-C Bonds and Catalytic Formation of Heterocycles By of [Word Count] Introduction Heterocyclic compounds are among the most interesting and widely studied aspect of organic chemistry. In principle, a heterocyclic compound refers to a compound that has at atoms from at least two elements in its rings. Heterocyclics are thus the exact opposite of homocyclic compounds whose rings only contain atoms of a one element. Despite the fact that heterocyclic compounds are likely to be inorganic, most of them have one carbon in their structures. The importance of heterocyclics in the synthesis of chemical compounds led to the emergence and spread of heterocyclic chemistry as branch of the discipline(Boutadla et al., 2009). This branch deals with the synthesis, properties and application of heterocyclic compounds and their derivatives. Heterocyclics are largely categorized as unsaturated and saturated heterocyclics, depending on their structures(Pfaltz&Drury, 2004). The saturated heterocyclics have been noticed to behave like their acyclic derivatives. The core focuses of heterocyclic compound studies are the unsaturated derivatives of 5- and 6- membered rings, their applications and their predominance of low-numbered rings. Among the 5- and 6-membered unsaturated heterocyclics are pyridine, thiophene, pyrrole and furan. Similarly studied to a large extent are benzene-fused rings of these 5- and 6- membered unsaturated heterocyclics(Nakamura et al., 1998). These benzene-fused derivatives are quinoline, benzothiophene, indole, and benzofuran for pyridine, thiophene, pyrrole, and furan respectively. The following are structures of a heterocyclic and a homocyclic compounds namely pyridine, a heterocyclic and cyclo-octasulfur, a homocyclic compound. From the structures of these compounds it is evident that the C-H bond is quite important in their reactions. In fact, it is the activation of this C-H bond that allows for the formation and introduction of other functionality groups/bonds such as M-C or C-C bonds to heterocyclic compounds(Benudhar et al., 2013). Pyridine Cyclo-octasulfur, The core theme in organometallic chemistry is the construction and transformation of metal-carbon bonds. Consequently, most of researches and literatures seem to focus on the traditional M-C bonds formed using the tetravalent carbon bond. However, fewer researchers have concentrated on non-traditional M-C bonds, often referred to as M-C cage bonds, which are found in carborane cages in which the carbon is hypervalent(Nakamura et al., 1998). This paper explores the reactivity of M-C bonds and outlines a plan for the catalytic formation of heterocyclics via the catalytic activation of the M-C bond. Specifically, the aim of this paper is the synthesis of some ligands that contain heterocycles or vinyl groups that can undergo C-H activation to form cyclometallated complexes(Benudhar et al., 2013). Further, the paper investigates the reactivity of the cyclometallated complexes with alkynes and alkenes. Thus, the goal is to assess the relative reactivity of different types of M-C bonds. One of the methods used in the catalytic synthesis of heterocycles is the amphibilic metal ligand activation (AMLA). In the AMLA process, the steps in the activation of the C-H bond entail the use of an electrophilic metal in combination with a deprotonation using an intramolecular base, frequently acetate. Chiral ligands are chemical compounds adapted for and largely used in the asymmetric synthesis of heterocyclic compounds. Chiral ligands are pure organic enantiomers that combine with metallic centers through the process of chelation to yield asymmetric catalysts(Nakamura et al., 1998). It is this catalyst that later engages in the chemical reaction in which the chirality of a ligand is transferred to the product of the reaction. That is, while initially the ligand is chiral, at the end of the reaction, it is the product, which is chiral. In model situations or reactions, one equivalent catalyst results in multiplied equivalents of reactants and even larger equivalents of products(Nakamura et al., 1998). It is because of this multiplication of the catalyst equivalent in the product equivalents that this kind of reaction in which a chiral ligand catalyst is used has become a favourite of commercial producers of heterocyclic compounds(Nakamura et al., 1998). Considering that chiral ligands are rather expensive. An example of a chiral ligand used in the asymmetric synthesis of heterocyclic compounds in the diphosphineDiPAMP, which is used in the commercial and small-scale production of L-DOPA as shown in the reaction. Other chiral ligands (privileged ligands) used in the asymmetric synthesis of heterocyclics are TADDOL, BOX, DuPhos, BINAP, BINOL and DIOP. The structures of these chiral ligands are shown below the reaction catalyzed by Di PAMP(Nakamura et al., 1998). In more than 95% of the studied cases of catalytic activation of the C-H bond, it has been established that phenyl groups are targeted for activation. In this regard, many studies have aimed at exploring the ease of activating the C-H bonds in heterocyclics in ligands 1 where X = O, S, NH or NR, or activation of a vinyl group to form (2) [M (ring) = RhCp*, IrCp* or Ru(p-cymene)]. The cyclometallated products of C-H activation may react with unsaturated species like alkynes. Regrettably, the effects of the M-C bonds formed from phenyl, heterocycles or vinyl groups are yet to be extensively studied. Nonetheless, quite many commercial manufacturers have all-inclusive ranges of products and building blocks not only for use by industries but also large and small research and educational institutions. Such manufacturers specialise in customer synthesis of heterocyclic compounds, mostly 5-, 6- and 7-membered rings with one or more nitrogen, oxygen and sulphur atoms in molecules and their metal complexes and catalysts(Tehshik et al., 2003). There are certain unique heterocyclic compounds, which have been practically shown to be rather reactive ligands, hence are not advisable for use in the formation of metal complexes(Vetter & Jones, 2004). On the contrary, these unique heterocyclic compounds are used in the formation of building units for medicinal chemistry. To hasten and increase the formation of heterocyclics, catalysts are currently being used in heterocyclic research and production with the chiral catalysts preferred in the asymmetric syntheses(Vetter& Jones, 2004). Below is a heterocyclic compound, Terpyridine and its catalytic formation. One experiment in which C-H activation and functionalization has been studied is the use of cheap cobalt catalysts obtained from N-heterocyclic carbenes (NHC). The NHCs are found to efficiently catalyze the arylation of C-H bond in hetroaryls-substituted arenes with available aryl chlorides(Boutadla et al., 2009).Experiments have also shown that the catalysation of C-H bond fuctionalization by cobalt catalysts occur at rather efficient rates in ambient temperatures.The other features of these C-H activation and functionalization reactions are high site-selectivity, ample scope and preferential reaction of electron-deficient aryl chlorides. Experiment for C-H Activation by Octahedral Rh (II) Complexes Current times have seen an increase in the use of late transition metals such as Ruthenium to achieve the objective of direct C-H functionalization of aromatic substrates. Rh (II) has been particularly used in these investigations on catalysis of aromatic and olefinic C-H bond, referred to as hydroarylation and hydrovinylation of olefins. The following is plan for an experiment involving the use of Rh (II) octahedral complexes to activate the C-H bond. First, all the synthetic procedures in the experiment will be carried out in anaerobic conditions using Schlenk’s standard techniques or under nitrogen-filled glovebox. The purity of the glovebox will be maintained via intervallic flush out of nitrogen and monitored using oxygen analyzers. The concentration of oxygen will be maintained at less than 15 ppm. After observing all these conditions, Tetrahydrofuran will be dried through distillation from sodium or benzophene and kept in 4 Angstrom (A)molecular sieves. Second, anhydrous diethyl ether will be purged with dinitrogen and stored over 4 Angstrom (A) molecular sieves. Third, commercially available substituted m-xylene reagents will be obtained and distilled over CaH2 then stored over the 4 Angstrom (A) molecular sieves. This process will be followed by the purification of hexanes by passing them through a column of activated alumina and washing out with dinitrogen. Importantly, d6and THF-d8will be degassed with three freeze-pump-thaw-cycles. These reagents will then be stored in a environment of dinitrogen over 4 Angstrom (A) molecular sieves. The most important aspect of the experiment will be the recording of the hydrogen (1H) and carbon (13C) nuclear magnetic resonance (NMR) in a Varian Mercury 300 or 400MHz and a Varian Mercury 300 MHz spectrometer respectively. The MHz spectrometer for recording the NMR for 13C will be operating at 75MHz. These recordings will be compared with the residual proton signals (1H NMR). The other core component of the plan for the C-H activation experiment is the preparation of the right conditions for the reaction. Since most C-H activation reactions occur in quite harsh conditions characterized by high temperatures, strong oxidant, and acidic or basic conditions, a lot of time and care will be taken in ensuring such conditions prevail. Nonetheless, these conditions significantly lower the attractiveness of these experiments. Fortunately, rather mild reactions catalyzed by organocatalysts have been developed(Song et al., 2012). In addition, metal centres with many electrons, hence stable at high oxidation states are used as catalysts for such reactions(Boutadla et al., 2010). Consequently, later transition metals such as Rh, which promote oxidative addition, are quite ideal for C–H activation. Moreoverd8 metals, which are capable of undergoing a square planar arrangement, are probable candidate catalysts due to the presence of two vacant coordination sites, which limit steric hindrance. Work Plan for the Experiment Expt. Title: Use of Rh (II) octahedral complexes to activate the C-H bond. Time allocation Targeted essential learning’s Experiment Overview Instruments/ chemicals Techniques Approximately 3 days, 8 hours in total. 7/10/13 – 10/10/13 To assess the relative reactivity of different types of CMC bonds. To make some ligands containing heterocycles (or vinyl groups) which can undergo CH activation to form cyclometallated complexes and then investigate the reactivity of the cyclometallated complexes with alkynes and alkenes. Depiction of a Model for Ru(II)-Mediated C-H Assessable elements ( investigation and reflection) Stating the hypothesis to be tested, Formulating the context of the experiment, Studying published scientific literature at the library and online , Formulating a theoretical model. This model of the transition state for C-H Activation is also consistent with recent studies of arene C-H activation via 1,2-addition across Ru-X (X ) OH or NHPh) Ir-OMe and Rh–OAr bonds. changes that enhance the basicity of the ligand receiving the activated hydrogen atom or the acidity of the C-H bond are likely to reduce the activation barrier for C-H bond cleavage. For arene substituents X, the PMe3 ligand is calculated to provide faster reaction rates for C-H bond activation than the CO derivative, which is in agreement with previous kinetic studies of TpRu complexes, as well as a less pronounced sensitivity to arylsubstituent effects. Approximately 3 day, 12 hours In total. 14/10/13 – 17/10/13 Planning and preparing for the lab work. Procedures to be performed under anaerobic conditions in a nitrogen-filled glove box. Glove box, Nitrogen, oxygen analyzer. Maintain glove box purity by periodic nitrogen purges and monitoring by an oxygen analyzer . Approximately 2 day, 10 hours in total. 22/10/13 – 24/10/13 Preparation of functionalised heterocycles. Functionalised heterocycles to be prepared under the ideal conditions; storage of these compounds to be highly noted. Substituted m-xylene reagents to be purchased from commercial sources. Tetrahydrofuran, sodium/benzophenone, 12 A molecular sieves, Anhydrous diethyl ether, dinitrogen, Substituted m-xylene reagents, CaH2. Tetrahydrofuran to be dried by distillation. Anhydrous diethyl ether to be purged with dinitrogen. Substituted m-xylene reagents to be distilled. Approximately 1 day, 6 hours in total. 4/11/13 Isolation of functionalised heterocycles. Isolation of these compounds must be done under sensitive conditions. Hexanes, alumina, dinitrogen, Benzened6, THF-d8, freeze–pump, dinitrogen, 4 A molecular sieves. Hexanes to be and purged. Benzened6 and THF-d8 to be degassed. Approximately 1 day, 5 hours in total. 6/11/13 CH activation to form cyclometallated complexes Metal-mediated C-H activation is a key step in overall catalytic cycles for the addition of C-H bonds across olefin double bonds using TpRu(L)(NCMe)R systems. R and R? can be hydrogen, alkyl, alkenyl, aryl, alkynyl, or a related group. The reaction below shows the mechanism of C-H activation by a ?-bond metathesis & mechanism of Oxidative Hydrogen Migration: C-H activation via ?-bond metathesis pathways with late transition metals has revealed different transition states where “parallelogram”-shaped transition state and a weak metal-hydrogen interaction are implied; with differences in electronic structure between the two mechanisms. This is displayed in the chemical equation below: H ?+ - H+ LnM+R-H LnM LnM-R R ?- Varian Mercury 300 or 400 MHz spectrometer H NMR spectra to be recorded on a Varian Mercury 300 or 400 MHz spectrometer. Approximately 5 days, 4 hours each day. 8/11/13 – 13/11/13 Investigate the reactivity of the cyclometallated complexes with alkynes and alkenes Reactions of Substituted meta-Xylene Compounds with TpRu(PMe3)(NCMe)Me. TpRu(PMe3)(NCMe)Me, 2,6- dimethylnitrobenzene, 2,6 dimethylbromobenzene, m-xylene,2,6-dimethylanisole, and 2,6-dimethylaniline, hexamethyldisiloxane, 0.4 mL of THF-d8, oil bath. In separate experiments, TpRu(PMe3)(NCMe)Me to be reacted with 5 equiv of 2,6- Dimethylnitrobenzene, 2,6-dimethylbromobenzene, m-xylene,2,6-dimethylanisole, and 2,6-dimethylaniline. Approximately 2 days, 33hours 19/11/13 – 21/11/13 Investigate the reactivity of the cyclometallated complexes with alkynes and alkenes Reactions of Substituted meta-Xylene Compounds with TpRu(PMe3)(NCMe)(p-NO2-C6H2Me2) TpRu(PMe3)-(NCMe)Me, 2,6-dimethylnitrobenzene , THF , Schlenk tube, THF, silica gel column. TpRu(PMe3)- (NCMe)Me (0.208 g, 0.466 mmol) to be added to a mixture of 2, 6-dimethylnitrobenzene (4 mL) and THF (2 mL) in a Schlenk tube. Approximately 4 days, 30 hours in total. 28/11/13 – 2/12/13 Investigate the reactivity of the cyclometallated complexes with alkynes and alkenes Reactions of Substituted meta-Xylene Compounds with TpRu(PMe3)(NCMe)(p-Br-C6H2Me2) (2). TpRu(PMe3)(NCMe)- Me, 2,6- Dimethylbromobenzene, THF, Schlenk tube, silica gel column, TpRu(PMe3)(NCMe)- Me (0.205 g, 0.460 mmol) is to be added to a mixture of 2,6- Dimethylbromobenzene (4 mL) and THF (2 mL) in a Schlenk tube Approximately 1 week. 4/12/13 – 11/12/13 Preparation of the laboratory report from experiments done To assess the relative reactivity of different types of CMC bonds. - Compose and generate professional scientific reports that include well-crafted sections on: abstract, introduction, experimental, results, discussion, references, supplemental information Procedure format Starting materials All reactions requiring anhydrous conditions were conducted in flame-dried glass apparatus under an atmosphere of N2. All synthetic procedures were performed under anaerobic conditions in a nitrogen-filled glovebox or by using standard Schlenk techniques. Glovebox purity was maintained by periodic nitrogen purges and was monitored by an oxygen analyzer [O2(g) < 15 ppm for all reactions]. Thermodynamic quantities were calculated at 298.15 K and 1 atm. Determination of the relative rate of arene C-H activation was done, in which the site of C-H bond cleavage is para to variable functionality in a six-membered benzene ring. Such reactions have three primary requirements: (1) C-H activation must occur selectively para to the substituent “X”, (2) reactions between the metal and the functionality “X” should be suppressed, and (3) overall reactions should occur in relatively high yields. In order to direct reactivity to the C-H bond para to functionality, we probed reactions of TpRu(PMe3)(NCMe)Me with 2-substituted 1,3-dimethyl benzene (i.e., meta-xylyl) compounds. It was anticipated that the meta-methyl groups would protect the functionality “X” and serve to direct C-H activation to the position para to X. TpRu(PMe3)(NCMe)Me initiates C-H activation of benzene to produce TpRu(PMe3)(NCMe)Ph and free methane. In contrast, the reactions of TpRu(PMe3)(NCMe)Me with meta-xylyl compounds that have electron-withdrawing groups in the 2-position (X ) NO2 or Br) produce the corresponding TpRu(PMe3)(NCMe)(p-X-C6Me2H2) complexes. Part 1 General techniques: Tetrahydrofuran was dried by distillation from sodium/benzophenone prior to use. The product was stored over 4 A molecular sieves. Anhydrous diethyl ether was purged with dinitrogen and stored over 4 A molecular sieves. Substituted m-xylene reagents were distilled over CaH2 at 15 mmHg and stored over 4 A molecular sieves. Hexanes were purified by passage through a column of activated alumina and purged with dinitrogen. Benzened6 and THF-d8 were degassed with three freeze–pump–thaw cycles and stored under a dinitrogen atmosphere over 4 A molecular sieves. The reaction below shows the mechanism of C-H activation by a ?-bond metathesis & mechanism of Oxidative Hydrogen Migration (Jordan, 2007): C-H activation via ?-bond metathesis pathways with late transition metals has revealed different transition states where “parallelogram”-shaped transition state and a weak metal-hydrogen interaction are implied; with differences in electronic structure between the two mechanisms. This is displayed in the chemical equation below (Popeney, & Guan, 2010): H ?+ - H+ LnM+R-H LnM LnM-R R ?- Preparative chromatographic separations were performed whereby 1H NMR spectra were recorded on a Varian Mercury 300 or 400 MHz spectrometer. 13C NMR spectra were recorded on a Varian Mercury 300 MHz spectrometer (operating frequency 75 MHz). 31P NMR spectra were obtained on a Varian 400 MHz spectrometer and referenced against an external standard of H3PO4 (? ) 0). All commercially available reagents were purchased from commercial sources and were used as received unless otherwise noted. Part 2 General procedure for reactions of Substituted meta-Xylene Compounds with TpRu(PMe3)(NCMe)Me. TpRu(PMe3)(NCMe)Me (0.011 g, 0.033 mmol), 5 equiv of m-xylene (0.020 mL, 0.165 mmol), and hexamethyldisiloxane (0.004 mL, 0.054 mmol) in 0.4 mL of THF-d8 were added to a screw-cap NMR tube and heated at 60 °C in a temperaturecontrolled oil bath. 1H NMR spectra were periodically acquired until consumption of TpRu (PMe3)(NCMe)Me was complete. For reactions of 2,6-dimethylnitrobenzene and 2,6-dimethylbromobenzene, TpRu(PMe3)(NCMe)(p-NO2-3,5-dimethylbenzene) and TpRu(PMe3)(NCMe)(p-Br-3,5-dimethylbenzene) were produced in 48% and 33% yields (determined by integration versus internal standard), respectively (Balcells, Clot, & Eisenstein, 2010). General procedure for reactions of Substituted meta-Xylene Compounds with TpRu(PMe3)(NCMe)(p-NO2-C6H2Me2) TpRu(PMe3)- (NCMe)Me (0.208 g, 0.466 mmol) was added to a mixture of 2,6- dimethylnitrobenzene (4 mL) and THF (2 mL) in a Schlenk tube, and the reaction was stirred for approximately 30 h at 60 °C. The red solution was dried to a film under vacuum. The resulting film was dissolved in approximately 1 mL of THF and applied to a silica gel column constituted with 40% diethyl ether in hexanes. The product was eluted and collected as the second band (red) using a gradient elution of 40% to 60% diethyl ether in hexanes. The red eluent was dried to an orange solid in vacum (0.091 g, 33%). Spectra recordings were made (Boutadla et al, 2009). General procedure for reactions of Substituted meta-Xylene Compounds with TpRu(PMe3)(NCMe)(p-Br-C6H2Me2) (2). TpRu(PMe3)(NCMe)- Me (0.205 g, 0.460 mmol) was added to a mixture of 2,6- dimethylbromobenzene (4 mL) and THF (2 mL) in a Schlenk tube, and the reaction was stirred for approximately 24 h at 60 °C. The brown solution was dried to a film under vacuum, reconstituted in approximately 1 mL of THF, and applied to a silica gel column constituted with 40% diethyl ether in hexanes. The product was eluted and collected as the second band (yellow) using a gradient elution of 40% to 80% diethyl ether in hexanes. The pale yellow eluent was dried to a white solid in vacuo (0.064 g, 23%). Spectra recordings were made (Ess, Goddard III, & Periana, 2010). Bibliography BALCELLS, D., CLOT, E., & EISENSTEIN, O. (2010). C? H Bond Activation in Transition Metal Species from a Computational Perspective. Chemical reviews, 110(2), 749-823 BENUDHAR, P., SONG, W., SHEVCHENKO, G. A., AND ACKERMANN, L. (2013) Cobalt-Catalyzed C-H Bond Functionalizations with Aryl and Alkyl Chlorides. 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