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BHARATHIDASAN UNIVERSITY,
MASTER OF SCIENCE
IN CHEMISTRY
By
M. Mohan Raj
(Regd.No. 2002MS05)
DEPARTMENT OF CHEMISTRY
BHARATHIDASAN UNIVERSITY
May 2004
___________________________________
Professor
CERTIFICATE
This is to certify that the dissertation entitled The Reactivity of Methylene Blue Towards Silver Nitrate and Mercury(II) Chloride submitted in partial fulfilment for the degree of Master of Science in Chemistry to Bharathidasan University, under the semester system, is a bonafide record of work done by Mr. M. Mohan Raj (Reg.No : 2002MS05) under my supervision and guidance and that the dissertation
has not previously formed the basis for the award of any degree, diploma, associateship, fellowship or other similar titles.
(K. Panchanatheswaran)
Table of Contents
Acknowledgement I
Abstract II
List of Figures IV
Introduction 1
Experimental Aspects
1). Instrumentation 13
Conclusion 42
References 43
ACKNOWLEDGEMENT
It is with great pleasure that I thank my guide Dr. K. Panchanatheswaran, Professor, for his valuable guidance, unstinted support, useful discussions and constant encouragement throughout the course of this study.
Dr. M. Palaniandavar, Professor and Head, Department of Chemistry, is gratefully thanked for having provided the necessary facilities.
My sincere thanks are due to all the faculty members, research scholars and the non-teaching staff for their encouragement.
Ms. S. Jose Kavitha spent her valuable time in solving the crystal structure of the one of the products, I thank and acknowledge
her services.
With profound gratitude Mr. T. R. Sarangarajan, Lecturer, SASTRA, Thanjavur and Mr. S. Chandrasekar, Lecturer, Government Arts College, Ariyalur are thanked for their support. I am very happy to thank my seniors Ms. M. Baby Mariyatra, Mr. E. Mothi Mohamed, and Mr. B. S. Krishnamoorthy for their support and help.
I offer my special thanks to my colleague, Ms. P. Suguna, for boosting my spirits, and to my friends, classmates and juniors for providing me support and comfort.
I am greatly indebted to my parents and sister for their love for me without which the completion this work would not have been possible. Above all, I thank God Almighty for His merciful blessings
ABSTRACT
The reaction of Methylene Blue with silver nitrate has yielded a violet solid, soluble in water, methanol and ethanol. Recrystallization of the product in water gave the diffraction quality crystals. Single crystal X-ray investigations were used to determine the crystal and molecular structure of the product. The compound crystallized in the space group P-1, whose structure was found to contain Methylene Blue cation and nitrate anion along with two water molecules. Several intermolecular attractions involving N-HO, C-HO and pi-pi interactions have been found in the product. Analogous reaction with mercury(II) chloride gave violet brown solid. Attempts to crystallize the product were not successful. The product was formulated to be either a complex of Methylene Blue with mercury (II) chloride or one with Methylene Blue cations and tetrachloromercurate anion. The leuco base of Methylene Blue was obtained by its reaction with silver nitrate and mercury(II) chloride. The colourless solids were not characterized completely.
List of Tables
_________________________________________________
_________________________________________________
Blue Nitrate. 27
Nitrate. 28
List of Figures
1. Structures of Phenothiazine drugs. 4 2. Structures of Methylene Blue derivatives. 6 3. Atom numbering scheme in Methylene Blue derivatives 7 4. IR spectrum of Methylene Blue 19 5. IR spectrum of the Methylene Blue Nitrate. 20 6. UV-Visible spectrum of Methylene Blue. 21 7. UV-Visible spectrum of Methylene Blue Nitrate. 22 8. Molecular structure of Methylenes Blue Nitrate with 50%
Mercury(II) Chloride. 39
CHAPTER I
Introduction
INTRODUCTION
Methylene Blue was first synthesized by the German chemist Heinrich in 1876. Robert Koch discovered the tubercle bacillus with the help of Methylene Blue. Paul Ehrlich who later discussed the antisyphilis drug, Salvarsan, noticed that the dye imparted colour only to the carriers of illnesses and at the same time destroy them without attacking the bodys own cells. The revolutionary idea led to the development of chemotherapy, one of the greatest advances in medical science. Methylene Blue is not only a good colouring agent for living cells but also an excellent redox indicator in aqueous solution as indicated below.
SNN23N(CH)32(CH) NS)N(CH32)(CH23N+ ............................reductionoxidationClH2+.HClmethylene blue(blue) leucomethylene blue(colorless) H The redox system of Methylene Blue Leucomethylene Blue
Methylene Blue, 3,7-bis-(dimethlamino)phenothiazonium chloride is by the far the most important phenothiazine dyestuff and is prepared by the oxidation of N,N-dimethyl-p- phenylenediamine in situ with sodium thiosulfate , sulfuric acid and sodium dichromate at
0C under carefully controlled conditions. Further dimethylamine is then added together with more dichromate to form the green indamine thiosulfonic acid, which is finally treated with copper(II) sulfate and further quantity of dichromate at 60-70C to give Methylene Blue.
222233NMe222NMeMeNNMe2NMe2NMe2NMe2NMe2NHNHNMe22SOSH3SOSH+........ NaSOO___ _ ................ __ __ O2) NSN(CH3)(CH23NHNNMe22 .................... SOCu4NS2MeN2MeN2MeN2MeN2MeN .................... ___ _ O+ HSO3Methylene blue(Indamine Thiosulfonic acid) Leuco methylene blue
The dyestuff may be isolated as the sparingly soluble zinc chloride double salt after first screening off the insoluble chrome residues. Medicinal quality Methylene Blue is obtained by a further
recrystallisation from dilute hydrochloric acid and brine. An alternative and versatile laboratory synthesis of 3,7-diaminosubstituted phenothiazine dyes is based upon the reaction of 3,7-dibromophenothiazonium bromide prepared from phenothiazine with amines.
Phenothiazine Dyes2:
Phenothiazine dyes are mostly salts of the oxidized form of 3,7-diaminophenothiazine with substituents on the amino groups. The first phenothiazine dye to be made was 3,7-di-aminophenothiazonium chloride, known as Lauths violet.
Methylene Blue3:
SNNN3CH3CH3CHH3C+ Cl H_ O2
SNEtNH+ MeNHEtMeCl
Toluidine Blue:
MeSNNH22MeN2MeN2MeN2MeN2MeN+ Cl
Methylene Blue:
Cl+NMe2NMe2NMe2NMe2NMe2NHSNMeMe
OHOHSO3_ 2MeN2MeN2MeN2MeN2MeN+ SN
Leuco-Methylene Blue2:
A pale yellow water insoluble solid. (m.p 185C) may be obtained from the indaminethiosulfonic acid precursor by boiling an aqueous solution with dilute acid or more conveniently, by reduction of Methylene Blue in aqueous solution with sodium dithionite. It is readily re-oxidised to Methylene Blue on exposure to air and can be N-acylated. Thus N-benzoyl-leuco-Methylene Blue is obtained by benzoylation of leuco-Methlyene Blue with benzoyl chloride in pyridine, in aqueous alkaline medium, or in a variety of waterimmiscible solvents.
Benzoyl-leuco-Methylene Blue is used in carbonless, pressuresensitive copying papers. In these systems it is dissolved, along with other color formers, for example Crystal Violet Lactone, in a nonpolar high boiling solvent and the solution is encapsulated in gelatin walled microcapsules. The suspension of capsules is applied to the underside of a sheet of paper. Application of pressure, by either writing or typing, to this paper causes the impression to a second, underlying, sheet of paper the upper surface of which is coated with an acidic material, generally an activated mineral such as silica or attapulgite clay. A methylene Blue print is formed by hydrolysis of the N-benzoyl group on the active surface and subsequent aerial oxidation of the Leucomethylene Blue so produced.
Methylene Blue forms several derivatives containing different anions whose structures were determined by X-ray Crystallography. The following are examples.
+ C3HCH3CH3CH3NNSNNCS_
SNNN3CH3CH3CHH3C+ HNNNHNHOOO2OH
Phenothiazine Drugs7
Antipsychotic Agents:
Drug substances, which depress Central Nervous System and are able to calm severely disturbed psychiatric patients without affecting consciousness or causing any neurological effects are called antipsychotic agents. They produce strong sedation without inducing sleep and cause a state of indifference.
Phenothiazine Derivatives
Many phenothiazine derivatives have been synthesized and several of them are useful in the treatment of psychotic states. Chlorpromazine is one of the derivatives, which was effective in the treatment of various psychotic disorders and also efficacious against nausea and vomiting.
Some fairly consistent patterns of relation between structure and antipsychotic activity among individual classes of compounds has been
noted. Stereochemical and conformational considerations are important for determination of psychotropic activity. In addition, water solubility, lipidwater partitioning acid-base properties and surface activity have been established to play a significant role in exhibiting potent antispychotic properties.
A third carbon unbranched side chain gives the most active compound in tranquilizing area i.e. amino group separated by third carbon atoms is optimal for antipsychotic activity. A basic tertiary amino moiety provides maximum antipsychotic potency 7.
Generic and
Proprietary
Name
Chemical
Name
Side Chain
R1
Chloropromazine
(Thorazine,
Largatil)
2-Chloro-10 (3-dimethylamnio)propylphenothazine,II
-(CH2) 3-(NH3) 2
Cl
Promazine
(sparine)
10-(3-dimethylamino)propyl-phenothiazine,III
Triflupromazine
(vesprin)
10-(3-dimetylamino)propyl)-2-(trifluoromethylphenothiazine, IV
-(CH2) 3-N(NH3)2
CF3
Promethazine
(Phenergan)
10-(2-Dimethylaminopropyl)
phenothiazine, V
N(CH2)CHCH3(CH3)2
Trifluoperazine
(Stelazine)
10(3-(4-methyl-)piperazinyl))
Propyl-2trifluoromethylphenothiazine, VI
NNCH33()CH2
CF3
Prochloroperazine
(Compazine)
NNCH33()CH2
Cl
Fluphenazine
(Permititil,Prolixin)
10-(3-(4-(2-hydroxyethyl) piperazinyl)
CH2)(3NNH2CC2HHO
CF3
Mosoridazine
(Serentil)
10-2-(1-methylsulfinyl) Phenothiazine,IX
N3()CH2CH3
OSCH
Drugs7
Methylene Blue
The dye methylene blue (MB) is widely used as a stain and has a number of biological uses as discussed below8. It can be used to treat urinary tract infections, to distinguish between cancerous and normal tissue and it has potential as a prophylactic treatment for Alzheimers disease. The metabolism and excretion of MB in living organisms was the subject of a number of investigations the earliest dating back to 1885. Early investigations showed that MB was eliminated form the body in unchanged from as well as in some leuco- dye forms. A detailed investigation was carried out in 1972 which confirmed these studies. It was shown that extracts of urine from human patients dosed with 10 mg sample of MB contained MB but also a leuco- dye form.The reaction between Chondroitin 4-Sulfate with Methylene Blue has been studied9. The results show that via an electrostatic interaction Methylene Blue aggregates on Chondroitin 4-Sulfate as concluded by CD spectra .
_______________________
n)( HOHHOOOOSO3HCCHOH2HCOOHOOOOHO+NaCNHO
Methylene Blue has well established photochemical properties and has been used in a variety of photochemical applications including photodynamic therapy(PDT)10, based on the property of cetain biocompatible sensitizers to generate reactive species when they absob light, resulting in the destruction of neighboring biomolecules and cell death.
Methylene Blue is used as a redox indicator in the estimation of titanium(III) chloride, in place of starch in iodometric titrations; its insoluble perchlorate and dichromate can serve as the basis of gravimetric determinations2. Methylene Blue can be oxidised by ammonium persulfate in presence of Au(III). This serves as the basis for the determination Pd(II)11. Arsenic can be determined in parts-per-million (ppm) level by absorbance measurement. This method is based on the quantitative colour bleaching of the dye, Methylene Blue by arsine catalysed by Ag or Au nano particles in micellar medium. This arsine has been generated in situ from sodium arsenate by sodium borohydride reduction. The absorbance measurement was carried out at the .max of the dye at 660 nm12. Methylene Blue can be reduced to the leuco-base form by reduction with ascorbic acid also13.
CHAPTER II
Methylene Blue is a cationic dye and important for its analytical and biological applications. It will be interesting to know about its reactions towards its metal salts, No metal complexes of Methylene Blue is known at present, although it has many sites for coordination. The structural unit of Methylene Blue viz, phenothiazine is present in many psychiatric drugs. The leuco base of Methylene Blue can also be prepared by the reaction with reducing agents. This can also react with metal salts, perhaps in different fashion.
Extraction of palladium from the nuclear waste of the power plants is one of the current challenges in nuclear chemistry. Making use of the known affinity of sulfur to Pd2+, sulfur based extractants are proposed for the above purpose. The interaction of Methylene Blue, a sulfur containing heterocyclic compound, with both Ag+ & Hg2+ is studied. The above ions closely resemble Pd2+ and are chosen for model studies. In order to ascertain the interaction of Ag+ & Hg2+, the reactions of Methylene Blue with AgNO3 and HgCl2 have been attempted.
CHAPTER III
Experimental Aspects
Experimental Aspects
1. Instrumentation
The IR spectrum was taken as KBr pellets using Perkin Elmer FTIR spectrophotometer at the Department of Chemistry, Bharathidasan University, Tiruchirappalli. The UV-Visible spectra were recorded using carry 300-model Varian UV-Visible spectrophotometer at the Department of Chemistry, Bharathidasan University, Tiruchirappalli. X-ray intensisty data were collected using the EPSRC National Crystallographic Services Southampton, England with Brucker Nonius KappaCCD area detector. The structure solution and refinement were carried out using the following programs, SHELXS97 and SHELXL97. Molecular diagrams were obtained with ORTEP3 package using 50 % probability thermal ellipsoids for the non hydrogen atoms and PLATON97 package.
2. Synthetic Chemistry
Silver nitrate (0.339 g, 2 mmol) and Methylene Blue (0.373 g, 1 mmol) were mixed in 40 ml of water. The mixture was stirred for half an hour. Diffraction quality violet crystals were obtained upon complete evaporation of water. m.p >280C.
IR (cm-1): 3418, 1599, 1486, 1443, 1384, 1356, 252, 1176, 1147, 1082, 961, 884, 814, 612.
Mercury(II) chloride (0.145 g, 1 mmol) was dissolved in methanol and Methylene Blue (0.2 g, 1 mmol) in water was added to it. The mixture was stirred for few minutes. The brown solid was filtered off. m.p >280C. Yield: 73%.
IR (cm-1): 3463, 1599, 1491, 1436, 1398, 1336, 1241, 1219, 1177, 1138, 1056, 1035, 948, 886, 851, 821, 663.
Sodium hydroxide (0.2 g) was added to 50 ml of water in a roundbottomed flask followed by 0.09 g of glucose. The mixture was treated with Methylene Blue (0.186 g, 1 mmol) in water. The mixture was heated in steps of 10C up to 50C. The blue coloured solution became colourless. This indicated the formation of Leucomethylene Blue, which was found to be unstable to air.
Mercury(II) chloride(0.135 g, 1 mmol) was dissolved in methanol and to that aqueous solution of Leucomethylene Blue (which was prepared by procedure (iii)) was added. The mixture was stirred for some time and filtered. The filtrate was evaporated to give rose red solid. m.p >280C.
Silver nitrate (0.0844 g, 1 mmol) was dissolved in water and to that aqueous solution of Leucomethylene Blue (which was prepared by procedure (iii)) was added. The mixture was stirred for some time and filtered. The filtrate was evaporated to give rose red solid. m. p >280C.
CHAPTER IV
The product is insoluble in chloroform whereas Methylene Blue is partially soluble in chloroform. The IR spectrum of the product shows features very different from that of Methylene Blue (Fig. 4 & 5). The spectrum has peaks due to Methylene Blue and the nitrate ion. The peak at 961 cm-1 which is absent in Methylene Blue, shows the presence of nitrate ion. The UV spectra of Methylene Blue nitrate indicates Red shift of absorption to 293 nm with respect to the absorption at 259 nm in Methylene Blue itself (Fig. 6 & 7)(Table. 2). In order to assign the structure of the solid X-ray Crystallographic investigation was undertaken. The Ortep diagram of the product is shown in (Fig. 8). The X-ray crystal structure shows that the product (1) Methylene Blue nitrate consists of Methylene Blue cation, nitrate anion and two water molecules. The Methylene Blue cation can be represented by structures I and II.
(CH3)2NNSN(CH3)2+N(CH3)2SN(CH3)2N+
I II
Structure II is predominant in the chloride and thiocyanate salts. The cation of the product adopts structure II as evident from the pronounced shortening of bonds C1-C2 (1.359(4) A) and C4-C12 (1.373(4) A) compared with the other carbon-carbon bonds. The two C-S bonds are equal in length, supporting that structure II is more appropriate
).2Hfor the cation. The bond lengths and angles are comparable to those of other Methylene Blue derivatives (Table 3 & 4). The relevant crystallographic data are given in Tables 5 to 10. In contrast to the chloride salt (MBCl.5H2O) the degree of hydration of the nitrate salt (MBNO3.2H2O) is lower. The analytical data (Table 11) also suggest the formula, C16H18N4SO3.2H2O(MB(NO32O).
The crystal structure is stabilized by pi-pi interaction between the adjacent aromatic moieties stacked in antiparallel fashon along b axis at a distance of 3.740(18) A as well as interlinking of the aromatic moieties by hydrogen bonds. This interaction occurs pairwise (Fig. 9). The nitrate ion and the water molecules form one-dimensional chain in a direction (Fig. 10). This is linked to the aromatic ring via C-HO and NHO interactions. The adjacent stacked pair is stabilized by hydrogen bonding interaction involving N(10) of the aromatic ring, nitrate and water molecules (Fig. 11). These intermolecular interactions contribute to the supramolecular structure of the product (Fig. 12).
In the IR spectrum of Methylene Blue (Fig. 4) the .cs which occurs at 1250 cm-1 is shifted to 1241 cm-1 in the product (2) (Fig. 13). This is indicative of a reaction. From the IR spectral data it can be inferred that coordination might have occurred through sulfur. The formulation of (MB)2HgCl4 is also possible for the product. This is supported by the
In the IR spectrum of Methylene Blue (Fig. 4) the .CN stretching frequency occurs at 1446 cm-1, which is significantly shifted to 1454 cm-1, in the product (3) (Fig. 14). Similarly, the .C=C is shifted from 1599 cm-1 to 1642 cm-1. This shows that the reaction has occurred and the coordination might have occurred through the N atom.
In the IR spectrum for the Methylene Blue (fig. 4) the .CN stretching frequency occurs at 1446 cm-1, which is shifted to 1454 cm1 in the product. Similarly, the .C=C is shifted from 1599 cm-1 to 1634 cm-1 in the product (4) (Fig. 15). This shows that the reaction has occurred between the two reagents and the coordination, if any, might have occurred through the N atom.
The correct structures can be assigned using X-ray crystallographic investigations. However, attempts to prepare crystals of products of the reactions of Lecuomethylene Blue with mercury(II) chloride and silver nitrate were not successful, although several attempts were made.
4013060801001204000400100020003000%TWavenumber[cm-1] IR cm-1 : 3397, 1599, 1489, 1446, 1395, 1354, 1339, 1250, 1220, 1180, 1143, 1064, 1036, 947, 884, 854, 808, 666, 536,
4000.03000200015001000450.028.7354045505560657074.0cm-1%T
IR (cm-1): 3418, 1599, 1486, 1443, 1384, 1356, 252, 1176, 1147, 1082, 961, 884, 814, 612.
UV/10mg/10ml
Methylene Blue
.max (nm)
Methylene Blue
nitrate
.max (nm)
665
665
259
293
Chloride Thiocyanate Acetone solvate C(1)-C(2) 1.341 1.357 1.343 C(1)-C(11) 1.417 1.411 1.426 C(2)-C(3) 1.445 1.436 1.423 C(3)-N(3) 1.331 1.48 1.344 C(3)-C(4) 1.419 1.391 1.416 N(3)-C(32) 1.454 1.489 1.463 N(3)-C(31) 1.465 1.546 1.444 C(4)-C(12) 1.349 1.341 1.375 S(5)-C(13) 1.738 1.736 1.728 S(5)-C(12) 1.721 1.742 1.729 C(6)-C(13) 1.356 1.356 1.368 C(6)-C(7) 1.401 1.401 1.391 C(7)-N(7) 1.344 1.314 1.355 C(7)-C(8) 1.423 1.447 1.443 N(7)-C(71) 1.444 1.536 1.456 N(7)-C(72) 1.444 1.508 1.453 C(8)-C(9) 1.349 1.346 1.35 C(9)-C(14) 1.421 1.409 1.409
N(10)-C(11) 1.336 1.329 1.324 N(10)-C(14) 1.337 1.353 1.343 C(11)-C(12) 1.439 1.418 1.438 C(13)-C(14) 1.42 1.401 1.443