化学原料药开发-异构体的分类 ISOMERS

ISOMERS

Definition

Isomers are compounds that have the same molecular (empirical) formula, but different structures, and demonstrate physico-chemical and pharmacological differences

Classification

Structural Isomers

Definition

Compounds with the same empirical formula, but whose atoms are connected in a different sequence

Chain isomers

–have different branching patterns of carbon chains

Position isomers

–the functional group is located on different carbons in the chain

–tend to have similar chemical properties

Functional group isomers

–have different types of bonds and hence different functional groups

–tend to have very different chemical properties

Tautomers

–compounds in which, under differing conditions eg pH, the substituent groupings may alter their position

–structural isomers that readily convert from one isomeric form to another and hence exist in equilibrium

Stereoisomers

Definition

Compounds which have the same empirical formula and whose atoms are attached in the same sequence, but differ in the spatial arrangement of the atoms

Significance

–may have marked pharmacokinetic and pharmacodynamic differences eg levo-bupivacaine is less cardiotoxic than dextro-bupivacaine, only levo isomer of morphine has opioid activity –different 3 dimensional arrangement → different ability to interact with receptors, enzymes and non-specific binding sites

–isomer-specific ability of a drug to produce a pharmacological effect is evidence supporting the presence of receptors

Enantiomers

–stereoisomers that are non-superimposable mirror images (like left and right hands)

–contain a chiral centre (an asymmetric carbon with four different groups attached to it) –identical physical properties, except the direction in which they rotate polarised light

Classification Systems

a) Rotation of polarised light to the:

left: levorotatory l- (-)

right: dextrototatory d- (+)

a racemic mixture contains equal amounts of levo and dextro isomers and therefore has no overall rotating effect on polarised light

b) Cahn Ingold Prelog convention

Ligands around the chiral carbon are assigned a priority based on their atomic number

(higher atomic number = higher priority)

Rectus (R-) priorities increase in clockwise direction

Sinister (S-) priorities increase in anti-clockwise direction

Not important to know the exact priority rules. Note that this system has nothing to do with rotation of polarised light and therefore classification in one system does not always

correspond to the same classification in the other. “Coincidentally”, this seemingly arbitrary nomenclature (R, S) are the initials of Mr R. S. Cahn.

c) Simple sugars and amino acids can be classified as D- or L- according to the clockwise or anticlockwise spatial arrangement of COOH, NH3, H and hydrocarbon chain around the chiral carbon. This is an old classification system, don’t bother learning it, just be aware of it.

(D- and L- are not to be confused with d- and l-!!)

Diastereoisomers

–Stereoisomers with different orientation of substituent groups on either side of a rigid bond (eg double bond or ring structure)

–Alternatively, can be thought of as isomers with two chiral carbons

Classification systems

a) cis- and trans-

cis- functional groups are on the same side of the double bond

trans- functional groups are on opposite sides of the double bond

eg mivacurium is presented as a mixture of isomers:

trans-trans 60%

cis-trans 30%

cis-cis 10%

b) other systems include syn-/anti- and Z-/E- (forget about this crap)

More detailed info on isomers can be found at https://www.360docs.net/doc/5e13658472.html,

Classification of Isomers

Isomers:Compounds that have identical chem ical and molecular formulas but differ in the nature of sequence of bonding of their atom s or in their arra ngement of atom s in space. According to their topology they are classified as either structural or stereoisom ers. Isomers are broadly classified into two broad categories:

1.1

Structural Isomers: Compounds that have the sam e atom s present but differ in their order of connectivity. They are also called as constitutional isomers. They have the sam e molecular formula but different structures. It can be distinguished by planar diagrams such as fischer projections.

1.1.1

Skeletal Isomers: Compounds that have the sam e functional groups, but differ in the length of the side chains. They are also called as chain isom ers. For example: pentane, 2-m ethyl butane and 2,2 dimethyl propane.

1.1.2

Positional Isomers:Compounds that have the same functional groups, but are present on different positions of the chain. For example: butan-1-ol and butan-2-ol.

1.1.3

Functional Isomers: Compounds that have different functional groups. For example: ethanol and m ethoxy methane.

1.1.4

Tautomers:Compounds whose structures differ in arrangem ent of atom s but which are in dynamic equilibrium with each other.

1.1.4.1

Keto-Enol tautom erism:

1.1.4.2

Ring-Chain isomerism: seen in case of glucose

1.2

Stereoisomer:Compounds that have the sam e chemical formula, sam e atom s, sam e connectivity and differ only in the arrangement of their atom s in space.

1.2.1

Anomers: Stereoisomers where the m olecule is cyclized and the difference in configuration is about the anom eric carbon only. In case of aldoses the anomeric carbon is C1 and for ke toses it is C2. e.g. sugar hemiacetal. Glucose in open chain form is not chiral at C1 but in ring form has two optically active stereoisom ers: alpha & beta glucose.

1.2.2

Rotamers and Conformers:On the basis of spatial arrangement of atom s in the molecule that can be achieved by rotation(or torsion) around one or m ore single bonds, they are classified as rotam ers and conform ers. Conformers assum e the chair/boat and equitorial/axial form s. Rotamers assume the different newm ann projections (staggered/eclipsed/gauche).

1.2.3

Configurational Isomers have a chiral (stereogenic center). Chiral center refers to a carbon atom attached to four different groups. The m olecule is said to possess chirality and to have a stereogenic

center.

1.2.3.1

Enantiomer:Stereoisom ers that are non-identical, mirror-symmetric for all atom s, nonsuperimposable, optically active (e.g. levo/dextro-rotatory), inverted only by breaking bonds and remaking them in the reverse sense. e.g.: D-glucose and L-glucose.

1.2.3.2

Diastereomer: Stereoisomers that are not mirror images, but have identical configuration for at least one asymmetric center and at least one different configuration for the remaining asymmetric centers. e.g. Threonine has 2 chiral centers and therefore 4 diastereomers.

1.2.3.2.1

Epimers:They are a special case of diastereoisom erism where there is a difference for one and only one asymmetric center. e.g. D-glucose and D-m annose; D-glucose and D-galactose are epimers.

1.2.3.3

Meso-isomer (Achiral molecules):super-imposable m irror im ages which have m ore than one stereogenic center. Meso-isom ers have two planes of symmetry; the usual mirror plane of reflection and a second plane perpendicular to it through the m olecule (in the ``middle'' of the m olecule). The asymmetric centers are distributed around this second place so that they are mirror inverses of each other. Hence opti cal rotations from the two ``halves'' of the molecule cancel out.

1.2.3.4

Geometric Isomers: Stereoisomers which are isomeric about double bonds. If the bond is C=C, the term s are cis/trans; if the bond is C=N, the terms are syn (cis-like) and anti (trans-like). For example: cis-2-butene and trans-2-butene.

Chiral Center Naming Classification:

? +/- Indicates the direction in which plane of polarized light is rotated(clockwise/anticlockwise).

? D/L (Dextrorotatory/Levorotatory): Plane of polarized light is rotated to the right or left.

? alpha/beta stereochemistry of the anom eric carbon. It is used for sugars.

? R-S convention: The four groups surrounding the stereocenter are given a priority from a -> d (from highest to lowest). The m olecule is then observed from the side with the lowest priority group. If the rem aining three groups form a clockwise array (a->b->c), then it is R convention. If it is in anti-clockwise then S convention. Priority is assigned according to atom ic number, with the higher the atomic number the higher the priority. This is used for chiral molecules (enantiomers/diastereomers/epimers).

? E-Z convention: The two groups attached to the carbon around the double bond are given the priority. If the two highest priority groups are on the sam e side of the double bond, then the m olecule is given the Z convention(similar to cis); and if on the opposite side then E convention(similar to trans). e.g.: 1-chloro-1-brom o-2-iodoethene is differentiated on basis of E-Z convention. Priority is assigned according to the atomic number; with the higher the atomic number, the higher the priority. Hyrdogen always has the lowest priority. If there are two identical atom s attached to the stereocenter (say the carbon of the m ethyl group and carbon of the ethyl group) then work along the chain of the attached group until a difference occurs.