CIS TRANS ISOMERS AND NMR

 

Cis and trans coupling appear differently on ¹H NMR spectrum

Here are a couple of terms to know:

• Vicinal - Coupling between hydrogens on adjacent carbons. 
• Geminal - Coupling between nonequivalent hydrogens on the same carbon atom. 

Coupling Constants Around a Double Bond

Type of coupling	Name	Range (Hz)	Typical (Hz)
	Vicinal, cis	6-14	10
	Vicinal, trans	11-18	16
	Geminal	0-3	2
	None	4-10	6
	Allylic	0.5-3.0	2

When alkynel hydrogen atoms are not symmetrically substituted on a double bonded carbon, the hydrogens of a cis and trans isomer will yield a different shift on the NMR spectrum. Because the coupling constant is smaller in a cis isomer than in a trans isomer, the NMR spectrums of the two isomers are different conveying the hydrogens in a cis isomer to be slightly more upfield to-- the right of the spectrum-- and trans hydrogens to be more downfield to the left.                                                  

Sometimes coupling will lead to very complicated patterns as a result of the J values that vary widely due to the relationship between the hydrogens involved. When this occurs, information can still be derived to determine the structure of a molecule by looking at the number of signals, the chemical shift of each one, integration, and splitting patterns similarly to identifying alkane NMR. 

Alkenyl carbons are deshielded in ¹³C NMR

For background information on ¹³C NMR, please refer to ¹³C Nuclear Magnetic Resonance from the previous chapter. Compared to alkane carbons with one bond, alkene carbons show a relatively low field shift on the ¹³C NMR spectrum and absorb about 100 ppm lower field. Also, in broad-band decoupled ¹³C NMR, sp² carbons absorb as sharp single lines so with these two methods, it is easy to determine the presence of a double bond in ¹³C NMR spectrum.

Here are the common ¹³C Chemical Shift Ranges:

Note that the carbon-carbon double bonds are found in the range between 100-170 ppm. Carbon atoms on alkenes that are attatched to another carbon group are found more downfield than carbon alkenes attatched to hydrogens.

Let's try a ¹H NMR practice problem with C₄H₇Cl:

 Remember from previous sections that to solve an NMR spectrum with double bonds, we must know the Degrees of Unsaturation. From this, we get degrees of unsaturation= (9-7)/2=1 so there is one pi bond or ring in our molecule. Next we must look at the integration of the NMR spectrums.

• ppm= 1.8 with 3H reveals a CH₃attached to an unsaturated functional group
• ppm= 4.0 with integration of 2H is a CH₂ most likely attached to the Cl
• ppm = 4.9 and 5.1 are singlets of 1H and must be our two alkene hydrogens

There are three ways to attach the discovery we made, but only one of them are the correct answer. Since the coupling of the two alkene hydrogens are small whereas vicinal hydrogens tend to be large, we conclude that the hydrogens are geminal and appear on the same carbon. This leaves the two other groups to be located on the other alkene carbon.

Stereo Chemical Information from coupling constant

Distinction between cis and trans isomers

Trans coupling is greater than for cis. From the value the isomers can be identified as in the following example.

• For coupling the two hydrogens must have different chemical shift.
• Trans coupling (range :11 to 19 Hz) is greater than cis coupling (range: 5 to 14 Hz).
• ³J_HH means coupling between two hydrogens separated by a distance of three bonds (vicinal coupling). If it is coupling between hydrogens at the same carbon then it is ²J_HH (geminal coupling)

In some molecules the cis-trans, distinction is made even from the position of the absorption, as in cis and trans stilbenes. In trans case the hydrogens are deshielded by two aromatic rings while in the cis case it is by one ring.

Variation of dihedral angle with coupling constant

Dihedral angle: Consider the following Newman and Sawhorse projections for ethane.

• Looking from the front H_b is eclipsed by Ha the angle between the plane containing H_a and H_b is zero (they are in the same plane).
• The second conformation has H_b at a different spatial position, they are not in the same plane. The plane containing H_b is 60⁰ to the right of the plane containing H_a. This is the dihedral angle, in the first case the dihedral angle is zero.
• In the third case though the two atoms are in the same plane H_b has undergone a rotation of 180⁰ and that is the dihedral angle.
• The dihedral angle is used when two are separated by three bonds.
• Martin Karplus was the first to study the variation of coupling constant ³J_HH with dihedral angle.
• The magnitude of the coupling constant between hydrogens of adjacent carbon atoms depend directly on the dihedral angle.
• This magnitude is greatest when this is zero or 180⁰ and smallest when it is 90⁰.
• When it is zero side-side overlap of the two C-H bond orbitals will be maximum, when it is 180⁰ back lobes overlap is maximum leading to higher “J”. When it is 60⁰ C-H bond orbitals overlap is at a minimum since they are perpendicular with each other leading to lower “J”.

Stereochemistry of cyclohexane derivatives

The information from the above can be used to assign the configuration of the anomeric carbon in cyclic sugars. In the case of α- glucose at the anomeric carbon the equatorial proton is has a chemical shift of δ 5.2 which is down field by 0.5 for the corresponding axial proton in β-glucose.

 Coupling Constants : Cis-Trans Isomers of Olefins

The magnitude of the ³J(H,H) coupling constant in olefins follows the general rule J_trans > J_cis and this is a convenient way to distinguish between cis and trans isomers:

 

 

³J is also influenced by the olefin's substituents, the distinction is meaningful only for one by direct comparison of the isomers or for olefins with very similar substitution pattern.

( Z ) - hex - 2 - en - 1 - yl acetate

(Z)-hex-3-en-1-yl acetate

 ( E ) - hex - 2 - en - 1 - yl  acetate

(2E)-Hex-2-en-1-yl acetate

(E)-2-Hexenyl acetate

.

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BHUSAWAL, MAHARASHTRA , INDIA

Bhusawal

City in India

Bhusawal also spelt as Bhusaval is a city and a municipal council in Jalgaon district in the state of Maharashtra, India.Wikipedia

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Famotidine

FAMOTIDINE

76824-35-6

3-(2-Guanidinothiazol-4-ylmethylthio)-N-sulfamoylpropanamidine

MK-208
YM-11170
YM-1170

Histamine H2 Receptor Antagonists

Gastroesophageal Reflux Disease,

Agents forGastric Antisecretory Drugs (GERD)

Astellas Pharma (Innovaator)Launched – 1985

read at
http://newdrugapprovals.org/2014/11/19/famotidine/

Aplaviroc hydrochloride

Aplaviroc

4-(4-{[(3R)-1-butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo- 1,4,9-triazaspiro[5.5]undecan-9-yl]methyl}phenoxy)benzoic acid

for the treatment of HIV infection

461023-63-2 of hydrochloride

461443-59-4 (free base)

873140
AK-602
GW-873140
ONO-4128

ono…….innovator

Ono Pharmaceutical Co., Ltd.

Base

4-[4-[[(3R)-1-Butyl-3-[(R)-cyclohexylhydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl]methyl]phenoxy]benzoic acid

(3R)-1-butyl-2,5-dioxo-3-[(1R)-1-hydroxy-1-cyclohexylmethyl]-9-[4-(4-carboxyphenyloxy)phenylmethyl]-1,4,9-triazaspiro[5.5]undecane

Molecular Formula: C33H43N3O6

Molecular Weight: 577.71

Percent Composition: C 68.61%, H 7.50%, N 7.27%, O 16.62%

References: CCR5 chemokine receptor antagonist; inhibits HIV entry by blocking interaction of viral coat protein gp120 with the receptor. Prepn: H. Habashita et al., WO02074770 (2002 to Ono); eidem, US 04082584 (2004).

Study of CCR5 binding and mechanism of action: C. Watson et al., Mol. Pharmacol. 67, 1268 (2005).

Antiretroviral activity in immunodeficient mice: H. Nakata et al., J. Virol. 79, 2087 (2005). Clinical pharmacokinetics: K. K. Adkison et al., Antimicrob. Agents Chemother. 49, 2802 (2005).

Derivative Type: Hydrochloride

CAS Registry Number: 461023-63-2

Manufacturers’ Codes: AK-602; GW-873140; ONO-4128

Molecular Formula: C33H43N3O6.HCl

Molecular Weight: 614.17

Percent Composition: C 64.53%, H 7.22%, N 6.84%, O 15.63%, Cl 5.77%

Therap-Cat: Antiviral.

IDENTIFIERS
CAS NUMBER	461023-63-2
ATC CODE	None
PUBCHEM	CID 3001322
CHEMSPIDER	2272720
UNII	98B425P30V
KEGG	D06557
CHEMBL	CHEMBL1255794
CHEMICAL DATA
FORMULA	C33H43N3O6
MOL. MASS	577.711 g/mol

Aplaviroc (INN, codenamed AK602 and GSK-873140) is a CCR5 entry inhibitor developed for the treatment of HIV infection.[1][2] It is developed by GlaxoSmithKline.

In October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns.[3][4] Some authors have claimed that evidence of poor efficacy may have contributed to termination of the drug’s development;[5] the ASCENT study, one of the discontinued trials, showed aplaviroc to be under-effective in many patients even at high concentrations.[6]

Aplaviroc hydrochloride, an orally-effective, long-acting chemokine CCR5 receptor antagonist, had been under development by Ono and GlaxoSmithKline for the treatment of HIV infection. In early 2006, the companies discontinued development of the antagonist based on reports of elevated liver function test values from clinical studies.

Originally developed at Ono, aplaviroc was licensed to GlaxoSmithKline in 2003 for development, manufacturing and marketing. GlaxoSmithKline also obtained rights to evaluate the agent in non-HIV conditions worldwide with the exception of Japan, South Korea and Taiwan.

A low-molecular-weight compound, aplaviroc prevents HIV viral infection by blocking the binding of the virus to the CCR5 receptor

……………….

WO 2002074770

0r

http://www.google.com/patents/EP1378510A1?cl=en

Example 9(54)

(3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane • hydrochloride
• [0359]
  

  TLC:Rf 0.43(chloroform:methanol = 5:1);
  NMR (CD₃OD):δ 8.05 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.38 (s, 2H), 4.17 (d, J = 2.1 Hz, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.60-3.40 (m, 3H), 3.30-3.10 (m, 2H), 2.56-1.86 (m, 6H), 1.82-1.60 (m, 5H), 1.52-1.16 (m, 6H), 1.06-0.82 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).
  
  read at
   http://newdrugapprovals.org/2014/11/19/aplaviroc-ak602-gsk-873140/
   

Drug Patents International

Drug Patents International:



'via Blog this'

Fast 2D NMR for Kinetic Studies

Fast 2D NMR for Kinetic Studies

2D COSY NMR made fast enough to follow the kinetics of organic reactions and identify intermediates
Read more

http://www.chemistryviews.org/details/news/6831001/Fast_2D_NMR_for_Kinetic_Studies.html

LAMOTRIGINE

 READ

http://newdrugapprovals.org/2014/11/12/%D0%BB%D0%B0%D0%BC%D0%BE%D1%82%D1%80%D0%B8%D0%B6%D0%B8%D0%BD-lamotrigine/

Lamotrigine

CAS r: 84057-84-1

CAS Name: 6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine

Additional Names: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine; LTG

Manufacturers’ Codes: BW-430C

Trademarks: Lamictal (GSK)

Molecular Formula: C9H7Cl2N5

Molecular Weight: 256.09

Percent Composition: C 42.21%, H 2.76%, Cl 27.69%, N 27.35%

Literature References: Prepn: M. G. Baxter et al., EP 21121 (1981 to Wellcome Foundation); D. A. Sawyer et al., US 4602017(1986).

HPLC determn in plasma: C.-L. Cheng et al., J. Chromatogr. B 817, 199 (2005).

Anticonvulsant activity: A. A. Miller et al.,Epilepsia 27, 483 (1986).

Mechanism of action studies: M. J. Leach et al., ibid. 490; X. Xie, R. M. Hagan,Neuropsychobiology 38,119 (1998).

Series of articles on clinical pharmacology, antiepileptic efficacy and safety:Epilepsia 32, Suppl. 2, S1-S21 (1991).

Clinical trial in bipolar depression: J. R. Calabrese et al., J. Clin. Psychiatry 60,79 (1999). Review of clinical experience in epilepsy: H. Choi, M. J. Morrell,Expert Opin. Pharmacother. 4, 243-251 (2003); in bipolar disorder: Z. Bhagwagar, G. M. Goodwin,Expert Opin. Pharmacother. 6, 1401-1408 (2005).

Properties: White to pale cream-colored powder. Crystals from isopropanol, mp 216-218° (uncorr). pKa 5.7. Soly at 25° (mg/ml): water 0.17; 0.1M HCl 4.1. LD50 in mice, rats (mg/kg): 250, >640 orally (Sawyer).

Melting point: mp 216-218° (uncorr)

pKa: pKa 5.7

Toxicity data: LD50 in mice, rats (mg/kg): 250, >640 orally (Sawyer)

Therap-Cat: Anticonvulsant. In treatment of bipolar depression.

Keywords: Anticonvulsant.

PATENT NO	EXPIRY DATE
5698226*PED	Jul 29, 2012

 NMR, IMPURITIES, MASS, IR ETC…………..http://shodhganga.inflibnet.ac.in/bitstream/10603/4518/9/09_chapter%202.pdf

AND

http://www.ijppsjournal.com/Vol4Issue1/2904.pdf

EXAMPLES

Procedure I

To a round bottomed flask was added aminoguanidine hydrochloride (116.1 g, 1.05 mol) and dimethylformamide (900 mL). To this mixture was added methanesulfonic acid (130.4 g, 1.36 mol) followed by adding 2,3- dichlorobenzoylcyanide (150.0 g, 0.75 mol). The reaction mixture was stirred for 1 hour and then the dehydrating reagent, thionyl chloride, (45.2g, 0.38 mol) was added. The reaction mixture was stirred for another hour and then basified with KOH solution (4N). The precipitate was filtered and washed with water.

Yield: 401.3 g damp cake (KF = 39.2%).

Analytically pure sample of the intermediate is prepared as following:

20.0 g of the damp cake was suspended in 60 ml MeOH and stirred at room temperature for 3 hours. The solid was filtered and dried in vacuum at room temperature to give 5.4 g analytic pure iminoguanidine as a yellow solid.

m.p.: 179 ~ 180° C (corrected).

MS (m/z): 256.3 [M+] IR: 3491.8; 3457.1 (Amine N-H stretching); 2207.5 (CN stretching); 1681.9 (Imine C=N stretching); 1055.5 (Caryi-Cl stretching).

Η-NMR (300 MHz, DMSO-D6): 7.66 (ad, J = 7.9 Hz, 2H), 7.41 (dd, J = 7.9; 7.9 Hz, 1H), 6.70 (br s, NH2).

^C-NMR (75 MHz, DMSO-D6): 163.6, 135.3, 132.4, 130.0, 129.5, 129.0, 128.2, 114.4, 113.8.

Elemental analysis: C H N

Calculated: 42.21 2.76 27.35

Found: 42.10 2.49 27.69

Procedure II:

A round bottomed flask was charged with iminoguanidine (401.3 g from procedure I), isopropanol (1000.0 ml) and KOH (85%, 12.0 g, 0.18 mol). The reaction mixture was refluxed for 3 hours. Isopropanol was distilled and water (800 ml) was added. The reaction mixture was stirred for 3 hours, the solid was filtered and washed with water. The damp cake is dried under vacuum to yield 168.5 grams of lamotrigine monohydrate as crystalline solid (82% based on 2,3-dichlorobenzoyl cyanide).

Procedure III (without isolation of intermediate of formula IV):

To a round bottomed flask was added aminoguanidine hydrochloride (116.1 g, 1.05 mol) and dimethylformamide (900 ml). To this mixture was added methanesulfonic acid (130.4 g, 1.36 mol) followed by 2,3-dichlorobenzoyl cyanide (150.0 g, 0.75 mol). The reaction mixture was stirred for 1 hour and then dehydrating reagent thionyl chloride (45.2g, 0.38 mol) was added slowly. The reaction mixture was stirred for another hour and then basified with KOH solution (4 N). The Reaction mixture was heated under reflux (100 ~ 105° C) for 3 ~ 4 hours and cooled slowly to room temperature. The solid was filtered and washed with water. After drying, 160.7g of lamotrigine monohydrate as a crystalline solid (78% based on 2,3-dichlorobenzoyl cyanide) was obtained.

See also FIG. 1, 2, 3.

Karl Fischer (water content): 5.92 – 6.03%

DSC: 106.86, 216.65° C (onset).

MS (m/z): 256.3 [M+]

IR: 3496.9; 3450.3; 3338.5; 3211.0; 1658.7; 1524.0; 1328.8; 1027.1.

iH-NMR (300 MHz, DMSO-D6): 7.66 (ad, J = 7.9 Hz, 2H), 7.41 (dd, J = 7.9; 7.9 Hz, 1H), 6.70 (br s, NH2).

13C-NMR (75 MHz, DMSO-D6): 163.6, 135.3, 132.4, 130.0, 129.5, 129.0, 128.2, 114.4, 113.8.

Procedure IV (preparation of anhydrous lamotrigine from lamotrigine monohydrate):

150 g lamotrigine monohydrate (from procedure II or III) was recrystallized in 900 mL isopropanol giving 132 g (94%) of anhydrous lamotrigine as a crystalline solid.

See also FIG. 4, 5, 6.

m.p.: 216 – 217° C (corrected).

MS (m/z): 256.3 [M+]

Η-NMR (300 MHz, DMSO-D6): 7.69 (dd, J = 1.7; 7.9 Hz, 1H), 7.43 (dd, J = 7.9; 7.6 Hz, 1H), 7.35 (dd, J = 1.7; 7.6 Hz, 1H), 6.70 (br s, NH2), 6.44 (br s, NH2).

13C-NMR (75 MHz, DMSO-D6): 162.1, 154.1, 138.3, 136.8, 132.0, 131.6, 130.6, 128.5. Elemental analysis: C H N

Calculated: 42.21 2.76 27.35

Found: 42.10 2.58 27.46

 http://www.google.com/patents/WO2003078407A1?cl=en

READ

http://newdrugapprovals.org/2014/11/12/%D0%BB%D0%B0%D0%BC%D0%BE%D1%82%D1%80%D0%B8%D0%B6%D0%B8%D0%BD-lamotrigine/