Developing ligands for chelation

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Introduction

Research in the treatment of contaminated and sewage water has become a necessity because of the alarming rise in diseases caused by the consumption of water. Water plays an important role in the industrial activities as well as, for the domestic purposes. Water is getting contaminated by the use of dyes, chemicals, detergents and also heavy metals. For economical, environmental and health benefits, treatment of waste water has become a must. The waste water can be recycled and re-used for industrial purposes.

Discharge of heavy metals such as silver, lead and copper has been detected in water worldwide and the water has become toxic. This has caused adverse effects on the aquatic life and human beings. The quality of water has therefore become of paramount importance.

Chelating agent sometimes referred to as chelants, chelators or sequestering agent, which are mostly organic compounds, are defined as the binding or complexation of a bi or multidentate ligands. These chelants according to (ASTM-A-380) are chemicals that form soluble, complex molecules with certain metal ions, having the ability to inactivate the ions to prevent then from reacting with other elements or ions to produce precipitates. The ligands are said to form a chelate complex with the substrate.

The main aim of this project is to find alternate methodologies for developing ligands to chelate with copper and silver ions and thus remove these toxic metals from wastewater.

The main objectives of this work are:

  1. The synthesis of per-6-ethylene diamine ?-cyclodextrin via Vilsmeier Haack reaction and use as ligand for binding of copper and silver ions.
  2. Synthesis of 2, 3 dimercapto-iodo-propane and use as pendant arms for calyx-4-arene to bind copper and silver ions.
  3. Synthesis of the cyclen macrocycle from the prior synthesis of 1, 2 bis (p-toluenesulfonato) ethane and acyclic tetratosylamide. The macro cycle will also be complexed with silver and copper ions.

The report is presented in 5 main sections:

Chapter one which presents the literature reviews of copper and its toxicity, silver and its toxicity, the ligands (macrocycles: crown ethers, cyclodextrin, calixarene) and their properties.

Chapter two: this section deals with the results and discussions.

Chapter three: outlines the various experimental procedures and techniques used for the synthesis of ligands and complexation of these ligands to the heavy metal ions.

Chapter four: accounts for the conclusion and future works.

Chapter five: Appendix

LITERATURE REVIEW

COPPER

Copper and its toxicity

Reddish brown in colour, copper metal occurs naturally in soil, sediment, water, air and rocks. It is the third most commercially used metal after aluminium and iron. Its physical properties render it very useful. It is essential for tissues, bones and the nervous system.

Copper is found in plants and animals tissues. A deficiency of copper leads to anaemia and abnormalities. However, very large single or long-term intakes of copper are injurious to human health. About 1000µg of copper is consumed daily, with drinking water contributing approximately 150µg per day, is considered to be safe to health. Intake exceeding 1000µg of copper per day is toxic to health. The U.S Environment Protection Agency (U.S. EPA) has determined that copper level in drinking water should not exceed 1300µg/L.

Copper toxicity can arise from many sources amongst are breathing air, eating acidic food cooked in copper cookware or drinking water from corrosive water pipelines.

Copper and its alloys are widely used in the plumbing, electrical and electronic industries. Also copper compounds are used as fungicides, algaecides, in food supplements and fertilizers. Discharge of copper in domestic wastewater, mining wastewater and pollution from industries are the prime sources of copper in surface and ground water.

High levels of copper toxicity occur from water in contact with copper plumbing and copper containing fixtures that are corrosive in water distribution system. The level of copper in drinking water increases with the corrosivity of the water and the length of time it remains in contact with the plumbing. (U.S. EPA, 1991)

Copper is hazardous to health if we have an elevated level of copper. The immediate effects of copper toxicity are nausea, diarrhea, stomach cramps and vomiting. Prolonged exposure to copper leads to kidney and liver damage in infants. Severe cases of copper poisoning have led to anemia and to the disruption of liver and kidney functions. Individuals with Wilson's and Menke's diseases (genetic disorders resulting in abnormal copper absorption and metabolism) are at higher risk from copper exposure than the general public, and can have serious health problems.

Other diseases that may result from excess copper intake are problems with the respiratory tract, gastrointestinal tract, malfunctioning of the liver and endocrine, a decrease in the haemoglobin and erythrocyte, haematuria and a massive gastrointestinal bleeding. (U.S. EPA, 1990)Copper is also toxic to aquatic life.

Precipitation reaction giving insoluble salts of copper in the form of, carbonates, hydroxides and sulphides help to remove copper found in wastewater. The insoluble salts are thereafter removed through filtration, settling or the ion-exchange methods. (John Strand berg, Menlo Park)

Copper complexation

The fact that toxicity of copper is reduced or eliminated due to copper complexation with organic (amino acids, carbonates, phosphates, humates), or inorganic moieties is beneficial to the aquatic organisms. The copper complex formed is readily sorbed onto suspended solids (Meador, 1991). Studies have also highlighted that copper can be harmful even when bound to solids. The Environmental Protection Agency in U.S. has concluded that the bioavailability of copper was due to the complexation of copper with dissolved organic compounds naturally present. This has in turn decreased the toxicity of copper in natural waters.

After studies conducted on the analytical chemistry of copper (II) ions in sea water, it has been proven that the dissolved or inorganic complexes could not be determined by analytical methods. (A.Zirino and K Bruland et al; 1988)

Complexation of lewis base with copper ions has been shown to reduce copper toxicity. Voltametry technique was used to measure the free copper ions in sea water and, the stability constants and copper binding ligands' concentration were obtained by voltametry titration. (Coale and Bruland et al; 1988)

[Cu]/ [Cu L] = 1/ [Cu] [L] + 1/ [L] - K cond

Where;

[Cu] is the copper (II) ions in the free state and inorganic copper complexes,

[L] is the concentration of ligand used during titration

From the above equation, it was clearly shown that increasing concentration of ligands in the titration flask decreased the equilibrium constant. The possibility that organic matter in sea water may contain a statistical distribution of binding constant still remains since it could not be detected by analytical methods.

For complexation of copper, chemically synthesized ligands can be used. Triethylenetetramine was complexed with copper ions. Its efficacy was compared from bidentate ligands i.e. ethylene diamine and ammonia. It was concluded that copper ion extraction was faster when trien was used as ligand. This is due to the kinetic stability formed between copper ions and the ligand during complexation. Also copper was extracted over calcium at a low acidic pH of 5 where it was observed that without trien it was easier to remove calcium ions rather than copper ions but in presence of trien, copper ions readily complexed with trien. After complexation, the complexes formed were removed via adsorption on sodium dodecylsulphate. Copper ions were extracted in this manner even in the most diluted solution.

Despite being simple and inexpensive, the colorimetric and gravimetric methods for the measurement of copper become limited to situations where extreme sensitivity is not required. Atomic absorption spectrophotometric (AAS) methods are useful for the measurement of low concentration of copper. Other more sensitive and specialized methodologies available are X-ray fluorescence, ion-selective electrodes and potentiometric methods, and anodic stripping and cathodic stripping voltametry.

Coagulation or filtration methods are among the several other methods used to remove copper ions from water apart from the complexation method discussed above. These methods proceed via the removal of pollutants by chemically conditioned particles. These particles are made to agglomerate into larger particles which were separated and the pollutants were run through various filter traps to hold them for disposal. The disadvantage is that this method is expensive and it also destroyed the habitat that surrounded the water. (Huang, 2004)

SILVER AND ITS TOXICITY

Silver occurs in nature and in ores such as argentite (Ag2 S) and horn silver (Ag Cl). Pure silver has a shiny white metallic luster. It is hard, ductile and malleable. It has the highest electrical and thermal conductivity of all metals but not used as electrical wires due to its cost. Silver is stable in pure air and water but it tarnishes on exposure with ozone, hydrogen sulphide or air containing sulphur.

It is used in the photography and electronics, medicines, in nuclear reactors and as catalysts in oxidation reactions. Also it is used in dentistry. Due to its constant and frequent uses in industries for decades, silver has reached our water and has accumulated in our sediments. It is categorized among the heavy metals. Silver ions are very toxic to microorganisms. Excessive exposure to silver and its compounds can be toxic and highly detrimental to health. Accidental intake of a large dose of silver nitrate has been proven to cause corrosive damage to gastrointestinal tract, abdominal pain, diarrhea, vomiting, convulsions and eventually death. Long term exposure to silver or silver compounds causes liver and kidney damage, Argyria (a grey or blue-grey permanent discoloration of the skin and mucous membrane. Also silver oxide and silver nitrate dusts exposure results in upper and lower respiratory irritation, deposition of granular silver containing deposits in eyes causing impaired night vision. (U.S EPA; 1994)

The main source of silver contamination of water is silver thiosulphate complexes in photographic developing solutions. Silver can remain in our oceanic sediments for about 100 years. The availability of silver in its free state in the marine environment is highly controlled by salinity. This is due to the fact that silver has a great affinity for chloride ions. (U.S. EPA; 1985)

METHODS TO DETERMINE SILVER IN WATER

It is very important to first detect silver ions in water before using ligands or macrocycles to complex with silver ions (complexation technique) and also prior to use of other techniques of silver ion extraction to prevent wastage of chelants and time. All the methods that will be adopted must be simple, efficient, effective, inexpensive and rapid. Atomic absorption spectrometry (AAS), fluorometry, flow injection analysis and electro analysis are amongst the analytical techniques used to determine the amount of silver ions.

SILVER EXTRACTION THROUGH COMPLEXATION

There are various ways adopted to extract silver ions from the body and contaminated water. Many ligands have been synthesized for the complexation of heavy metals till date to eliminate or reduce the toxicity of heavy metals in water estuaries and our body.

The complexation and extraction of silver was carried out by making use of dithizone (diphenyl thiocarbazone) as complexing agent in cloud point extraction and applying selective per concentration of silver in trace amounts. This method was applied to the determination of silver in water samples. (University of Tabriz, Iran; 2002)

Another method of silver extraction was the extraction of silver over palladium using ketonic derivatives of calixarenes from highly concentrated nitric acid where extraction of silver with calixarene derivatives were investigated using high concentration of hydrochloric or nitric acids in chloroform. In comparison, silver ions were bound to carboxylate derivatives and unmodified calixarenes and it was observed that silver complexation was reduced. Among the derivatives of calixarenes, the ketonic derivative was found to be capable of removing traces of silver from large amounts of palladium even though these ligands do bind with palladium.

Likewise, silver was complexed and extracted using allyloxy calixarenes as ligands where a series of these calix-4-arenes derivatives bearing the allyl groups and/ or benzyl group as pendant arms were synthesized and functionalized at the phenolic oxygen atoms. The stoichiometry of silver with different amines used to bind the lower rim was determined by measuring conductance. Conductivity decreased upon addition of ligands indicating lower mobility of metals ions in Free State. The cation-binding abilities for silver (I) ions were evaluated and the results showed that silver readily bound itself to the allyl calix-4-arene derivatives rather than the benzyls ones. Extraction of silver was dependent on the conformational rigidity of the calix-4-arene. The cone conformer being of highest preference as rate of silver extraction was increased. (Daniel Couton et al; 1996)

Investigations have been carried out on the interaction of silver cation in a variety of solvents with the lower rim calix-4-arene containing aliphatic and alicyclic amines as pendant arms. Conductimetric measurements have indicated that a 1:1 (ligand-metal cation) stoichiometry of the metal ion complex was established. Potientometric titrations were also carried out using silver electrons to derive the stability constants of these ligands and the silver cation in these solvents.

Also by making use of dithizone (diphenyl thiocarbazone) as complexing agent and applying selective per concentration of silver in trace amounts, the complexation and extraction of silver was carried out. This method was applied in the determination of silver in water samples.

Multi-metal assemblies

The use of multi metal assembly is made because of their high stability constant and lower Gibbs energy. Also compare to a linear monodentate or bidentate ligands, they can bind many metals ions simultaneously forming complexes that can help to remove heavy metal ions from contaminated water easily and rapidly.

Bidentate ligand like ethylenediamine used as pendant arms to be attached to these macrocycles to facilitate complexation and extraction of metal ions and 2, 3 dimercapto-1-propanol has many pharmaceutical uses.

Macrocycles

A macrocycle is defined by IUPAC as a cyclic macrocycle or a macromolecular cyclic portion of a molecule. Any molecule consisting a ring of more than nine or arbitrarily large number of atoms is considered to be macrocyclic.

Macrocycles often have strong and specific binding with metals. The property of coordinating macrocyclic molecules is the macrocycle effect. This increases the thermodynamic stability of the macrocyclic complexes over the linear analog.

Macrocycles are synthesized from smaller and linear molecules with ring formation through intermolecular or intramolecular reactions. Also steps are taken to prevent polymerization to occur. They are classified in two main classes. Crown ethers and cryptands being oxygen donors and nitrogen macrocycles which mainly consist of polyaza macrocycles or aza crown ethers.

The oxygen donors' macrocycles have a tendency to complex with large metal ions such as the alkali and the alkaline earthed metal ions while the nitrogen donors' macrocycles have preference for the transition metal ions and post transition metals ions.

Macrocycles have many applications but amongst these, those mostly considered are the use of macrocylces for water purification where it is used to remove heavy metal from aqueous solution, as chemical sensor, for chelation therapy where it is used in the removal of heavy metals such as lead from the body (use of chelating agents such as EDTA)

Macrocycles with pendant donor groups play a very important role on the biomedical application because the pendant arms provide an increase in the stability constant particularly with octahedral metal ions.

Name: 2-p-nitro-benzyl-1, 4, 7, 10-tetraazocyclododecane-N, N', N'', N'''-tetra acetic acid

TETRA-AZAMACROCYCLIC LIGANDS

Mcrocyclic ligands such as cyclen and cyclam are termed as tetra-azamacrocyclic ligands. Compared to chain ligands, the ligands form complexes with enhanced thermodynamic and kinetic stabilities with respect to the metal ions.

The side bridged cyclam has two adjacent nitrogen atoms linked by an ethylene bridge, forming a piperazine fragment within the macrocycle.

In bridged cyclam chelators, one feature of configurational restraint is the reduction in flexibility of the macrocycle making it kinetically more stable and also favourable complexation results were observed for crossed bridged chelators. Side bridged chelants were used in radiopharmaceutical applications where they can chelate with 64 Cu (radioisotope of copper). X-ray crystallography showed that Jahn-Teller distortion through either across the macrocycle or along the axis where the pendant arms were coordinated bonds revealing the flexible nature of the chelator. Chelator flexibility, cavity size matches and complexation/decomplexation kinetics are all key factors in determining the utility of these chelators as radiopharmaceutical components.

Cyclen

Cyclen or 1, 4, 7, 10- tetraazacyclododecane is a macrocycle. They are capable of selective binding cations (Wikimedia Foundation, U.S).

MACROMOLECULES WITH SCAFFOLDS

CYCLODEXTRIN

Cyclodextrins are non-reducing, non hydroscopic cyclic glucose oligosaccharides formed from the cyclomaltodextrin enzymatic modification of starch. These exist as ?, ? or β cyclodextrins with 6, 7 or 8 O-glycopyranonsyl residues with the glucose residues having the chair conformation. Molecules can be encapsulated within the cavity provided by the cyclodextrin structure. The physical and chemical properties of a molecule can be favourably altered as a result of encapsulation. The stability, solubility, volatility and physical state are amongst the properties that can be modified by encapsulation.

In this project, β cyclodextrin was used due to its anomalous behaviour with water.

The rigid structure of β cyclodextrin strongly affects the surrounding water ordering, which lowers the configurational entropy and results in the anomaly of β cyclodextrin water solubility. (C.T Siskorski et al; 1996)

Cyclodextrin has a bottomless bowl-shaped structure where the molecule is strengthened by hydrogen-bonding between the hydroxyl groups around the outer rims. Their rings are amphiphatic with hydrophobic groups on the outside of the molecular cavity and inner surface is hydrophobic.

The C1 geometry of β cyclodextrin;

Why the hydroxyl group goes axial and the Hydrogen goes equatorial at the carbon number 1?

This is because the -CH2OH group at the carbon number 1 is bulky compared to the hydrogen atom and therefore, prefers the axial position rather than the equatorial position. This also provides rigidity in the lower rim and stability in the molecule.

Other than the pharmaceutical applications for drug release, cyclodextrin can be employed in a variety of other applications in many fields. This is due to the unique nature imparted by the structure of cyclodextrin. It can form host-guest complexes with hydrophobic molecules. In the food industry, cyclodextrin are used in the preparation of cholesterol free products, alpha-cyclodextrin is used in the weight loss supplements. Furthermore, they have the ability to stabilize volatile or unstable compounds and to reduce unwanted taste or odour which is of great help in the preparation of alcoholic drinks. Also to note, cyclodextrin can be used for environmental protection as the can immobilize toxic compounds including heavy metals inside their rings. They can also form complexes with stable substances like insecticides or sewage sludge and thereby enhance their decomposition. (Biwer A, Antranikian G, Heinzle E et al; 2000)

Calixarene

Calixarenes are termed as macrocycles or cyclicoligomers with defined upper rim, a narrow lower rim and a central annulus. This type of molecule resembles a vase and thus the name calyx and arene due to the aromatic building block.

Calixarenes have hydrophobic cavities that can hold smaller molecules or ions. They are sparingly soluble in water and are high melting point crystalline solids.

Their synthesis proceeds via an electrophilic aromatic substitution, which can either be acid or base catalysed, where phenol react with formaldehyde by elimination of water and then aromatic substitution.

They are one of the most useful types of macrocyclic scaffolds (Ziegler and Zinke)

Calix-4-arene

Calix-4-arene is thus named since it has four units in the ring. It exists in four conformations namely the cone conformer, partial cone conformer, 1, 2 and 1, 3 alternate conformers. Out of the four conformers, the cone conformer is the most desirable since it has the largest available surface area for host-guest interaction. Also the four hydroxyl groups interact with each other via hydrogen bonding thereby stabilizing the cone conformer. These have been used for a variety of molecular recognition, nanotechnology, and supramolecular applications. Those having substituents in their lower rim are more commonly used as it facilitates the complexation of heavy metals due to expansion of the cavity when subsituent is added. They form complexes with cadmium, lead, lanthanides and actinides. The tetrameric calixarenes, where nitrogen and sulphur are used in the coordination centre, are more selective for soft metal ions such as sodium but forms weak complexes with alkali and alkaline earthed metals.

Calixarenes have many applications and the most well known are in the enzymatic mimetic, as ion sensitive electrodes or sensors, as selective membrane, in non-linear optics and in HPLC stationary phase.

Conclusion

The rapid increase in level of toxicity caused by heavy metals in our water and related diseases caused by consumption and usage of the contaminated water has caused researchers to investigate more in this field and to work out methods to eliminate the heavy metals from our water.

Many methods have been devised till now but the most efficient method till date applied to this problem is the complexation of ligands with the metal ions. This has to some extent help in the extraction of heavy metals from contaminated water.

Amongst the ligands used, priority were given to macrocyclic ligands like cyclam and cyclen, supramolecules like cyclodextrin having a lower rim which provides a large surface area to bind ligands to chelate with the metal ions.

Also, molecules with scaffolds like the calix-4-arene can be used to bind ligands as pendant arms in order to complex the ligands with the heavy metal ions.

Removal of these complexes from the contaminated water is done in simple manner.

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