Tadalafil Analytical/Spectral Visit

Uncategorized Comments Off

Mar 112015

Tadalafil

INTRODUCTION Tadalafil is a potent and selective phosphodiesterase-5 (PDE-5) inhibitor, asecondary messenger for the smoothmuscle relaxing effects of nitric oxide,which plays an important role in thevasodilation of erectile tissues.1-3 OralPDE-5 inhibitors have become the preferredfirst-line treatment for erectile dysfunction worldwide.4

PREPARATION

Diastereoselective synthesis of (+)-tadalafil (1)describes a process for the synthesis of tadalafil (1) and itsintermediate of formula5which involves reactingD-tryptophan methylester 2 with a piperonal 3 in the presence of methanol and conc. HCl to

give compound 4 . The later compound is then reacted with chloroacetyl chloride in the presence of NaHCO 3

to afford the intermediate5, which is reacted with methylamine in chloroform to give tadalafil in 88% yield

Stereoselective synthesis of (+)-tadalafil (1) and(+)-6-epi-tadalafil (8)[20]The target isomeric tadalafil molecule is shown . Thus,D-tryptophan methyl ester reacted with piperonal3under Pictet–Spen-gler reaction condition (TFA/CH2Cl2/MeOH) to furnish two diastereo-mers4and6in 25% and 24% yields, respectively. Condensation of4or6with chloroacetyl chloride provided acylated intermediate 5or7in almostquantitative yield. Subsequent cyclization of5withN-methyl amine inmethanol at 50C for 16 h provided diastereomers tadalafil (1) in 54%yield. Compound1is in full accordance with the literature data {[a]D20¼+71.4 (c 1.00, CHCl3); lit. [a]D20¼+71.2 (c 1.00, CHCl3)}[17,18]. Thus,under the elongated reaction time, 48 h, compound8was obtained fromprecursor7with decreased yield of 21%

depicts an efficient and stereospecific synthesis of tadalafil (1)as well as 12a-epi-tadalafil (11). Pictet–Spengler reaction ofD-trypto-phan methyl ester hydrochloride9with equal molar piperonal byrefluxing for 4 h in nitromethane affordedcis-10-HCl in 98% ee and94% yield. The hydrochloride salt ofcistetrahydro-b-carboline deriva-tivecis-10-HCl was directly treated with 1.5 equiv of chloroacetyl chlo-ride in dichloromethane at 0o

C in the presence of 3 equiv oftriethylamine to formN-chloroacetyl tetrahydro-b-carboline derivative5

in 92% yield. Then compound5reacted with 5 equiv of methylamineovernight in DMF at room temperature to furnish tadalafil1in95% yields.

US PATENT

D. Ben-Zion, D. Dov, United States Patent, US 2006/0276652 A1, 2006.

B.D. Pandurang, B.B. Bharat, S.S. Sachin, P.S. Pranay, United States Patent, US 7, 223,

863 B2, 2007.

FROM L TRYPTOPHAN

X. Sen, S. Xiao-Xin, X. Jing, Y. Jing-Jing, L. Shi-Ling, L. Wei-Dong, Tetrahedron

Asymmetr. 20 (2009) 2090.

S. Xiao-Xin, L. Shi-Ling, X. Wei, X. Yu-Lan, Tetrahedron Asymmetr. 19 (2008) 435

S. Xiao, X. Lu, X.-X. Shi, Y. Sun, L.-L. Liang, X.-H. Yu, J. Dong, Tetrahedron Asymmetr.

20 (2009) 430.

IR OF TADALAFIL

1H NMR OF TADALAFIL

13 C NMR OF TADALAFIL

COSY NMR OF TADALAFIL

DEPT NMR OF TADALAFIL

HSQC NMR OF TADALAFIL

HMBC NMR OF TADALAFIL

MASS SPECTRUM OF TADALAFIL

UV OF TADALAFIL

RAMAN SPEC OF TADALAFIL

SECTION 1 SECTION 2 .. SECTION 3 Journal of Pharmaceutical and Biomedical Analysis 47 (2008) 103–113 Analysis of illegally manufactured formulations of tadalafil (Cialis®) by 1H NMR, 2D DOSY 1H NMR and Raman spectroscopy Saleh Trefia, Corinne Routaboul b, Saleh Hamieh a, Veronique Gilard ´ a, Myriam Malet-Martino a,∗, Robert Martino a a Groupe de RMN Biom´edicale, Laboratoire SPCMIB (UMR CNRS 5068), France b Service commun de spectroscopie IR et Raman, Universit´e Paul Sa LC-DAD apparatus and chromatographic conditions HPLC was carried out using a Waters 2695 Alliance model with a Waters 2996 diode array detector. The analytical column was a reversed-phase column Luna C18 (100 mm × 3 mm i.d.; 3m particle size; Phenomenex, UK). The column temperature was 30 ◦C. The mobile phase consisted of a mixture (35:65, v/v) of acetonitrile and phosphate buffer (10 mmol L−1, pH 3). The flow rate was 0.6 mL min−1 and the volume injected 10 L. A detection wavelength of 225 nm was chosen as it allows the detection of all tadalafil or sildenafil analogues. For quantitative analysis, a calibration curve was constructed from the analysis of four solutions containing pure tadalafil in a concentration range of 0.01–0.1 mg mL−1. Each standard solution was injected in triplicate in the chromatographic system. The linearity (R2 > 0.999) was evaluated by least-squares linear regression analysis. LC–MS analysis The HPLC system used consisted of an Agilent 1100 series apparatus. An Applied System QTRAP triple quadrupole mass spectrometer, equipped with a turbo ion spray (TIS) interface, was used for detection. Both were controlled by an Agilent Analyst software (version 1.4). HPLC conditions were as follows. The column temperature was 30 ◦C. The mobile phase consisted of a mixture (50:50, v/v) of acetonitrile and a buffer solution (ammonium acetate 10 mmol L−1, pH 7). The flow rate was 0.6 mL min−1 and the volume injected 5 L. The mass spectrometer was operated in positive ionisation mode with TIS heater set at 450 ◦C. Nitrogen served both as auxiliary, collision gas and nebuliser gas. The operating conditions for TIS interface were—(i) in MS mode: mass range 200–550m (1 s), step size 0.1m; Q1 TIS MS spectra were recorded in profile mode, IS 5000 V, DP 85 V; (ii) in MS–MS mode: precursor mass 489 m; mass range 10–500 m (0.35 s); step size 0.15m; LC–MS–MS spectra were rec d in profile mode, IS 5000 V, DP 85 V and CE 40 V Fig. 3. DOSY NMR spectra in CD3CN:D2O (80:20) of genuine Eli Lilly Cialis® (A), formulation 6 Fig. 2. Raman spectra of pure tadalafil (A) and genuine Eli Lilly Cialis®: whole tablet (B), uncoated tablet from 200 to 1800 cm−1 (C), from 2500 to 3200 cm−1 (D). TiO2; talc (as shoulders of TiO2 bands); () lactose; () sodium lauryl sulfate; () magnesium stearate; (T) tadalafil. …………… Instrumentation The HPLC system consisted of a 1100 series quaternary pump, degasser, automatic injector, thermostatted column compartment, and diode array detector (Agilent Technologies, Palo Alto, CA);Vortex TecnoKartell TK3; shaker BIOSAN Multi Bio RS-24, and innovative mixing cycle (VWR international, USA).The data were collected using the system software (Chemstation 1990- 2002, Agilent Technologies). Chromatographic Conditions The separation was achieved on an Agilent LiChrospher 100, C18 column, 5-μm particle size, 250 x 4 mm I.D., with a 2-μm precolumn filter.The mobile phase consisted of 65% water acidified with glacial acetic acid (0.1 mM, pH 2.5- 2.7) and 35% acetonitrile. The flow rate was 0.8 mL/min, and UV detection was performed at 280 nm. All analyses were made at room temperature. The injection volume was 25 μL, and a small volume of air was bubbled through each sample before injection. pg 171-175

Lydia Rabbaa

Saint Joseph University, Lebanon · faculty of pharmacy

…………………………………… Research In Pharmaceutical Biotechnology Vol. 2(1), pp. 001-006, February, 2010 Available online at http://www.academicjournals.org/RPB Validation and stability indicating RP-HPLC method for the determination of tadalafil API in pharmaceutical formulations B. Prasanna Reddy1*, K. Amarnadh Reddy2 and M. S. Reddy3 1Department of Quality control, Nosch Labs Pvt Ltd, Hyderabad-500072, A.P, India. 2 Department of AR and D, Aurigene Discovery Technologies Ltd, Bangalore, India. 3Department of Plant Pathology and Entomology, Auburn University, USA.

Battu.Prasanna Reddy Ph.D

The present study describes the development and subsequent of a stability indicating RP-HPLC method for the analysis of tadalafil. The samples separated on an Inertsil C18, (5 m , 150 mm x 4.6 mm i.d) by isocratic run using acetonitrile and phosphate buffer as mobile phase), with a flow rate of 0.8 ml/min, and the determination wavelength was 260 nm for analysis of tadalafil. The described method was linear within range of 70 – 130 μg/ml (r2 = 0.999). The precision, ruggedness and robustness values were also within the prescribed limits (< 1% for system precision and < 2% for other parameters). Tadalafil was exposed to acidic, basic, oxidative and thermal stress conditions and the stressed samples were analyzed by the proposed method. Chromatographic peak purity results indicated the absence of coeluting peaks with the main peak of tadalafil, which demonstrated the specificity of assay method for estimation of tadalafil in presence of degradation products. The proposed method can be used for routine analysis of tadalafil in quality control laboratories. Tadalafil hydro-2-methyl-6-[3,4-(methylenedioxy)phenyl]pyrazino-[1’,2’:1,6]pyrido[3,4-b]indole-1,4-dione (Figure1), is a phosphodiesterase type 5 inhibitor used in the management of erectile dysfunction. It is not officially included in any of the pharmacopoeias. It is listed in the Merck Index (Budavari et al., 2001) and Martindle and complete drug reference (Sean et al., 2002). There are several (Cheng et al., 2005) methods for determination of tadalafil such as HPLC-EIMS (Zhu et al., 2005) and capillary electrophoresis methods (Aboul-Enein, 2005) and by HPLC (Aboul, 1994). The present work was designed to develop a simple, precise and rapid analytical LC procedure, which would serve as stability indicating assay method for analysis of tadalafil active pharmaceutical ingredient. *Corresponding author. E-mail: drbpkreddy@gmail.com. Tel: +91-9848392677. Prasanna Reddy. Manager, Quality Control, Nosch Labs Pvt Ltd. Hyderabad, INDIA http://bloggerbattu.blogspot.in/ REFERENCES 1. Pomerol JM, Rabasseda X.Tadalafil, a furtherinnovation in the treatment of sexual dysfunction. Drugs Today (Barc). 2003;39:103-113. 2. Francis SH, Corbin JD. Molecular mechanismsand pharmacokinetics of phosphodiesterase-5 antagonists. Curr Urol Rep. 2003;4:457-465. 3. Seftel AD. Phosphodiesterase type 5 inhibitordifferentiation based on selectivity, pharmacokinetic,and efficacy profile. Clin Cardiol.2004;27(4 suppl 1):I14-I19. 4 Bella AJ, Brock GB.Tadalafil in the treatment of erectile dysfunction. Curr Urol Rep. 2003;4:472-478. 7A. Daugan, P. Grondin, C. Ruault, A.-C. Le Monnier de Gouville, H. Coste, J. Kirilovsky,F. Hyafil, R. Labaudinie

re, J. Med. Chem. 46 (2003) 4525.

[8] A. Daugan, P. Grondin, C. Ruault, A.-C. Le Monnier de Gouville, H. Coste, J.M. Linget,

J. Kirilovsky, F. Hyafil, R. Labaudinie`

re, J. Med. Chem. 46 (2003) 4533.

[9] M.W. Orme, J.C. Sawyer, L.M. Schultze, World Patent WO 02/036593 17 S. Xiao-Xin, L. Shi-Ling, X. Wei, X. Yu-Lan, Tetrahedron Asymmetr. 19 (2008) 435.

[18] Merck index 2006, 14th edition pages 1550–1551.

[19] N.M. Graham, M.N.A. Charlotte, G. Eugene, A.M. William, Bioorg. Med. Chem. Lett. 13

(2003) 1425.

[20] Y. Zhang, Q. He, H. Ding, X. Wu, Y. Xie, Org. Prep. Proced. Int. 37 (2005) 99.

Tadalafil
Systematic (IUPAC) name


(6R–trans)-6-(1,3-benzodioxol-5-yl)- 2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1′, 2′:1,6] pyrido[3,4-b]indole-1,4-dione
Clinical data
Trade names	Cialis
AHFS/Drugs.com	monograph
MedlinePlus	a604008
Pregnancy category	B
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	varies
Protein binding	94%
Metabolism	CYP3A4 (liver)
Half-life	17.5 hours
Excretion	feces (> 60%), urine (> 30%)
Identifiers
CAS number	171596-29-5
ATC code	G04 BE08
PubChem	CID 110635
DrugBank	DB00820
ChemSpider	99301
UNII	742SXX0ICT
KEGG	D02008
ChEBI	CHEBI:71940
ChEMBL	CHEMBL779
PDB ligand ID	CIA (PDBe, RCSB PDB)
Chemical data
Formula	C₂₂H₁₉N₃O₄
Molecular mass	389.404 g/mol

The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

drugs Comments Off

Feb 172015

ARKIVOC Volume 2006
Part (v): Commemorative Issue in Honor of
Facilitator: Luba Ignatovich
Scientific Editor: Mikael Begtrup

2. The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study (EL-1719AP)
Rosa M. Claramunt, Concepción López and José Elguero
Full Text: PDF (193K)
pp. 5 – 11

The structure of Omeprazole in the solid state: a 13C and 15N NMR/CPMAS study

Rosa M. Claramunt,a Concepción López,a and José Elguero b *

a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain

b Instituto de Química Médica, CSIC, Juan de la Cierva, 3. E-28006 Madrid, Spain E-mail: iqmbe17@iqm.csic.es

To our friend Professor Edmunds Lukevics on his 70th anniversary

Edmunds Lukevics

Abstract

The 13C and 15N CPMAS spectra of a solid sample of Omeprazole have been recorded and all the signals assigned. The sample consists uniquely of the 6-methoxy tautomer. For analytical purposes, the signals of the other tautomer, the 5-methoxy one, were estimated from the data in solution (Magn. Reson. Chem. 2004, 42, 712).

Keywords: Omeprazole, NMR, 13C, 15N, CPMAS, tautomerism, benzimidazole

see at

http://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/2006/5/graphical-abstracts/

http://www.arkat-usa.org/get-file/22955/

Edmunds LUKEVICS

(14.12.1936 – 21.11.2009)

Professor Edmunds LUKEVICS
Latvian Institute of Organic Synthesis,
Head of the Laboratory of Organometallic ChemistryAizkraukles iela 21,
Riga, LV-1006
Latvia

Born: December 14, 1936, Liepaja, Latvia
Departed: November 21, 2009, Riga, Latvia

Interests:

Organometallic Compounds
Heterocyclic Compounds
Biological Activity of Organic Compounds

Main Research:

Development of methods for the synthesis of organosilicon and -germanium derivatives of furan, thiophene and nitrogen-containing heterocycles ; study of the influence of organosilicon ,-germanium and -tin substituents on the direction of substitution and addition reactions of furan and thiophene derivatives ; study of hydrosilylation and hydrogermylation reactions, synthesis and investigation of properties of penta- and hexacoordinated organosilicon and -germanium derivatives; application of alkenyl silanes and germanes in the synthesis of nitrogen-containing heterocycles; application of phase-transfer catalysis and ultrasonic irradiation in organometallic synthesis; synthesis of biologically active organosilicon and organogermanium compounds and studies of their properties.

Education:

University of Latvia (Faculty of Chemistry), 1958
Dr.chem. (Candidate of Science in former USSR, Ph.D. in Western countries), Latvian Academy of Sciences, Riga, 1966
Dr.habil.chem. (Doctor of Science in former USSR), Latvian Academy of Sciences, Riga, 1973

Experience:

Latvian Institute of Organic Synthesis –

Junior Researcher, 1958-1967
Senior Researcher, 1968-1970
Head, Laboratory of Organometallic Chemistry, 1970 – 2009
Vice-director, 1980-1982
Director, 1982 – 2003

Honours and Awards:

Corresponding Member, Latvian Academy of Sciences , 1982
Full Member, Latvian Academy of Sciences , 1987
Member, New York Academy of Sciences, 1993
The Latvian Academy of Sciences Gustavs Vanags Prize (in Chemistry), 1986
Latvian SSR State Prize, 1974, 1989
S.Hiller Medal (Latvian Institute of Organic Synthesis), 1990
G.Vanags Medal (Riga Technical University), 1991
D.H.Grindel Medal (company ‘Grindex’, Latvia), 1995
L.Liepina Medal (Institute of Inorganic Chemistry, Riga), 1996
The Latvian Academy of Sciences Grand Medal, 1996
Silver Medal of Milan University, 1996
Schmiedebergs Medal (Latvian Pharmacological Society), 1998
The Latvian Academy of Sciences and Company “GRINDEX” Prize, 1999
Paul Walden’s Medal (Riga Technical University), 2000
Latvian Academy of Sciences Presidium Award, 1971, 1973, 1977, 1981, 1982, 1985,1987, 1989, 1992
International Man of the Year (The International Biographic Centre of Cambridge, England), 1992-1993, 1994-1995
Man of the Year (The American Biographical Institute), 1994, 2005
The first-level Badge of Honour of the Order of Three Stars, 1997
Company “Grindex” gold badge of honour, 2001
The Cabinet of Ministers of the Republic of Latvia Prize , 2004
American Medal of Honor (ABI), 2005
Gold Medal for Latvia (ABI), 2006
The Plato Award (IBC), 2006
Man of Achievement (ABI), 2007

Professional Activities:

Member of Presidium and Senate, Latvian Academy of Sciences, 1987-1991
Member of Board, Division of Chemical and Biological Sciences, Latvian Academy of Sciences, 1983-1993
Member, Latvian Academy of Sciences Commission on Terminology, 1987- 1999
Chairman, Habilitation and Promotion Council (Chemistry and Pharmacy), Latvian Institute of Organic Synthesis, 1994 -1999
Member (Chairman,1991-1993, 1997-2002), Latvian Council of Science Expert Committee for Chemistry, 1991 – 2006
Vice-chairman, Habilitation and Promotion Council (Chemistry), University of Latvia, 1998- 2009
Member of Editorial Board for:

Khimiya Geterotsikicheskikh. Soedinenii (Chemistry of Heterocyclic Compounds, Springer), 1980-1985; Editor-in-chief, 1985 – 2009
Proceedings of Latvian Academy of Sciences, 1982-1990
Latvian Journal of Chemistry, 1991 – 2009
Bioorganicheskaya Khimiya, 1989 – 1993
Applied Organometallic Chemistry, 1990 – 2009
Main Group Metal Chemistry, 1992 – 2009
Metal-Based Drugs, 1993 – 2003
Mendeleev Communications, 1994 – 2009
Advances in Heterocyclic Chemistry, 1994 – 2009
Silicon Chemistry, 2001-2007
Arkivoc, 2001 – 2009
Bioinorganic Chemistry and Applications, 2003 – 2006
Heterocyclic Communications, 2005 – 2009
Molecules, 2008 – 2009
Journal of Organic and Pharmaceutical Chemistry (Ukraine), 2009 – 2009

Chairman, Scientific Council “Chemistry and Technology of Sulfur Organic Compounds”, USSR State Committee of Science and Technics, 1982-1987
Chairman, Council “Application of Organometallic Compounds in National Economy”, USSR (Russian) Academy of Sciences, 1984-1992
Member, United Libraries Informative Council, USSR Academy of Sciences, 1985-1990
Member, Scientific Council “Physiologically Active Compounds”, USSR Academy of Sciences, 1986-1992
Member, Scientific and Technical Council, USSR Ministry of Medical and Microbiological Industry, 1987-1990
Member, Soviet National Committee on collecting and estimating information in science and technics “CODATA”, 1987-1990
Member of Council for Coordination of scientific work, Department of Biochemistry, Biophysics and Physiologically Active Compounds, USSR Academy of Sciences, 1988-1991
Member of International Organizing Committees
– International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin and Lead, 1992, 1995, 1998, 2001
– International Symposium on Organosilicon Chemistry, 1993, 1996, 1999, 2002, 2005, 2008.

Memberships:

Member of Organometallic Chemistry Division, Federation of European Chemical Societies, 1995-2005
Member of Organometallic Chemistry Division, European Association for Chemical & Molecular Sciences, 2006
Member, Latvian Chemical Society, 1995
Member, American Chemical Society, 1997
Member, National Geographic Society, 1997
Honorary Member, Pharmacological Society of Latvia, 1998

Lectures

Invited Lectures at Universities

Indian Institute of Science, Bangalore (India), 1989
Indian Institute of Technology, Bombay (India), 1989
University of Dresden (Germany), 1989
Universities of Bordeaux, Tolouse, Montpellier, Marseilles (France), 1990, 1994
University of Lund (Sweden), 1992
University of Alcala de Henares ( Spain), 1993
Tohoku University (Sendai, Japan), 1991, 1992
Tokyo University of Science (Japan), 1997
Kyoto University (Japan), 1997
Universities of Kyoto and Kanagawa, Japan, 2002.

Invited Lectures and Symposium’s Plenary Lectures:

40th Nobel Symposium (Lidingö, Sweden), 1977
VI Symposium on Chemistry of Heterocyclic Compounds (Brno, Czechoslovakia), 1978
7th International Symposium on Organosilicon Chemistry (Kyoto, Japan), 1984
VI FECHEM Conference on Organometallic Chemistry (riga, Latvia), 1985
II Soviet-Indian Symposium on Organometallic Chemistry( Irkutsk, Russia), 1989
17th DDR-Poland Colloquy on Organometallic Chemistry (Holzhau, Germany), 1989
6th International Conference on Organometallic and Coordination Chemistry of Germanium, Tin and Lead (Brussels, Belgium), 1989
Huang Minlon Symposium on Organic Chemistry (Shanghai, China), 1989
International Chemical Conference on Silicon and Tin ( Kuala Lumpur, Malaisia), 1989
9th International Symposium on Organosilicon Chemistry (Edinburgh, UK), 1990
1st Meeting of the European Society of Sonochemistry, Autrans (Grenoble, France), 1990
11th International Symposium on Medicinal Chemistry (Jerusalem, Israel), 1990
S.Hiller Memorial Lectures (Riga, Latvia), 1990
1st Meeting of Japanese Germanium Discussion Group (Tokyo, Japan), 1991
International Conference on Environmental and Biological Aspects of Maingroups Organometals (Padua, Italy), 1991
3rd Swedish-German workshop: Nucleic Acid Synthesis, Structure and Function (Uppsala, Sweden), 1992
2nd ANAIC Conference on Materials Science and Environmental Chemistry of Main Group Elements (Kual Lumpur, Malaysia), 1993
Todai Symposium “Ge-Sn-Pb Tokyo’93”: International Symposium on Organic, Bioorganic and Bioinorganic Chemistry of Compounds of higher row Group 14-elements (Tokyo, Japan), 1993
10th International Symposium on Organosilicon Chemistry (Poznan, Poland), 1993
3rd Meeting of the European Society of Sonochemistry (Figueira da Foz, Portugal), 1993
14th Nordic Meeting of Structural Chemists (Helsinki, Finland), 1993
8th International Conference on the Organometallic Chemistry of Germanium, Tin and Lead (Sendai, Japan), 1995
8th IUPAC Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (Santa Barbara, USA), 1995
8th Symposium Heterocycles in Bioorganic Chemistry (Como, Italy), 1996
9th International Conference on the Coordination and Organometallic Chemistry of Germanium, Tin, and Lead (Melbourne, Australia), 1998
12th International Conference on Organosilicon Chemistry (Sendai, Japan), 1999
International Conference on Organic Synthesis “Balticum Organicum Sinteticum-2000″(Vilnius, Lithuania), 2000
X International Symposium “Jubilee Krka Prizes” (Novo Mesto, Slovenia), 2000

Recent/Representative Publications:

E.Ya. Lukevits, M.G.Voronkov. Organic Insertion Reactions of Group IV Elements, 1966, New York: Consultants Bureau, 413 pp.
S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Heteropolymers and Heterocompounds, 1970, NewYork: Plenum Press, 633 pp.
S.N.Borisov, M.G.Voronkov, E.Ya.Lukevits. Organosilicon Derivatives of Phosphorus and Sulfur, 1971, NewYork; London: Plenum Press, 343 pp.
M.G.Voronkov, G.I..Zelchan, E.Ya.Lukevits. Silizium und Leben, 1975, Berlin: Akademie-Verlag, 370 pp.
E.Lukevics, O.Pudova, R.Sturkovich. Molecular Structure of Organosilicon Compounds, 1989, Chichester: Ellis Horwood Ltd., 359 pp.
E.Lukevics, T.Gar, L.Ignatovich, V.Mironov. Biological Activity of Germanium Compounds, 1990, Riga: Zinatne, 191 pp. (in Russian).
E.Lukevics, A.Zablocka. Nucleoside Synthesis: Organosilicon Methods, 1991, Chichester: Ellis Horwood, 496 pp.
E.Lukevics, L.Ignatovich. Biological activity of organogermanium compounds. – In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1653-1683.
E.Lukevics, O.Pudova. Biological activity of organogermanium compounds. – In: The Chemistry of Organic Germanium, Tin and Lead Compounds/Ed. Z.Rappoport/, Wiley, Chichester, 2002, vol. 2, pt. 2, pp. 1685-1714.

E.Lukevics, O.Pudova. Silyl imidic esters. – In: Science of Synthesis, Thieme, 2002, vol. 4, pp. 305-315.
E. Lukevics, P. Arsenyan, S. Belyakov, O. Pudova. Synthesis, structure and chemical transformations of ethynylgermatranes – Eur. J. Inorg. Chem., 2003, Iss.17, pp.3139-3143.
R. Abele, E. Abele, M. Fleisher, S. Grinberga, E. Lukevics. Novel fluoride ion mediated synthesis of unsymmetrical siloxanes under phase transfer catalysis conditions. – J. Organomet. Chem., 2003, vol.686, N 1/2, pp.52-57.
E. Lukevics, L. Ignatovich, I.Shestakova. Synthesis, psychotropic and anticancer activity of 2,2-dimethyl-5-[5-trialkylgermyl(silyl)-2’-hetarylidene]-1,3-dioxane-4,6-diones and their analogues. – Appl.Organomet. Chem., 2003, vol. 17, N 12, pp.898-905.
P. Arsenyan, K. Rubina, I. Shestakova, E. Abele, R. Abele, I. Domracheva, A. Nesterova, J. Popelis, E. Lukevics. Synthesis and cytotoxicity of silylalkylthio-substituted N-heterocycles and their hydroselenites. – Appl. Organomet. Chem., 2003, vol. 17, N 11, pp.825-830.
E. Lukevics, L. Ignatovich, T. Shul’ga, S. Belyakov. The crystal structure of 2-benzo[b]thienylgermatrane. – Appl. Organomet. Chem., 2003, vol. 17, N 9, pp.745-746.
K. Rubina, E. Abele, P. Arsenyan, M. Fleisher, J. Popelis, A. Gaukhman, E. Lukevics. The role of palladium catalyst and base in stereoselective tranformations of (E)-2-chlorovinylsulfides. –Tetrahedron, 2003, vol.59, N 38, pp.7603-7607.
I. Iovel, L. Golomba, J. Popelis, S. Grinberga, E. Lukevics Catalytic hydrosilylation of furan, thiophene, and pyridine aldimines. – Chem. Heterocycl. Comp., 2003, vol.39, N 1, pp.49-55.
G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E. Lukevics. Design of ß-lactams with mechanism based nonbacterial activities. – Current Medicinal Chemistry, 2003, vol.10, N 17, pp.1741-1757.
E. Lukevics, P. Arsenyan, O. Pudova. Methods for the synthesis of oligothiophenes. – Heterocycles, 2003, vol.60, N 3, pp.663-687.
V.Dirnens, V.Klusa, J.Skuyins, S.Svirskis, S.Germane, A.Kemme, E.Lukevics. Synthesis and pharmacological activity of silyl isoxazolines-2. – Silicon Chemistry, 2003 (publ. 2004), vol. 2, N 1/2, pp. 11-25.
I.Iovel, L.Golomba, M.Fleischer, J.Popelis, S.Grinberga, E.Lukevics. Hydrosilylation of (hetero)aromatic aldimines in the presence of Pd(I) complex. – Chem.Heterocycl. Comp., 2004, vol. 40, N 6, pp. 701-714.
P.Arsenyan, O.Pudova, J.Popelis, E.Lukevics. Novel radial oligothienylsilanes. – Tetrahedron Lett., 2004, vol. 45, N 15, pp. 3109-3111.
E.Lukevics, L.Ignatovich, S.Belyakov. Crystallographic report: 2-furfurylgermatrane. – Appl. Organomet. Chem., 2004, vol. 18, N 4, p. 203.
G. Veinberg, I. Shestakova, M. Vorona, I. Kanepe, E. Lukevics. Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones. – Bioorg. Med. Chem. Letters, 2004, vol. 14, No 1, 147-150.
E.Lukevics, L.Ignatovich, T.Shulga, S.Belyakov. 1-[4-(2-Thienyl)phenyl]germatrane. – Appl. Organomet. Chem., 2005, vol. 19, N 1, pp. 167-168.
E.Lukevics, L.Ignatovich. Biological activity of organosilicon compounds. – In: Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 83-107.
E.Lukevics, L.Ignatovich. Biological activity of organogermanium compounds. – In: Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The Use of Metals in Medicine / Eds. M.Gielen, E.R.T.Tiekink/, 2005, J.Wiley & Sons, Ltd. Chichester, pp. 279-295.
Yu.Melnik, M.Vorona, G.Veinberg, J.Popelis, L.Ignatovich, E.Lukevics. Synthesis and stereoisomerization of 2-(1-alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans. – Chem. Heterocycl. Comp., 2005, vol. 41, N 6, pp. 718-721.
L.Ignatovich, J.Popelis, E.Lukevics. Synthesis and NMR spectra of diaryl- and dihetarylsilacycloalkanes. – In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 559-562.
L.Ignatovich, D.Zarina, I.Shestakova, S.Germane, E.Lukevics. Synthesis and bological activity of silicon derivatives of 2-trifluoroacetylfuran and their oximes. – In: Organosilicon Chemistry VI / Eds. N.Auner and J.Weis/, Wiley-VCH Weinheim, 2005, vol. 1, pp. 563-568.
E.Lukevics, L.Ignatovich, I.Sleiksha, I.Shestakova, I.Domrachova, J.Popelis. Synthesis and cytotoxic activity of silacycloalkylsubstituted heterocyclic aldehydes. – Appl. Organomet. Chem., 2005, vol. 19, N 10, pp. 1109-1113.
S.Belyakov, E.Alksnis, V.Muravenko, I.Turovskis, J.Popelis, E.Lukevics. Crystal structure and conformation of 8-(2-hydroxyethylamino)- and 8-(pyrrolidin-1-yl)adenosines. – Nucleosides, Nucleotides & Nucleic Acid, 2005, vol. 24, N 8, pp. 1199-1208.
A. Zablotskaya, I.Segal, S.Belyakov, E.Lukevics. Silyl modification of biologically active compounds. 11. Synthesis, physico-chemical and biological evaluation of N-(trialkoxysilylalkyl)tetrahydro(iso,silaiso)quinoline derivatives. Appl. Organomet. Chem. 2006, vol.20, N 2, 149-159.
A.Zablotskaya, I.Segal, J.Popelis, E.Lukevics, S.Baluja, I.Shestakova, I.Domracheva. Silyl modification of biologically active compounds. 12. Silyl group as true incentive to antitumour and antibacterial action of choline and colamine analogues. – Appl. Organomet. Chem. 2006, vol. 20, N 11, 721-728.
E.Lukevics, L.Ignatovich, I.Sleiksha, V.Muravenko, I.Shestakova, S.Belyakov, J.Popelis. Synthesis, structure and cytotoxic activity of 2-acetyl-5-trimethylsilylthiophene(furan) and their oximes. – Appl. Organomet. Chem. 2006, vol 20, N 7, 454-458.
L.Ignatovich, V.Muravenko, S.Grinberga, E.Lukevics. Novel reactions to form an Si-O-Ge group. – Chem.Heterocycl. Comp., 2006, vol. 42, N 2, 268-271.
E.Lukevics, I.Shestakova, I.Domrachova, A.Nesterova, Y.Ashaks, D.Zaruma. Synthesis of complex compounds of methyl derivatives of 8-quinolineselenol with metals and their cytotoxic activity. – Chem.Heterocycl. Comp., 2006, vol. 42, N 1, 53-59.
E.Lukevics, L.Ignatovich, I.Sleiksha, V.Romanov, S.Grinberga, J.Popelis, I.Shestakova. A New method for the synthesis of silicon- and germanium-containing 2-acetylfurans and 2-acetylthiophenes. –Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 143-150.
V.Dirnens, I.Skrastina, J.Popelis, E.Lukevics. Synthesis of isoxazolinylxanthines. – Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 193-196.
E.Lukevics, L.Ignatovich, S.Belyakov. Disordering in the crystal structure of thienylgermatranes. – Chem.Heterocycl. Comp., 2007, vol. 43, N 2, 243-249.
E.Lukevics, I.Shestakova, I.Domrachova, E. Yashchenko, D.Zaruma. Y.Ashaks. Cytotoxic di(8-quinolyl)disulfides. – Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 629-633.
V.M.Vorona, I.Potorocina, G.Veinberg, I.Shestakova, I.Kanepe, M.Petrova, E. Liepinsh, E.Lukevics. Synthesis and structural modification of tert-butyl ester of 7a-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em carboxylic acid.- Chem.Heterocycl. Comp., 2007, vol. 43, N 5, 646-652.
A.Zablotskaya, I.Segal, E.Lukevics, S.Belyakov, H.Spies. Tetrahydroquinoline and tetrahydroisoquinoline mixed ligand rhenium complexes with the SNS/S donor atom set.- Appl.Organomet.Chem.,2007, vol.21, N 4, 288-293.
A.Zablotskaya, I.Segal, M. Maiorov, D. Zablotsky, A. Mishnev E.Lukevics, I.Shestakova, I. Domracheva. Synthesis and characterization of nanoparticles with an iron oxide magnetic core and a biologically active trialkylsilylated aliphatic alkanolamine shell. J. Magn. Magn. Mater. 2007, 311, pp. 135-139.
Zablotskaya A., Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I. Synyhesis, physico-chemical and biological study of trialkylsiloxyalkylamine coated iron oxide/oleic acid magnetic nanoparticles for the treatment of cancer. – Appl. Organomet. Chem. 2008, vol. 22, pp. 82-88.
E.Lukevics, E.Abele. Four-membered rings with three heteroatoms not including oxygen, sulfur or nitrogen atom. – In: Comprehensive Heterocyclic Chemistry III., 2008, 2. Four-membered heterocycles together with all fused systems containing a four-membered heterocyclic ring (Exec. Ed. A. Katritzky, FRS: Eds Ch.A. Ramsden, E.V.Scriven, R.J.Taylor), pp. 973-989.
Soualami S., Ignatovich L., Lukevics E.,Ourari A., Jouikov V. Electrochemical oxidation of benzylgermatranes. – J. Organomet. Chem., 2008, vol.693 (7), pp. 1346-1352.
Lukevics E., Ignatovich L., Shul’ga T., Belyakov S. Synthesis and crystal structure of 1-(4-fluorophenyl)- and 1-(4-dimethylamino)phenylgermatranes. – Chem. Heterocycl.Comp. (Engl.Ed.), 2008, vol. 44 (5), pp. 615-620.
Abele E., Lukevics E. Synthesis of Heterocycles from Oximes. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. (Eds. Z.Rapoport, J.F.Liebmann ), J.Wiley, Chichester, 2009, Part I, pp. 233-302.
Erchak N., Belyakov S., Kalvinsh I., Pypowski K., Valbahs E., Lukevics E. Two polymorphic modifications of 1-(N-morpholiniomethyl)spirobi(3-oxo-2,5-dioxa-1-silacyclopentan)ate hydrate. –Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 9, pp.1137-1143..
Zablotskaya A.,Segal I., Lukevics E., Maiorov M., Zablotsky D., Blums E., Shestakova I., Domracheva I. Water-soluble magnetic nanoparticleswith biologically active stabilizers. – J.Magn.Mater.,2009, 321, pp. 1428-1432.
Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. – Appl. Organomet. Chem. 2009, DOI 10.1002, aoc, 1538.
Vorona M., Veinberg G.,Liepinsh E., Kazoka H., Andrejeva G., Lukevics E. Enzymatic synthesis of amoxycilloic acids. – Chem.Heterocycl. Comp.(Engl. Ed.), 2009, vol. 45, N 6, pp.782-754.
Zablotskaya A.,Segal I., Lukevics E. Iron oxide-based magnetic nanostructures bearing cytotoxic organosilicon molecules for drug delivery and therapy. – Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 150-157.
Ignatovich L., Muravenko V., Shestakova I., Domracheva I, Popelis J., Lukevics E. Synthesis and Cytotoxic activity of new 2-[(3-aminopropyl)- dimethylsilyl]-5-triethylsilylfurans. – Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 158-161.
Segal I., Zablotskaya A.,Lukevics E., Maiorov M., Zablotsky D., Blums E., Mishnew A., Georgieva R., Shestakova I., Gulbe A. Preparation and cytotoxic properties of goethite-based nanoparticles covered with decyldimethyl(dimethylaminoethoxy)silane metoxyde. – Appl. Organomet. Chem. 2010, vol. 24, N 3, pp. 193-197.
Ignatovich L., Muravenko V., RomanovsV, Sleiksha I., Shestakova I., Domracheva I, Belyakov S., Popelis J., Lukevics E. Synthesis, structure and cytotoxic activity of new 1-[5-organylsilyl(germyl)-2-furyl(thienyl)]nitroethenes. – Appl. Organomet. Chem. 2010, vol. 24, N 12, pp. 858-864.
Lukevics E., Abele E., Ignatovich L. Biologically Active Silacyclanes. – Adv. Heterocycl. Chem., 2010, vol. 99, pp. 107-141.
Abele E., Lukevics E. Synthesis, structure and reactions of organometallic derivatives of oximes. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 4), pp. 145-203.
Katkevics M., Kukosha T., Lukevics E. Heterocycles from hydroxylamines and hydroxamic acids. – In: The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Eds. by Zvi Rapoport, J.F.Liebman. 2011, Vol.2, Part 1 (Chapter 5), pp. 205-293.

Research Projects:

E.Lukevics (Head of Project). Silylheterocycles in Organic Chemistry. Latvian Council of Science (1993-1995).
E.Lukevics (Head of Project). Bifunctional Organosilicon Compounds. Latvian Council of Science (1993-1995).
E.Lukevics (Head of Project). Synthesis of Heterocyclic Organosilicon and Organogermanium Compounds, Investigation of their Physical and Chemical Properties. Latvian Council of Science (1997-2000 ).
E.Lukevics (Head of Project). Asymmetric and Catalytic Synthesis of Heteroaromatic Compounds. Latvian Council of Science (1997-2000 ).
E.Lukevics (Head of Program). The Development of Modern Methods of Organic Chemistry Directed towards the Development of Pharmaceutical Industry in Latvia. Latvian Council of Science (1997-2000 ).
E.Lukevics (Head of Project). Experimental and Theoretical Aspects of the Catalytical Synthesis of Heteroaromatic Compounds. Latvian Council of Science (2001 –2004 ).
E.Lukevics (Head of Project). Comparative Study of the Structure and Biological Activity of Organosilicon and Organogermanium Compounds. Latvian Council of Science (2001 – 2004).
E.Lukevics (Head of Project). Heterocyclic Derivatives of Tetra- and Hypercoordinated Germanium and Silicon. Latvian Council of Science (2005 -).
E.Lukevics ( Programme Director). Development of Organic Synthesis Methods for Obtaining of Biologically Active Compounds. Latvian Council of Science (2002 -2005 ).
E.Lukevics ( Programme Director). Development of Heteroatom Chemistry for Preparation of Biologically Active Compounds. Latvian Council of Science (2006 – 2009 ).
E.Lukevics (Head of Project). Carbofunctional Silylheterocycles. Latvian Council of Science (2009 ).

Hobbies:

Opera, Basketball, Mountains.

Edmunds LUKEVICS

Edmunds LUKEVICS
Head of Laboratory of Organometallic Chemistry

Latvian Institute of Organic Synthesis

Aizkraukles iela 21,
Riga, LV-1006
http://www.lza.lv/scientists/lukevics.htm

Born: December 14, 1936, Liepaja, Latvia
Departed: November 21, 2009, Riga, Latvia

Interests in inventing:

Development of medicament synthesis and technology
Development of the synthesis and technology of agricultural chemicals

Main invention:

In the sphere of medicament synthesis:

Acylete derivatives of aminobenzylpenicillin with antimicrobe activity.
Co-authors: G.Veinbergs, G.Kvitsors a.o.
Authors’ certificate of USSR Nr.1829360, 1992
Substituted 3-hydrazinopropionates and their pharmaceutically available salts with antiarythmic activity.
Co-authors: G.Bremanis, I. Kalvins, I.Ancena a.o.
Authors’ certificate of USSR Nr.1247012, 1986.
Patent of USA Nr. 4633014
Patent of England Nr. 2144121
Patent of France Nr. 2549050
Patent of Italy Nr.1175577

In the sphere of the synthesis of agricultural chemicals:

2,2 –dimethyl-6-alkyl–1,3-dioxa-6-aza-2-silacyclooctanes with antiinsect activity.
Co-authors: V.Markina, N.Smirnova a.o.
Authors’ certificate of USSR Nr.687855, 1978.
Lucerne productivity stimulator.
Co-authors: L.Sermans, V.Janisevska, G.Zelcans a.o.
Authors’ certificate of USSR Nr. 1161056, 1985

Selection of patent documents:

Totally: 104 authors’ certificates of USSR, 11 patents of Latvia, 3 patents of Germany, 3 patents of Canada, 3 patents of France, 3 patents of Italy, 1 patent of Japan, 1 patent of Switzerland, 4 patents of Great Britain, 5 patents of USA.

Patents of Latvia:

E.Lukevics, D.Feldmane, H.Kazoka, I.Turovskis. Method for obtaining metoxi-alpha-methylbenzyl alcohol. Patent of Latvia Nr. 11864, C 07 C 29/58, 1997;
E.Lukevics, V.Slavinska, Dz.Sile, M.Katkevics, E.Korcagova. Method for obtaining 2-oxo-4-phenylbutane acid ethylester. Patent of Latvia Nr. 11891, C 07 C 69/716, 1998;
E.Lukevics, V.Slavinska, Dz.Sile, M.Katkevics, E.Korcagova, V.Belikovs. Method for obtaining 2-oxo-4-phenylbutane acid ethylester. Patent of Latvia Nr. 11892, C 07 C 69/716, 1998;
E.Lukevics, I.Kalvins, A.Birmans. Cardioprotector “Mildronate”. Patent of Latvia Nr. 5402, A 61 K 31/205, 1994;
E.Lukevics, G.Veinbergs, I.Sestakova, I.Kalvins. Cephalosporin derivatives with citostatic activity. Patent of Latvia Nr. 11953, C 07 D 501/02, 1998.

Riga latvia

The building of the Brotherhood of Blackheads is one of the most iconic buildings of Old Riga (Vecrīga)

RIGA

Cook in traditional latvian dress serving local food for tourists Riga Latvia

Points of interest

View 15+ more

Freedom Monument

St. Peter’s Church, Riga

Museum of the Occupati…

Latvian Ethnographic Open Air…

Nativity Cathedral, Riga
Colleges and Universities

View 5+ more

University of Latvia

Riga

Riga Technical University

Riga

Riga Stradiņš University

Riga

Turība University

Riga

Art Academy of Latvia

Riga

Piece by Piece A guide to fragment-based drug discovery

DRUG DESIGN, drugs Comments Off

Dec 222014

DESIGNING A BETTER DRUG: The combination of chemical groups from three different fragments that bind weakly to an enzyme produce a potent new enzyme inhibitor (center) that binds in the nM range.COURTESY OF RODERICK HUBBARD

In search of better drugs and therapies, researchers are constantly looking for new ways to identify compounds that selectively block disease pathways. Industrial labs have relied on high-throughput screening to finger promising new molecules, but most academic labs lack the equipment and resources to scan many thousands, even millions, of compounds. For a long while this shut academic labs out of such searches, but a related technique, fragment-based drug discovery (also called fragment-based lead discovery), offers another way to develop small-molecule drugs and chemical probes for investigating biological processes. And this approach relies on instruments and expertise available at many academic institutions.

read at

Piece by Piece

A guide to fragment-based drug discovery

http://www.the-scientist.com/?articles.view/articleNo/35711/title/Piece-by-Piece/

RABEPRAZOLE SPECTRAL VISIT

SYNTHESIS, Uncategorized Comments Off

Dec 092014

1H NMR RABEPRAZOLE

RAB standard: (DMSOd6 400 MHz) δ 8.28 (d, 1H, J=5.56 Hz), 7.46 (m, 2H), 6.93 (d, 1H, J=5.68 Hz), 6.88 (m, 2H), 4.57 (AB, 2H, J=12.88 Hz), 4.10 (t, 2H, J=6.19 Hz), 3.49 (t, 2H, J=6.32 Hz), 3.25 (S, 3H), 2.17 (S, 3H), 1.98 (quin., 2H, J=6.19 Hz) ¹³C NMR (DMSOd6, 101 MHz) δ 162.61, 152.41, 147.95, 146.62, 121.74, 118.20, 117.32, 105.92, 68.30, 64.92, 59.64, 57.96, 28.67, 10.83.

The ¹H spectrum for the RAB starting material is shown with peaks labelled and integrated. Data were collected on a 400 MHz NMR in DMSOd6, corrected to TMS by residual non-deuterated solvent.

Figure S13 COSY NMR spectrum of RAB

The COSY spectrum for the RAB starting material is shown. This was used to assign the methoxypropoxy carbon chain δ 1.98, 3.49 and 4.10. Data were collected on a 400 MHz NMR in DMSOd6, corrected to TMS by residual non-deuterated solvent.

Figure S14 HMBC spectrum of RAB

The spectrum shows the long range coupling of ¹H to ¹³C nuclei. Coupling is observed between the 3-methyl group and the AB system, and between the various hydrogens on the alkyl chain.

SPIN SPIN COUPLING

Uncategorized Comments Off

Dec 032014

The source of spin-spin coupling

The ¹H-NMR spectra that we have seen so far (of methyl acetate and para-xylene) are somewhat unusual in the sense that in both of these molecules, each set of protons generates a single NMR signal. In fact, the ¹H-NMR spectra of most organic molecules contain proton signals that are ‘split’ into two or more sub-peaks. Rather than being a complication, however, this splitting behavior actually provides us with more information about our sample molecule.

Consider the spectrum for 1,1,2-trichloroethane. In this and in many spectra to follow, we show enlargements of individual signals so that the signal splitting patterns are recognizable.

The signal at 3.96 ppm, corresponding to the two H_a protons, is split into two subpeaks of equal height (and area) – this is referred to as adoublet. The H_b signal at 5.76 ppm, on the other hand, is split into three sub-peaks, with the middle peak higher than the two outside peaks – if we were to integrate each subpeak, we would see that the area under the middle peak is twice that of each of the outside peaks. This is called a triplet.

The source of signal splitting is a phenomenon called spin-spin coupling, a term that describes the magnetic interactions between neighboring, non-equivalent NMR-active nuclei. In our 1,1,2 trichloromethane example, the H_a and H_b protons are spin-coupled to each other. Here’s how it works, looking first at the H_a signal: in addition to being shielded by nearby valence electrons, each of the H_a protons is also influenced by the small magnetic field generated by H_b next door (remember, each spinning proton is like a tiny magnet). The magnetic moment of H_b will be aligned with B₀ in (slightly more than) half of the molecules in the sample, while in the remaining half of the molecules it will be opposed to B₀. The B_eff ‘felt’ by H_a is a slightly weaker if H_b is aligned against B₀, or slightly stronger if H_b is aligned with B₀. In other words, in half of the molecules H_a is shielded by H_b (thus the NMR signal is shifted slightly upfield) and in the other half H_a isdeshielded by H_b(and the NMR signal shifted slightly downfield). What would otherwise be a single H_a peak has been split into two sub-peaks (a doublet), one upfield and one downfield of the original signal. These ideas an be illustrated by a splitting diagram, as shown below.

Now, let’s think about the H_bsignal. The magnetic environment experienced by H_b is influenced by the fields of both neighboring H_aprotons, which we will call H_a1 and H_a2. There are four possibilities here, each of which is equally probable. First, the magnetic fields of both H_a1 and H_a2 could be aligned with B₀, which would deshield H_b, shifting its NMR signal slightly downfield. Second, both the H_a1 and H_a2 magnetic fields could be aligned opposed to B₀, which would shield H_b, shifting its resonance signal slightly upfield. Third and fourth, H_a1 could be with B₀ and H_a2 opposed, or H_a1opposed to B₀ and H_a2 with B₀. In each of the last two cases, the shielding effect of one H_aproton would cancel the deshielding effect of the other, and the chemical shift of H_b would be unchanged.

So in the end, the signal for H_b is a triplet, with the middle peak twice as large as the two outer peaks because there are two ways that H_a1and H_a2 can cancel each other out.

Now, consider the spectrum for ethyl acetate:

We see an unsplit ‘singlet’ peak at 1.833 ppm that corresponds to the acetyl (H_a) hydrogens – this is similar to the signal for the acetate hydrogens in methyl acetate that we considered earlier. This signal is unsplit because there are no adjacent hydrogens on the molecule. The signal at 1.055 ppm for the H_c hydrogens is split into a triplet by the two H_b hydrogens next door. The explanation here is the same as the explanation for the triplet peak we saw previously for 1,1,2-trichloroethane.

The H_bhydrogens give rise to a quartet signal at 3.915 ppm – notice that the two middle peaks are taller then the two outside peaks. This splitting pattern results from the spin-coupling effect of the three H_c hydrogens next door, and can be explained by an analysis similar to that which we used to explain the doublet and triplet patterns.

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

By now, you probably have recognized the pattern which is usually referred to as the n + 1 rule: if a set of hydrogens has n neighboring, non-equivalent hydrogens, it will be split into n + 1 subpeaks. Thus the two H_b hydrogens in ethyl acetate split the H_c signal into a triplet, and the three H_c hydrogens split the H_b signal into a quartet. This is very useful information if we are trying to determine the structure of an unknown molecule: if we see a triplet signal, we know that the corresponding hydrogen or set of hydrogens has two `neighbors`. When we begin to determine structures of unknown compounds using ¹H-NMR spectral data, it will become more apparent how this kind of information can be used.

Three important points need to be emphasized here. First, signal splitting only occurs between non-equivalent hydrogens – in other words, H_a1 in 1,1,2-trichloroethane is not split by H_a2, and vice-versa.

Second, splitting occurs primarily between hydrogens that are separated by three bonds. This is why the H_a hydrogens in ethyl acetate form a singlet– the nearest hydrogen neighbors are five bonds away, too far for coupling to occur.

Occasionally we will see four-bond and even 5-bond splitting, but in these cases the magnetic influence of one set of hydrogens on the other set is much more subtle than what we typically see in three-bond splitting (more details about how we quantify coupling interactions is provided in section 5.5B). Finally, splitting is most noticeable with hydrogens bonded to carbon. Hydrogens that are bonded to heteroatoms (alcohol or amino hydrogens, for example) are coupled weakly – or not at all – to their neighbors. This has to do with the fact that these protons exchange rapidly with solvent or other sample molecules.

Below are a few more examples of chemical shift and splitting pattern information for some relatively simple organic molecules.

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

Coupling constants

Chemists quantify the spin-spin coupling effect using something called the coupling constant, which is abbreviated with the capital letterJ. The coupling constant is simply the difference, expressed in Hz, between two adjacent sub-peaks in a split signal. For our doublet in the 1,1,2-trichloroethane spectrum, for example, the two subpeaks are separated by 6.1 Hz, and thus we write ³J_a-b = 6.1 Hz.

The superscript 3 tells us that this is a three-bond coupling interaction, and the a-b subscript tells us that we are talking about coupling between H_a and H_b. Unlike the chemical shift value, the coupling constant, expressed in Hz, is the same regardless of the applied field strength of the NMR magnet. This is because the strength of the magnetic moment of a neighboring proton, which is the source of the spin-spin coupling phenomenon, does not depend on the applied field strength.

When we look closely at the triplet signal in 1,1,2-trichloroethane, we see that the coupling constant – the `gap` between subpeaks – is 6.1 Hz, the same as for the doublet. This is an important concept! The coupling constant ³J_a-b quantifies the magnetic interaction between the H_a and H_b hydrogen sets, and this interaction is of the same magnitude in either direction. In other words, H_a influences H_b to the same extent that H_b influences H_a. When looking at more complex NMR spectra, this idea of reciprocal coupling constants can be very helpful in identifying the coupling relationships between proton sets.

Coupling constants between proton sets on neighboring sp³-hybridized carbons is typically in the region of 6-8 Hz. With protons bound to sp²-hybridized carbons, coupling constants can range from 0 Hz (no coupling at all) to 18 Hz, depending on the bonding arrangement.

For vinylic hydrogens in a trans configuration, we see coupling constants in the range of ³J = 11-18 Hz, while cis hydrogens couple in the ³J= 6-15 Hz range. The 2-bond coupling between hydrogens bound to the same alkene carbon (referred to as geminal hydrogens) is very fine, generally 5 Hz or lower. Ortho hydrogens on a benzene ring couple at 6-10 Hz, while 4-bond coupling of up to 4 Hz is sometimes seen between meta hydrogens.

Fine (2-3 Hz) coupling is often seen between an aldehyde proton and a three-bond neighbor. Table 4 lists typical constant values.

Complex coupling

In all of the examples of spin-spin coupling that we have seen so far, the observed splitting has resulted from the coupling of one set of hydrogens to just one neighboring set of hydrogens. When a set of hydrogens is coupled to two or more sets of nonequivalent neighbors, the result is a phenomenon called complex coupling. A good illustration is provided by the ¹H-NMR spectrum of methyl acrylate:

First, let’s first consider the H_c signal, which is centered at 6.21 ppm. Here is a closer look:

With this enlargement, it becomes evident that the Hc signal is actually composed of four sub-peaks. Why is this? H_c is coupled to both H_aand H_b , but with two different coupling constants. Once again, a splitting diagram can help us to understand what we are seeing. H_a istrans to H_c across the double bond, and splits the H_c signal into a doublet with a coupling constant of ³J_ac = 17.4 Hz. In addition, each of these H_c doublet sub-peaks is split again by H_b (geminal coupling) into two more doublets, each with a much smaller coupling constant of²J_bc = 1.5 Hz.

The result of this `double splitting` is a pattern referred to as a doublet of doublets, abbreviated `dd`.

The signal for H_a at 5.95 ppm is also a doublet of doublets, with coupling constants ³J_ac= 17.4 Hz and ³J_ab = 10.5 Hz.

The signal for H_b at 5.64 ppm is split into a doublet by H_a, a cis coupling with ³J_ab = 10.4 Hz. Each of the resulting sub-peaks is split again by H_c, with the same geminal coupling constant ²J_bc = 1.5 Hz that we saw previously when we looked at the H_c signal. The overall result is again a doublet of doublets, this time with the two `sub-doublets` spaced slightly closer due to the smaller coupling constant for the cisinteraction. Here is a blow-up of the actual H_bsignal:

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

When constructing a splitting diagram to analyze complex coupling patterns, it is usually easier to show the larger splitting first, followed by the finer splitting (although the reverse would give the same end result).

When a proton is coupled to two different neighboring proton sets with identical or very close coupling constants, the splitting pattern that emerges often appears to follow the simple `n + 1 rule` of non-complex splitting. In the spectrum of 1,1,3-trichloropropane, for example, we would expect the signal for H_b to be split into a triplet by H_a, and again into doublets by H_c, resulting in a ‘triplet of doublets’.

H_a and H_c are not equivalent (their chemical shifts are different), but it turns out that ³J_ab is very close to ³J_bc. If we perform a splitting diagram analysis for H_b, we see that, due to the overlap of sub-peaks, the signal appears to be a quartet, and for all intents and purposes follows the n + 1 rule.

For similar reasons, the H_c peak in the spectrum of 2-pentanone appears as a sextet, split by the five combined H_b and H_d protons. Technically, this ‘sextet’ could be considered to be a ‘triplet of quartets’ with overlapping sub-peaks.

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

In many cases, it is difficult to fully analyze a complex splitting pattern. In the spectrum of toluene, for example, if we consider only 3-bond coupling we would expect the signal for H_b to be a doublet, H_d a triplet, and H_c a triplet.

In practice, however, all three aromatic proton groups have very similar chemical shifts and their signals overlap substantially, making such detailed analysis difficult. In this case, we would refer to the aromatic part of the spectrum as a multiplet.

When we start trying to analyze complex splitting patterns in larger molecules, we gain an appreciation for why scientists are willing to pay large sums of money (hundreds of thousands of dollars) for higher-field NMR instruments. Quite simply, the stronger our magnet is, the more resolution we get in our spectrum. In a 100 MHz instrument (with a magnet of approximately 2.4 Tesla field strength), the 12 ppm frequency ‘window’ in which we can observe proton signals is 1200 Hz wide. In a 500 MHz (~12 Tesla) instrument, however, the window is 6000 Hz – five times wider. In this sense, NMR instruments are like digital cameras and HDTVs: better resolution means more information and clearer pictures

QUININE

Uncategorized Comments Off

Nov 282014

Quinine

Molecular Formula: C₂₀H₂₄N₂O₂
Molecular Weight: 324.417

IUPAC Name:

6′-Methoxycinchonan-9-ol

CAS Number: 56-54-2
PubChem: 1065
NMRShiftDB: 10016314
Spectrometer: Bruker AV 400 MHz
Probe: 1mm MicroProbe
Solvent: CDCl₃
Sample Concentration: ca. 200 µg

Quinine (US /ˈ k w aɪ n aɪ n /, UK /ˈ k w ɪ n iː n / or /k w ɪ ˈ n iː n / kwin-een) is a natural white crystalline alkaloid having antipyretic (fever-reducing),antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine, which, unlike quinine, is an antiarrhythmic. Quinine contains two major fused-ring systems: the aromatic quinoline and the bicyclic quinuclidine.

Quinine occurs naturally in the bark of the cinchona tree, though it has also been synthesized in the laboratory. The medicinal properties of the cinchona tree were originally discovered by the Quechua, who are indigenous to Peru and Bolivia; later, the Jesuitswere the first to bring cinchona to Europe.

Quinine was the first effective Western treatment for malaria caused by Plasmodium falciparum, appearing in therapeutics in the 17th century. It is pre-dated as a malarial treatment by the Chinese herbalist’s use of Artemisia annua, described in a 4th-century text, a plant from which the antimalarial drug artemisinin was derived. It remained the antimalarial drug of choice until the 1940s, when other drugs such as chloroquine that have fewer unpleasant side effects replaced it. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical circumstances, such as severe malaria, and in impoverished regions due to its low cost. Quinine is available with a prescription in the United States and “over-the-counter” (in minute quantities) in tonic water. Quinine is also used to treat lupus and arthritis. Quinine was also frequently prescribed in the US as an off-label treatment for nocturnal leg cramps, but this has become less prevalent due to a Food and Drug Administration statement warning against the practice.^[2]

Quinine is highly fluorescent (quantum yield ~0.58) in 0.1 M sulfuric acid solution and it is widely used as a standard for fluorescence quantum yield measurement.^[3]^[4] It is on the World Health Organization’s List of Essential Medicines, a list of the most important medications needed in a basic health system.^[5]

1D Proton Spectrum:

Medical uses

As of 2006, quinine is no longer recommended by the WHO (World Health Organization), as first-line treatment for malaria, and should be used only when artemisinins are not available.^[6]^[7]^[8]^[9]

Quinine is a basic amine and is usually presented as a salt. Various existing preparations include the hydrochloride, dihydrochloride,sulfate, bisulfate and gluconate. This makes quinine dosing complicated, since each of the salts has a different weight.

The following amounts of each salt form contain equal amounts of quinine:

quinine base 100 mg
quinine bisulfate 169 mg
quinine dihydrochloride 122 mg
quinine hydrochloride 111 mg
quinine sulfate (actually (quinine)₂H₂SO₄∙2H₂O) 121 mg
quinine gluconate 160 mg

All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR).^[10]^[11] The main problem with the rectal route is the dose can be expelled before it is completely absorbed; in practice, this is corrected by giving a half dose again.

In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin; the adult dose is two tablets every eight hours. No injectable preparation of quinine is licensed in the US; quinidine is used instead.^[12]^[13]

13C NMR

Top 10 FindIt Molecular Structures Consistent With Molecular Formula and Proton Resonances:

The correct structure is at position 7.


 Best 10 structures in decreasing rating (structure ID shown in parentheses):
    1: 0.957622 (  102439)    2: 0.957340 ( 3499717)    3: 0.955644 (   65753)
    4: 0.955078 (  847715)    5: 0.953062 ( 6336167)    6: 0.953047 (  585971)
    7: 0.952892 (    1065)    8: 0.950814 (    8547)    9: 0.949068 (  934598)
   10: 0.948731 ( 2037943)

2D Multiplicity-Edited HSQC Spectrum:

Determined HSQC Correlations:

Top 10 FindIt Molecular Structures Consistent With Proton and Protonated Carbon (HSQC) Resonances:

The correct structure is at position 1.


 Best 10 structures in decreasing rating (structure ID shown in parentheses):
    1: 0.937466 (    1065)    2: 0.915501 ( 6336167)    3: 0.900599 ( 3499717)
    4: 0.897815 (  183259)    5: 0.895740 ( 3083557)    6: 0.894629 (  101764)
    7: 0.894536 (   84495)    8: 0.891677 ( 4835740)    9: 0.890939 ( 3809868)
   10: 0.889296 ( 5191849)

Automated VerifyIt Proton Assignments:

Proton Assignments

Automated VerifyIt Carbon Assignments:

Carbon Assignments

2D COSY

2D DQF-COSY Spectrum:

AssembleIt HSQC & DQF-COSY Derived Carbon-Carbon Correlations:

AssembleIt HSQC & DQF-COSY Derived Correlations

2D N15_HMBC Spectrum:

AssembleIt HSQC & N15_HMBC Derived Nitrogen-Carbon Correlations:

AssembleIt HSQC & N15_HMBC Derived Correlations

2D HMBC Spectrum:

AssembleIt HSQC, HMBC, DQF-COSY & N15_HMBC Derived Correlations:

AssembleIt Derived Structure With NMRgraph Added Likely Oxygen Atoms:

Most likely structure (out of 277 possible ones) by agreement with carbon chemical shift prediction

Comments:

Quinine is used as an antimalaria drug.

Before performing a full structure elucidation, consider running FindIt. Only the molecular formula, proton, and/or (potentially only protonated) carbon shift information are needed.

At natural abundance, a 1D carbon spectrum is 5,700 times less sensitive to acquire than a 1D proton spectrum. Acquiring the shown HSQC and HMBC spectra instead is still faster than acquiring one 1D carbon spectrum. The full quinine structure elucidation is demonstrated using about 200 micro grams of sample. Only the shown NMR data from a room-temperature 1 mm capillary probe are used. No molecular formula (MF) or information from other spectroscopic methods are needed.

History

Quinine^[34] is an effective muscle relaxant, long used by the Quechua, who are indigenous to Peru, to halt shivering due to low temperatures. The Peruvians would mix the ground bark of cinchona trees with sweetened water to offset the bark’s bitter taste, thus producing tonic water.

19th-century illustration of Cinchona calisaya

Quinine has been used in unextracted form by Europeans since at least the early 17th century. It was first used to treat malaria in Rome in 1631. During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome. Malaria was responsible for the deaths of severalpopes, many cardinals and countless common Roman citizens. Most of the priests trained in Rome had seen malaria victims and were familiar with theshivering brought on by the febrile phase of the disease. The Jesuit brother Agostino Salumbrino (1561–1642), an apothecary by training who lived inLima, observed the Quechua using the bark of the cinchona tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was still a successful medicine for malaria. At the first opportunity, Salumbrino sent a small quantity to Rome to test as a malaria treatment. In the years that followed, cinchona bark, known as Jesuit’s bark or Peruvian bark, became one of the most valuable commodities shipped from Peru to Europe. When King Charles II was cured of malaria at the end of the 17th Century with quinine, it became popular in London.^[35] It remained the antimalarial drug of choice until the 1940s, when other drugs took over.^[36]

The form of quinine most effective in treating malaria was found by Charles Marie de La Condamine in 1737.^[37]^[38] Quinine was isolated and named in 1820 by French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou.^[39] The name was derived from the original Quechua (Inca) word for the cinchona tree bark, quina or quina-quina, which means “bark of bark” or “holy bark”. Prior to 1820, the bark was first dried, ground to a fine powder, and then mixed into a liquid (commonly wine) which was then drunk. Large-scale use of quinine as a prophylaxis started around 1850.

Quinine also played a significant role in the colonization of Africa by Europeans. Quinine had been said to be the prime reason Africa ceased to be known as the “white man’s grave”. A historian has stated, “it was quinine’s efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa”.^[40]

To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings beginning in the early 19th century. The Dutch government persisted in its attempt to smuggle the seeds, and by the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the world’s quinine production.^[40] During World War II, Allied powers were cut off from their supply of quinine when the Germans conquered the Netherlands and the Japanese controlled the Philippines and Indonesia. The United States had managed to obtain four million cinchona seeds from the Philippines and began operating cinchona plantations inCosta Rica. Nonetheless, such supplies came too late; tens of thousands of US troops in Africa and the South Pacific died due to the lack of quinine.^[40] Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the southwest Pacific died as a result.^[41]^[42]^[43]^[44]

Synthetic quinine

Main article: quinine total synthesis

Robert B. Woodward

Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering.^[45] Since then, several more efficient quinine total syntheses have been achieved,^[46] but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.

References

“Qualaquin (quinine) dosing, indications, interactions, adverse effects, and more”.Medscape Reference. WebMD. Retrieved 29 January 2014.
“FDA Drug Safety Communication: New risk management plan and patient Medication Guide for Qualaquin (quinine sulfate)”. Food and Drug Administration. 2010-08-07. Retrieved 2011-02-21.
Joseph R. Lakowicz. Principles of Fluorescence Spectroscopy 3rd edition. Springer(2006). ISBN 978-0387-31278-1. Chapter 2. page 54.
Quinine sulfate ogi.edu. Retrieved 16 August 2013
“WHO Model List of Essential Medicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
World Health Organization (2006). “Guidelines for the treatment of malaria”. World Health Organization. Retrieved 10 August 2009.
Dorndorp A, Nosten F, Stepniewska K, et al. (2005). “Artesunate verus quinine for treatment of severe falciparum malaria: a randomised trial”. Lancet 366 (9487): 717–25.doi:10.1016/S0140-6736(05)67176-0. PMID 16125588.
Reyburn, H; Mtove, G; Hendriksen, I; Von Seidlein, L (2009). “Oral quinine for the treatment of uncomplicated malaria”. Brit J Med 339: b2066. doi:10.1136/bmj.b2066.PMID 19622550.
Achan J, Tibenderana JK, Kyabayinze D, et al. (2009). “Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial”. Brit Med J 338: b2763. doi:10.1136/bmj.b2763.
Barennes H, et al. (1996). “Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria”. Brit J Clin Pharmacol 41 (5): 389. doi:10.1046/j.1365-2125.1996.03246.x.
Barennes, H.; Balima-Koussoubé, T; Nagot, N; Charpentier, JC; Pussard, E (2006).“Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial”. Brit Med J 332(7549): 1055–57. doi:10.1136/bmj.332.7549.1055. PMC 1458599. PMID 16675812.
Center for Disease Control (1991). “Treatment with Quinidine Gluconate of Persons with Severe Plasmodium falciparum Infection: Discontinuation of Parenteral Quinine”. Morb Mort Weekly Rep 40 (RR–4): 21–23. Retrieved 2006-05-06.
Magill, A; Panosian, C (2005). “Making Antimalarial Agents Available in the United States”. New Engl J Med 353 (4): 335–337. doi:10.1056/NEJMp058167.PMID 16000347.
Jamaludin A, Mohamad M, Navaratnam V, et al. (1988). “Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine”. Br J Clin Pharmacol 25 (2): 261–3. doi:10.1111/j.1365-2125.1988.tb03299.x. PMC 1386482. PMID 3358888.
Optically active isomers of quinine and quinidine and their respective biological actionAccessed 26/1/2009
Sanders, L. “Poison Pill”, The New York Times Magazine, 4/13/2008.
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8546
Dannenberg AL; Behal, FJ; Johnson, J; Johnson, Jamie (1983). “Use of quinine for self-induced abortion”. The Southern Medical Journal 76 (7): 846–849. doi:10.1097/00007611-198307000-00007. PMID 6867792.
Yeka A, Achan J, D’Alessandro U, Talisuna AO (2009). “Quinine monotherapy for treating uncomplicated malaria in the era of artemisinin-based combination therapy: an appropriate public health policy?”. Lancet Infect Dis 9 (7): 448–452. doi:10.1016/S1473-3099(09)70109-4. PMID 19555904.
“NPS warns on quinine”. Auspharm e News, 6 January 2010.
^ Jump up to:^a ^b Roche, R. J.; Silamut, K.; Pukrittayakamee, S.; Looareesuwan, S.; Molunto, P.; Boonamrung, S.; White, N. J. (1990). “Quinine induces reversible high-tone hearing loss”.British Journal of Clinical Pharmacology 29 (6): 780. doi:10.1111/j.1365-2125.1990.tb03704.x. edit
Paintaud, G.; Alván, G.; Berninger, E.; Gustafsson, L. L.; Idrizbegovic, E.; Karlsson, K. K.; Wakelkamp, M. (1994). “The concentration-effect relationship of quinine-induced hearing impairment”. Clinical Pharmacology and Therapeutics 55 (3): 317–23.doi:10.1038/clpt.1994.32. PMID 8143397. edit
Tange, R. A.; Dreschler, W. A.; Claessen, F. A. P.; Perenboom, R. M. (1997). “Ototoxic reactions of quinine in healthy persons and patients with Plasmodium falciparum infection”.Auris Nasus Larynx 24 (2): 131. doi:10.1016/S0385-8146(96)00031-4. edit
Department of Clinical Pharmacology, Huddinge University Hospital, Sweden (1994). “The concentration-effect relationship of quinine-induced hearing impairment”. Clin Pharmacol Ther 55 (3): 317–323. doi:10.1038/clpt.1994.32. PMID 8143397.
“FDA Orders Stop to Marketing Of Quinine for Night Leg Cramps”. FDA Consumer Magazine. Food and Drug Administration. July–August 1995. Archived from the originalon 2008-01-15. Retrieved 2009-07-31.
“FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About Off-Label Use of Quinine to Treat Leg Cramps”. United States Food and Drug Administration. 2006-12-11. Retrieved 2009-07-31.
“Malaria Surveillance – United States, 2004”. Center for Disease Control. 2006-11-22. Retrieved 2009-11-22.
Ballestero, JA; Plazas, PV; Kracun, S; Gómez-Casati, ME; Taranda, J; Rothlin, CV; Katz, E; Millar, NS et al. (2005). “Effects of Quinine, Quinidine, and Chloroquine on α9α10 Nicotinic Cholinergic Receptors”. Molecular Pharmacology 68 (3): 822–829.doi:10.1124/mol.105.014431. PMID 15955868.
Charming, Cheryl (2006). Miss Charming’s Guide for Hip Bartenders and Wayout Wannabes. USA: Sourcebooks, Inc. p. 189. ISBN 978-1-4022-0804-1.
“Basic Concepts in Fluorescence”.
Hobhouse, Henry (2004). Šest rostlin, které změnily svět (in Czech). Prague: Akademie věd České republiky. p. 59. ISBN 80-200-1179-X.
Microgram Bulletin, Volume 42, Number 10, October 2009, Page 79. Retrieved 22 September 2012.
Porritt, M., Cryptocaryon irritans, Reef Culture Magazine, 1. Retrieved 9th Jul 2009
History of quinine: Friedrich A. Flückiger and Daniel Hanbury, Pharmacographia: A history of the principal drugs of vegetable origin, met with in Great Britain and British India(London, England: Macmillan and Co., 1874), pages 302-331: Cortex Cinchonæ.
Rocco, Fiametta (2004). Quinine: malaria and the quest for a cure that changed the world. New York, NY: Perennial.
Loren, Humphrey (2000). Quinine and Quarantine.
de la Condamine (1738) “Sur l’arbre du quinquina” (On the quinquina tree) Histoire de l’Académie royale des Sciences, pages 226-243.
See also: Joseph de Jussieu, Description de l’arbre à quinquina: mémoire inédit de Joseph de Jussieu (1737) (Description of the quinquina tree: unpublished memoir of Joseph de Jussieu (1737)). De Jussieu accompanied de la Condamine on the latter’s expedition to Peru.
Pelletier and Caventou (1820) “Suite: Des recherches chimiques sur les quinquinas”(Continuation: Chemical research on quinquinas), Annales de Chimie et de Physique, vol. 15, pages 337-365. The authors name quinine on page 348: “…, nous avons cru devoir la nommer quinine, pour la distinguer de la cinchonine par un nom qui indique également son origine.” (…, we thought that we should name it “quinine” in order to distinguish it from cinchonine by means of a name that also indicates its origin.)
Conner, Clifford D. (2005). A People’s History of Science: Miners, Midwives, and ‘Low Mechanicks’. New York: Nation Books. pp. 95–96. ISBN 1-56025-748-2. Also citesPorter, Roy (1998). The Greatest Benefit to Mankind: A Medical History of Humanity. New York: W. W. Norton. pp. 465–466. ISBN 0-393-04634-6.
Louis Morton (1953). “29”. The Fall of the Philippines. Washington, D.C.: United States Army. p. 524.
Alan Hawk. “Remembering the war in New Guinea: Japanese Medical Corps — malaria”.
Lt. Gen. Leonard D. Heaton, ed. (1963). “8”. Preventive Medicine in World War II: Volume VI, Communicable Diseases: Malaria. Washington, D.C.: Department of the Army. pp. 401 and 434.
“Notes on Japanese Medical Services”. Tactical and Technical Trends (U.S. War Department) (36). 1943.
Woodward R, Doering W (1944). “The Total Synthesis of Quinine”. J Am Chem Soc 66(849).
Kaufman, Teodoro S.; Rúveda, Edmundo A. (2005). “Die Jagd auf Chinin: Etappenerfolge und Gesamtsiege”. Angewandte Chemie, Int. Ed. (in German) 117 (6): 876–907. doi:10.1002/ange.200400663.

External links

Quinine at the International Programme on Chemical Safety
Catalytic Asymmetric Synthesis of Quinine and Quinidine
Summary article on history of Quinine in the Chemical and Engineering News

In total synthesis, the Quinine total synthesis describes the efforts in synthesis of quinine over a 150 year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy: in 2001 Gilbert Stork published the first stereoselective quinine synthesis and he shed doubt (calling it a myth) on the earlier claim in 1944 by Bob Woodward and William Doering on account that they had obtained not quinine but a precursor molecule. In 2001, an editorial in Chemical & Engineering Newssupported Storks claim but according to a critical 30 page review in this matter published in 2007 in Angewandte Chemie the Woodward/Doering claim is valid.

Chemical structure

The aromatic component of the quinine molecule is a quinoline with a methoxy substituent. The amine component has a quinuclidine skeleton and the methylene bridge in between the two components has a hydroxyl group. The substituent at the carbon-3 position is a vinyl group. The molecule is optically active with five stereogenic centers (the N1 and C4 constituting a single asymmetric unit), making synthesis potentially difficult because it is one of 16 stereoisomers.

Quinine total synthesis timeline

1817: First isolation of quinine from cinchona tree by Pierre Joseph Pelletier and Joseph Caventou
1853: Louis Pasteur obtains quinotoxine (or quinicine in older literature) by acid-catalysed isomerization of quinine ^[1]

1856: William Henry Perkin attempts quinine synthesis by oxidation of N-allyl toluidine based on the erroneous idea that 2 equivalents of this compound with chemical formulaC₁₀H₁₃N plus three equivalents of oxygen yield one equivalent of C₂₀H₂₄N₂O₂ (quinine’s chemical formula) and one equivalent of water ^[2] His oxidations with other toluidines sets him on the path of mauveine which eventually leads to the birth of chemical industry.

1907: the correct atom connectivity established by Paul Rabe ^[3]
1918: Paul Rabe and Karl Kindler synthesize quinine from quinotoxine,^[4] reversing the Pasteur chemistry. The lack of experimental details in this publication would become a major issue in the Stork/Woodward controversy almost a century later.

The first step in this sequence is sodium hypobromite addition to quinotoxine to an N-bromo intermediate possibly with structure 2. The second step is organic oxidation withsodium ethoxide in ethanol. Because of the basic conditions the initial product quininone interconverts with quinidinone via a common enol intermediate and mutarotation is observed. In the third step the ketone group is reduced with aluminum powder and sodium ethoxide in ethanol and quinine can be identified. Quinotoxine is the first relay molecule in the Woodward/Doering claim.

Final step in Rabe Kindler synthesis: reduction

1939: Rabe and Kindler re investigate a sample left over from their 1918 experiments and identify and isolate quinine (again) together with diastereomers quinidine, epi-quinine and epi-quinidine ^[5]
1940: Robert Burns Woodward signs on as a consultant for the Polaroid Corporation at the request of Edwin H. Land. Quinine is of interest to Polaroid for its light polarizingproperties.
1943: Prelog and Proštenik interconvert an allyl piperidine called homomeroquinene and quinotoxine.^[6] Homomeroquinene (the second relay molecule in the Woodward/Doering claim) is obtained in several steps from the biomolecule cinchonine (related to quinidine but without the methoxy group):

The key step in the assembly of quinotoxine is a claisen condensation:

Claisen condensation in Prelog conversion of homomeroquinene to quinotoxine

1944: Bob Woodward and W.E. Doering report the synthesis of quinine ^[7] starting from 7-hydroxyisoquinoline. Although the title of their 1 page publication is The total synthesis of quinine it is oddly not the synthesis of quinine but that of the precursor homomeroquinene (racemic) and then with groundwork already provided by Prelog a year earlier to quinotoxine (enantiopure after chiral resolution) that is described.

homomeroquinene synthesis by Woodward / Doering

Woodward and Doering argue that Rabe in 1918 already proved that this compound will eventually give quinine but do not repeat Rabe’s work. In this project 27-year-old assistant-professor Woodward is the theorist and post doc Doering (age 26) the bench worker. According to William, Bob was able to boil water but an egg would be a challenge. As many natural quinine resources are tied up in the enemy-held Dutch East Indies synthetic quinine is a promising alternative for fighting malaria on the battlefield and both men become instant war heroes making headlines in the New York Times, Newsweek and Life magazine.

1944: The then 22 year old Gilbert Stork writes to Woodward asking him if he did repeat Rabe’s work.
1945: Woodward and Doering publish their second lengthy Quinine paper.^[8] One of the two referees rejects the manuscript (too much historic material, too much experimental details and poor literary style with inclusion of words like adumbrated and apposite) but it is published without changes nonetheless.
1974: Kondo & Mori synthesize racemic vinylic gamma-lactones, a key starting material in Stork’s 2001 quinine synthesis.:^[9]

The starting materials are trans-2-butene-1,4-diol and ethyl orthoacetate and the key step is a Claisen rearrangement

1988: Ishibashi & Taniguchy resolve said lactone to enantiopure compounds via chiral resolution:^[10]

In this process the racemic lactone reacts in aminolysis with (S)-methylbenzylamine assisted by triethylaluminum to a diastereomeric pair of amides which can be separated by column chromatography. The S-enantiomer is converted back to the S-lactone in two steps by hydrolysis with potassium hydroxide and ethylene glycol followed by azeotropic ring closure.

2001: Gilbert Stork publishes his stereoselective quinine synthesis.^[11] He questions the validity of the Woodward/Doering claim: “the basis of their characterization of Rabe’s claim as “established” is unclear”. The Chemical & Engineering News is equally critical.^[12]

2007: Researcher Jeffrey I Seeman in a 30 page review ^[13] concludes that the Woodward–Doering/ Rabe–Kindler total synthesis of quinine is a valid achievement. He notes that Paul Rabe was an extremely experienced alkaloid chemist, that he had ample opportunity to compare his quinine reaction product with authentic samples and that the described 1918 chemistry was repeated by Rabe although not with quinotoxine itself but still with closely related derivatives.
2008: Smith and Williams revisit and confirm Rabe’s d-quinotoxine to quinine route ^[14]

Stork quinine total synthesis

The Stork quinine synthesis starts from chiral (S)-4-vinylbutyrolactone 1. The compound is obtained by chiral resolution and in fact, in the subsequent steps all stereogenic centers are put in place by chiral induction: the sequence does not contain asymmetric steps.


Stork quinine synthesis		Introducing C8 and nitrogen

The lactone is ring-opened with diethylamine to amide 2 and its hydroxyl group is protected as a tert-butyldimethyl (TBS) silyl ether in 3. The C5 and C6 atoms are added as tert-butyldiphenylsilyl (TBDPS) protected iodoethanol in a nucleophilic substitution of acidic C4 with LDA at -78°C to 4 with correct stereochemistry. Removal of the silyl protecting group with p-toluenesulfonic acid to alcohol 4b and ring-closure by azeotropic distillation returns the compound to lactone 5 (direct alkylation of 1 met with undisclosed problems).

The lactone is then reduced to the lactol 5b with diisobutylaluminum hydride and its liberated aldehyde reacts in a Wittig reaction with methoxymethylenetriphenylphosphine(delivering the C8 atom) to form enol ether 6. The hydroxyl group is replaced in a Mitsunobu reaction by an azide group with diphenylphosphoryl azide in 7 and acid hydrolysis yields the azido aldehyde 8.


First ring closure		Second ring closure

The methyl group in 6-methoxy-4-methylquinoline 9 is sufficiently acidic for nucleophilic addition of its anion (by reaction with LDA) to the aldehyde group in 8 to form 10 as a mixture of epimers. This is of no consequence for stereocontrol because in the next step the alcohol is oxidized in a Swern oxidation to ketone 11. A Staudinger reaction withtriphenylphosphine closes the ring between the ketone and the azide to the tetrahydropyridine 12. The imine group in this compound is reduced to the amine 13 with sodium borohydride with the correct stereospecificity. The silyl protecting group is removed with hydrogen fluoride to alcohol 14 and then activated as an mesyl leaving group by reaction with mesyl chloride in pyridine which enables the third ring closure to 15. In the final step the C9 hydroxyl group was introduced by oxidation with sodium hydride, dmso and oxygen with quinine to epiquinine ratio of 14:1.

Woodward / Doering formal quinine total synthesis

The 1944 Woodward / Doering synthesis starts from 7-hydroxyisoquinoline 3 for the quinuclidine skeleton which is somewhat counter intuitive because one goes from a stable heterocyclic aromat to a completely saturated bicyclic ring. This compound (already known since 1895) is prepared in two steps.


Woodward/Doering quinine synthesis part I		Part II

The first reaction step is condensation reaction of 3-hydroxybenzaldehyde 1 with (formally) the diacetal of aminoacetaldehyde to the imine 2 and the second reaction step is cyclization in concentrated sulfuric acid. Isoquinoline 3 is then alkylated in another condensation by formaldehyde and piperidine and the product is isolated as the sodium salt of4.


Woodward/Doering quinine synthesis part III

Hydrogenation at 220°C for 10 hours in methanol with sodium methoxide liberates the piperidine group and leaving the methyl group in 5 with already all carbon and nitrogen atoms accounted for. A second hydrogenationtakes place with Adams catalyst in acetic acid to tetrahydroisoquinoline 6. Further hydrogenation does not take place until the amino group is acylated with acetic anhydride in methanol but by then 7 is again hydrogenated with Raney nickel in ethanol at 150°C under high pressure to decahydroisoquinoline 8. The mixture of cis and trans isomers is then oxidized by chromic acid in acetic acid to the ketone 9. Only the cis isomer crystallizes and used in the next reaction step, a ring opening with the alkyl nitrite ethyl nitrite with sodium ethoxide in ethanol to10 with a newly formed carboxylic ester group and an oxime group. The oxime group is hydrogenated to theamine 11 with platinum in acetic acid and alkylation with iodomethane gives the quaternary ammonium salt 12and subsequently the betaine 13 after reaction with silver oxide.

Quinine’s vinyl group is then constructed by Hofmann elimination with sodium hydroxide in water at 140°C. This process is accompanied by hydrolysis of both the ester and the amide group but it is not the free amine that is isolated but the urea 14 by reaction with potassium cyanate. In the next step the carboxylic acid group isesterified with ethanol and the urea group replaced with a benzoyl group. The final step is a claisen condensation of 15 with ethyl quininate 16, which after acidic workup yields racemic quinotoxine 17. The desired enantiomer is obtained by chiral resolution with the chiral dibenzoyl ester of Tartaric acid. The conversion of this compound to quinine is based on the Rabe/Kindler chemistry discussed in the timelime.

External links

Quinine Total Syntheses @ SynArchive.com
Quinine story at Harvard.edu Link

References

Pasteur, L. Compt. rend. 1853, 37, 110.
Perkin, W. H. J. Chem. Soc. 1896, 69, 596
Rabe, P.; Ackerman, E.; Schneider, W. Ber. 1907, 40, 3655
Rabe, P.; Kindler, K. Chem. Ber. 1918, 51, 466
P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. B 1939, 72, 263–264.
Proštenik, M.; Prelog, V. HelV. Chim. Acta 1943, 26, 1965.
The Total Synthesis of Quinine R. B. Woodward and W. E. Doering J. Am. Chem. Soc.; 1944; 66(5) pp 849 – 849; doi:10.1021/ja01233a516
The Total Synthesis of Quinine R. B. Woodward and W. E. Doering J. Am. Chem. Soc.; 1945; 67(5) pp 860 – 874; doi:10.1021/ja01221a051
SYNTHESIS OF γ-LACTONES BY THE CONDENSATION OF 2-ALKENE-1,4-DIOLS WITH ORTHOCARBOXYLIC ESTERS Kiyosi Kondo and Fumio Mori Chemistry Letters Vol.3 (1974) , No.7 pp.741-742 doi:10.1246/cl.1974.741
Synthesis and Absolute Configuration of the Acetalic Lignan (+)-Phrymarolin Fumito Ishibashi and Eiji Taniguchi Bulletin of the Chemical Society of Japan Vol.61 (1988) , No.12 pp.4361-4366 doi:10.1246/bcsj.61.4361
The First Stereoselective Total Synthesis of Quinine Gilbert Stork, Deqiang Niu, A. Fujimoto, Emil R. Koft, James M. Balkovec, James R. Tata, and Gregory R. Dake J. Am. Chem. Soc.;2001; 123(14) pp 3239 – 3242; (Article) doi:10.1021/ja004325r.
M. Jacobs, Chemical & Engineering News 2001, 79 (May 7), 5.
Review: The Woodward-Doering/Rabe-Kindler Total Synthesis of Quinine: Setting the Record Straight Jeffrey I. Seeman Angew. Chem. Int. Ed. 2007, 46, 1378–1413doi:10.1002/anie.200601551 PMID 17294412
Communication Rabe Rest in Peace: Confirmation of the Rabe-Kindler Conversion of d-Quinotoxine to Quinine: Experimental Affirmation of the Woodward-Doering Formal Total Synthesis of Quinine Aaron C. Smith, Robert M. Williams Angewandte Chemie International Edition 2008, 47, 1736–1740 doi:10.1002/anie.200705421

LIDOCAINE SPECTRAL VISIT

SYNTHESIS, Uncategorized Comments Off

Nov 272014

2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide

Lidocaine is used in drugs formulated for local anaesthetics.

MW= 234.34 g/mol; MP= 68-69 ^o C; bruttoformula: C₁₄H₂₂N₂O;

CAS-number: 137-58-6;

Lidocaine is an antiarrhythmic medicine and also serves as a local anaesthetic drug. It is utilized in topical application to relieve pain, burning and itching sensation caused from skin inflammations. This drug is mainly used for minor surgeries. Figure 1 shows the ¹H NMR spectrum of 200 mM lidocaine in CDCl₃.

Figure 1. Proton NMR spectrum of 200 mM lidocaine in CDCl₃.

Calculated H-NMR spectrum of lidocaine

¹H NMR Relaxation

Figures 2, 3 and 4 show the relaxation time measurements. It can be seen that the relaxation times are shortest for the CH₂ protons and longest for the CH protons. The first data point amplitude increases with the number of protons for the related peak.

Figure 2. Proton T₁ relaxation time measurement of 200 mM lidocaine in CDCl₃.

Figure 3. Proton T₂ relaxation time measurement of 200 mM lidocaine in CDCl₃.

Figure 4. COSY spectrum of 200 mM lidocaine in CDCl₃. The cross-peaks and corresponding exchanging protons are labeled by colour-coded arrows and ellipses.

2D COSY

Figure 4 shows the 2D COSY spectrum where two spin systems (6,7,8) to (10,11) can be clearly seen. For instance, the methyl groups at 10 and 11 positions bond to aromatic protons at 6 and 8 positions, while the methyl groups at 16 and 17 positions bond to the ethylene groups at 14 and 15 positions. No coupling occurs at positions (6,7,8) to (16,17) or (14,15).

2D Homonuclear J-Resolved Spectroscopy

The chemical shift in the 2D homonuclear j-resolved spectrum appears along the direct (f₂) direction and the effects of coupling between protons appear along the indirect (f₁) dimension. This enables the assignment of chemical shifts of multiplets and may help in measuring unresolved couplings. Also, a decoupled 1D proton spectrum is produced by the projection along the f1 dimension. The 2D homonuclear j-resolved spectrum of lidocaine, plus the 1D proton spectrum (blue line) are shown in Figure 5.

Figure 5. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl₃. The multiplet splitting frequencies for different couplings are colour- coded.

The projection which is vertical reveals how the multiplets disintegrate into a single peak, which makes the 1D spectrum more simplified. Peak multiplicities are produced by vertical traces from peaks in the 2D spectrum and help in determining the frequencies of proton-proton coupling. When coupling frequencies are compared between different peaks, information can be obtained regarding which peaks are bonded to each other. Also, Information regarding the coupling strength can be obtained from the size of the coupling frequencies. These couplings substantiate the results of the COSY experiment.

However, in this experiment, the effects of second order coupling appear in the f1 direction as additional peaks which are equidistant from the coupling partners detached from the zero frequency in the f1 dimension. These peaks provide proof of second order coupling partners, but are generally considered as artifacts. Figure 6 shows these coupling partners and additional peaks marked by colour-coded arrows and ellipses.

Figure 6. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl₃ showing the extra peaks due to strong couplings.

1D ¹³C Spectra

Figure 7 shows the ¹³C NMR spectra of 1 M lidocaine in CDCl₃. Since the 1D Carbonexperiment is highly susceptible to the ¹³C nuclei in the specimen, it easily and clearly resolves 9 resonances. In this experiment, only carbons coupled to protons are seen.

Figure 7. Carbon spectra of 1 M lidocaine in CDCl₃.

Given the fact that the DEPT spectra do not display the peaks at 170 and 135ppm, they must be part of quaternary carbons. The DEPT-135 and the DEPT-45 experiments provide signals ofCH_3,CH₂ and CH groups, while the DEPT-90 experiment provides only the signal of CH groups. However, in DEPT-135 the CH₂ groups occur as negative peaks. It can thus be summed up that the peaks between 45 and 60ppm belong to ethylene groups; the peaks between 10 and 20ppm are part of the methyl groups; and the peaks between 125 and 130ppm belong to methyne groups. A similar study can be carried out on the C and CH peaks.

Heteronuclear Correlation

The Heteronuclear Correlation (HETCOR) experiment identifies the proton signal that appears along the indirect dimension and the carbon signal along the direct dimension. Figure 8 shows the HETCOR spectrum of 1 M lidocaine in CDCl₃. in the 2D spectrum, the peaks reveal which proton is attached to which carbon. This experiment helps in resolving assignment uncertainty from the ID carbon spectra.

Figure 8. HETCOR spectrum of 1 M lidocaine in CDCl₃.

Heteronuclear Multiple Quantum Coherence

Heteronuclear Multiple Quantum Coherence (HMQC) is similar to the HETCOR experiment and is utilized to associate proton resonances to the carbons that are coupled directly to those protons. But in the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 9 shows the HMQC spectrum of 1 Mlidocaine in CDCl₃. In the 2D spectrum, the peaks show which proton is attached to which carbon. For conclusive peak assignment, a similar study with the HETCOR spectrum can be carried out.

Figure 9. HMQC spectrum of 1 M lidocaine in CDCl₃.

Heteronuclear Multiple Bond Correlation

The Heteronuclear Multiple Bond Correlation (HMBC) experiment can be employed to achieve long-range correlations of proton and carbon via two or three bond couplings. Similar to the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 10 shows the HMBC spectrum of 1 M lidocaine in CDCl₃.

Figure 10. HMBC spectrum of 1 M lidocaine in CDCl₃, with some of the long-range couplings marked.

The couplings amid the molecular positions appear analogous to the couplings seen in the COSY spectrum; however, the HMBC also displays couplings to quaternary carbons, which are not seen either in HMQC or COSY experiments. In addition, there is a correlation between protons and carbons. This is attributed to three-bond bonding from 14 and 15 and vice versa, as shown in light green in Figure 1.

Chemical reaction of lidocaine with singlet oxygen. Rate constants for the chemical reaction between lidocaine and O₂(^1D_g) were determined in methanol, acetonitrile and N,N-dimethylformamide. Lidocaine consumption was followed during the reaction. Rate constants for the chemical reaction, k_R^LID, are (1.05 ± 0.061) x 10⁵M^-1 s^-1, (1.42 ± 0.073) x 10⁵M^-1 s^-1and (0.61 ± 0.046) x 10⁵M^-1 s^-1 in acetonitrile, methanol and N,N-dimethylformamide, respectively.

By using the Mair method (4) for hydroperoxide determination, a concentration equivalent to 0.0153 M of hydroperoxide was found when 0.03 M lidocaine in acetonitrile was irradiated for 12 h in the presence of Rose Bengal. The amount of hydroperoxide produced agrees with the consumption of lidocaine. Although we cannot isolate reaction products in quantities adequate for spectroscopic characterization, a rough idea of the product distribution was obtained by GC-MS analysis of the main lidocaine derivatives produced in the photooxidations. When 0.03 M lidocaine was irradiated for 12 h in the presence of Rose Bengal the results shown in Fig. 2 a) are obtained with the mass spectrometer in the positive chemical ionization (CI+) mode. Only four peaks appear in the chromatogram, the main one, with a retention time of 15.59 min, is that of unreacted lidocaine. Fig. 2 b) shows that the mass spectrum is that of lidocaine. The CI+ and EI (not included) mass spectra corresponding to peaks at retention times of 14.57, 13.22 and 7.77 min, indicate that 2-(ethylvinylamino)-N-(2,6-dimethylphenyl)-acetamide, 2-(1-azapropily-den)-N-(2,6-dimethyl-phenyl)-acetamide and 2,6-dimethylaniline are the probable main products of photooxidation of lidocaine. Figs. 2 c), 2 d) and 2 e), show the CI+ mass spectra and corresponding structures.

Figure 2.a) GC-MS chromatogram of 30 mM lidocaine in acetonitrile after 12 h of irradiation in the presence of Rose Bengal. b) CI+ mass spectrum of compound with retention time 15.58 m. c) CI+ mass spectrum of compound with retention time 14.67 m. d) CI+ mass spectrum of compound with retention time 13.22 m. e) CI+ mass spectrum of compound with retention time 7.76 m.

Ethyl-2-butenoate NMR

Uncategorized Comments Off

Nov 262014

Ethyl-2-butenoate

¹H-NMR proton decoupled spectrum of Ethyl-2-butenoate in CDCl₃.

¹H-NMR proton coupled spectrum of Ethyl-2-butenoate in CDCl₃.

¹³C-NMR proton decoupled spectrum of Ethyl-2-butenoate in CDC_l3.

DEPT spectrum of Ethyl-2-butenoate

COSY spectra

The information on the H that are coupling with each other is obtained by looking at the peaks inside the grid. These peaks are usually shown in a contour type format, like height intervals on a map.
In order to see where this information comes from, let’s consider an example shown below, the COSY of ethyl 2-butenoate
First look at the peak marked A in the top left corner. This peak indicates a coupling interaction between the H at 6.9 ppm and the H at 1.8 ppm. This corresponds to the coupling of the CH₃ group and the adjacent H on the alkene.
Similarly, the peak marked B indicates a coupling interaction between the H at 4.15 ppm and the H at 1.25 ppm. This corresponds to the coupling of the CH₂ and the CH₃ in the ethyl group.
Notice that there are a second set of equivalent peaks, also marked A and Bon the other side of the diagonal.

(COSY spectra recorded by D. Fox, Dept of Chemistry, University of Calgary on a Bruker Advance DRX-400 spectrometer)

HETCOR spectra

The information on how the H are C are matched is obtained by looking at the peaks inside the grid. Again, these peaks are usually shown in a contour type format, like height intervals on a map.
In order to see where this information comes from, let’s consider an example shown below, the HETCOR of ethyl 2-butenoate.
First look at the peak marked A near the middle of the grid. This peak indicates that the H at 4.1 ppm is attached to the C at 60 ppm. This corresponds to the -OCH₂– group.
Similarly, the peak marked B towards the top right in the grid indicates that the H at 1.85 ppm is attached to the C at17 ppm. Since the H is a singlet, we know that this corresponds to the CH₃– group attached to the carbonyl in the acid part of the ester and not the CH₃– group attached to the -CH₂– in the alcohol part of the ester.
Notice that the carbonyl group from the ester has no “match” since it has no H attached in this example.

(HETCOR spectra recorded by D. Fox, Dept of Chemistry, University of Calgary on a Bruker Advance DRX-400 spectrometer)

DIISOPROPYLAMINE SPECTROSCOPY TAUGHT BY MOM, AUNT

Uncategorized Comments Off

Oct 182014

MOM

DIISOPROPYLAMINE

C₆H₁₅N

MW 101

the degree of unsaturation: the answer is 0. The molecule has no double bonds or rings.

IR Spectrum

Since the molecule has a nitrogen, look for a band in the region 3400-3250 – there is a single small band at 3384, which probably indicates the N-H stretch of a secondary amine. (Recall that tertiary amines will not show a band in this region because they do not have any N-H’s to stretch.)

NMR Spectrum

Diisopropylamine(108-18-9)¹HNMR

Amine protons show up from 0.5-3.0 ppm if the amine is not on an aromatic ring; the small “buried” peak at 1 ppm indicates a secondary amine peak:

There are only two other types of protons in the molecule: the doublet at 1 ppm indicates 12 hydrogens adjacent to one hydrogen and the septet at 2.9 ppm indicates 2 hydrogens adjacent to 6 hydrogens. The only way the molecule can be “put together” is to have each R group coming off the nitrogen to be the same, and to be -CH(CH₃)₂.

13C NMR

MASS

Summary

Example is diisopropylamine:

4-Ethoxybenzaldehyde NMR

Uncategorized Comments Off

Jul 282014

Example

C₉H₁₀O₂

MW 150

Calculate the degree of unsaturation: the answer is 5. If the degree of unsaturation is 4 or greater, look for an aromatic ring, which has a degree of unsaturation of 4 (3 double bonds plus 1 ring). In addition to an aromatic ring, the molecule can have a carbon-carbon double bond, a carbonyl, or another ring.

IR Spectrum

Look for a carbonyl, since the degree of unsaturation indicates that the compound could have a double bond and we know that the molecule has an oxygen. There is a band at 1697, suggesting an alpha, beta unsaturated aldehyde or ketone(1710-1665). To see if the compound might be an aldehyde, look for bands in the region 2830-2695. In the spectrum below, note the two bands in this region, suggesting that the compound is indeed an aldehyde.

The IR can also help determine whether or not the compound is an aromatic (although the NMR is a better diagnostic method for this). Look for the C–H stretch in aromatics from 3100-3000. There are a couple very small bands in this region.

There is one more oxygen in the molecule, it could be an ether or even an ester (if we are incorrect in assuming an aldehyde is indicated). Ether IR bands are difficult to distinguish from any other C-O stretch band – the C-O stretch of alcohols, carboxylic acids, esters, and ethers all show up in the region 1320-1000 (see Ethers).

Consult the section on Aromatics for more information on IR spectroscopy of aromatics.

NMR Spectrum

From the IR, we know that compound is probably an aromatic and an aldehyde. Aldehydes and aromatics are quite distinctive in the NMR: aldehydes show up from 9-10, usually as a small singlet; aromatic protons show up from 6.5-8.5 ppm. Let’s look at the NMR:

The singlet at 9.9 ppm indicates an aldehyde; the 4 protons from 7-8 ppm indicate a di-substituted aromatic ring.

The remaining two peaks represent an ethyl group, -CH₂CH₃: 2 protons split by 3 protons adjacent to 3 protons split by 2 protons. The -CH₂– portion of the ethyl group is shifted downfield further than the benzylic protons this indicates that it is next to an oxygen

Let’s draw an 8-carbon 10-hydrogen molecule incorporating these features: an aldehyde, a di-substituted aromatic ring, and an ethyl group: