Location of functional groups & molecular stereochemistry
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The document discusses various spectroscopic and chemical methods for determining the location of functional groups, molecular stereochemistry, and absolute stereochemistry in natural products. NMR and IR spectroscopy provide information on functional groups and their relationships. Chemical methods like oxidation, ozonolysis, ring formation reactions, and reaction with acids can reveal functional group positions and relationships. Absolute stereochemistry can be determined using methods like molecular rotation differences, asymmetric induction, optical rotation dispersion and circular dichroism, NMR techniques, and X-ray crystallography.
![Location of functional groups &
molecular stereochemistry
i] Spectroscopic interrelationships:
IR & NMR methods
ii] Chemical methods:
Oxidative strategies,
Ozonolysis,
Ring formation reactions,
Reaction with acids,
Rates of reaction.
iii]Determination of absolute stereochemistry:
Molecular rotation differences,
Asymmetric induction,
Optical rotation dispersion & circular dichroism,
NMR methods,
Crystallographic methods](https://image.slidesharecdn.com/locationoffunctionalgroupsmolecularstereochemistry-160609080911/85/Location-of-functional-groups-molecular-stereochemistry-1-320.jpg)
Location of functional groups & molecular stereochemistry
- 1. Location of functional groups & molecular stereochemistry i] Spectroscopic interrelationships: IR & NMR methods ii] Chemical methods: Oxidative strategies, Ozonolysis, Ring formation reactions, Reaction with acids, Rates of reaction. iii]Determination of absolute stereochemistry: Molecular rotation differences, Asymmetric induction, Optical rotation dispersion & circular dichroism, NMR methods, Crystallographic methods
- 2. Spectroscopic interrelationships: IR & NMR methods • Introduction The first two phases in the elucidation of the structure of a natural product lead to the identification of the functional groups and the structure of the carbon skeleton. • Information often accumulates during these stages on the position and stereochemistry of functional groups.
- 3. NMR Method • The chemical shift, • multiplicity and • Integral mode of the NMR spectrum give information on the detailed environment of a nucleus and its relationship to its neighbours.
- 4. • Chemical shift • Transannular interactions • Aromatic solvent induced chemical shift • Shift reagents such (europium) • y-gauche shielding • Nuclear Overhauser effect (NOE) useful role in locatinga hydrogen atom
- 5. • The Karplus equation, J= kcos2θ + constant, relates the magnitudeof the coupling constant J and the dihedral angle θ between two adjacent protons (see Figure 3.1).
- 6. Infrared Spectroscopy • Reveals not only the presence of specific functional groups, such as the hydroxyl and carbonyl groups, but it can also show interactions between them. • When a hydroxyl group is involved in hydrogen bonding, as in the case of 1,2-glycols, correlations have been established between the length of the hydrogen bond and the position of the hydrogen bonded 0-H absorption in the IR spectrum. This was at one time proposed as a method for determining the relative stereochemistryof vicinal glycols, but it has been superseded by more powerful NMR methods.
- 7. Chemical Methods Chemical strategies which can reveal useful information on the position, relationships and stereochemistry of a functional group. • Oxidative Strategies • Ozonolysis • Ring-forming Reactions
- 8. Oxidative Strategies • Spectroscopic changes that accompany the oxidation of an alcohol with chromium oxide to give a ketone / aldehyde and then an acid Alcohol Cromium oxide (Oxid.) Ketone/Aldehyde Acid Can be very useful –Location of functional gr. • Oxidation Gibberic acid (3.2) Non-enolizable α-diketone(3.3) The location of Ketone
- 9. • Baeyer--Villiger oxidation of ketones to lactones with a peroxy acid Scheme 3.5 Degradation of apoaromadendrene Apoaromadendrene 3.5 3.6 3.7Location of substitutes in Cyclopropane ring Stepwise degredation (7 membered ring) Ring opening
- 10. Oxidation of Clavatol Clavatol Alkaline hydrogen peroxide 3-hydroxy-2,6- dimethylbenzoquinone Used to establish the structure of this fungal metabolite. Scheme 3.6 Oxidation of clavatol
- 11. An example of its use came in establishing the position of the free hydroxyl group in the novioside derivative 3.12 which was obtained from the antibiotic novobiocin. When the anomeric methoxyl group was present, there was no reaction with sodium iodate.However, when this group was hydrolysed, the product 3.13 reacted with sodium iodate, showing that the free hydroxyl group was adjacent to the anomeric position. Scheme 3.7 Oxidation of diols with sodium iodate Cleavage reactions Plays an important role in determining the structures of variously modified sugars, particularly those in which some of the hydroxyl groups are methylated.
- 12. Ozonolysis • The has been oxidative cleavage of a double bond by ozone a valuable degradative method. • Many natural products contain an exocyclic methylene (C=CH2). On ozonolysis this affords formaldehyde and a ketone, which can then be the starting point for a further degradation. • Ozonolysis of gibberellin (3.15) established the presence of the exocyclic methylene on the five-membered ring. Gibberellin
- 13. Ring-forming Reactions • The formation of cyclic structures Show the relationships between functional groups. Powerful method for establishing stereochemical relationships. Scopine (3.21) Acid catalysed conversion Scopoline (3.22) Ether formation in structure determination This defined the relationship between the hydroxyl group and the epoxide in this relative of cocaine. Tropane alkaloid
- 14. Reaction with Acid • A number of rearrangements take place on treatment of an alkene with acid. One example is the acid-catalysed steviol-isosteviol rearrangement (3.23 to 3.24, Scheme 3.1 1) which, apart from providing structural evidence linking the alkene and hydroxyl groups, also served to link the ent-kaurene and beyerene families of diterpenoids. Isosteviol (3.24) was converted to the beyerene diterpenoid monogynol. A comparable rearrangement played an important role in establishing the structure of gibberellic acid. Acid-catalysed rearrangement in structure determination
- 15. Rates of Reaction • The rates of many simple reactions such as ester formation and ester hydrolysis are influenced by the steric environment of a functional group. • The differences in rate may enable selectivity to be achieved and a distinction to be made between • One example of the use of the rates of reaction in establishing stereochemistry came from a comparison of the rates of hydrolysis of methyl vinhaticoate (3.25, Scheme 3.12) with methyl podocarpate (3.26). • The former was hydrolysed much more rapidly, and so it was suggested that it was an equatorial ester. Methyl podocarpate was known to possess the axial hindered configuration. The rate of hydrolysis of esters.
- 16. The Determination of Absolute Stereochemistry • Most natural products possess an asymmetric centre, and normally they occur as only one enantiomer. • Where both enantiomers are known they may be obtained from different sources and have different biological properties. For example, the R(-)-enantiomer of carvone (3.27) tastes of spearmint whilst the S(+)-enantiomer tastes of caraway. • Although the majority of amino acids occur in the L-form. inversion to a D-amino acid occurs in some biosyntheses, such as that of penicillin. • The determination of the absolute stereochemistry of a natural product is an important aspect of structural work.
- 17. • The possession of chirality by a molecule carries with it the ability to rotate the plane of plane-polarized light. This information is used to characterize the enantiomers of a chiral molecule. • The specific rotation • The absolute stereochemistry of many of the major groups of natural products was established by a series of careful interrelationships with (+)-glyceraldehyde. • A degradation which establishes the absolute stereochemistry at one centre of a molecule is sufficient to determine the absolute stereochemistry of the whole molecule, provided the relative stereochemistry is known. Thus the absolute stereochemistry of a number of simple branched-chain alcohols and carboxylic acids was established by interrelationships in which the chirality of the asymmetric centre was not disturbed. • These simple derivatives included (-)-2-methylbutan-1-ol, (+)-2- methylbutanoic acid, (+)-methylbutanedioic acid and (+)-3-methylhexanedioic acid. These compounds then formed useful reference points for the degradation of the monoterpenoids.
- 18. Molecular Rotation Differences • The molecular rotation of a molecule may be regarded as the sum of the contribution to the rotation by each of its constituent chiral centres. • If two similar asymmetric molecules belonging to the same enantiomeric series are chemically altered in the same way, the change in the molecular rotation will be in the same direction ( + ve or -ve) in each case, and will often be of the same order of magnitude. • For example, in the sugars it was observed that if the change in the molecular rotation for the conversion of a lactone to the corresponding hydroxy acid was positive, the absolute stereochemistry of the carbon atom bearing the masked hydroxyl group was as shown in 3.29. • A series of molecular rotation differences following acetylation. benzoylation and oxidation of alcohols was used in the steroids and triterpenoids to correlate the stereochemistry of secondary alcohols.
- 19. Asymmetric Induction • Addition of Grignard reagent to a carbonyl group (On basis of the atrolactic acid mtd.) Asymetric induction Determine absolute stereochemistry • e.g. Phenylglyoxalate ester + Grignard reagent Hydrolysed product The chirality of the resultant atrolactic acid can be determined from its rotation. This reflects the chirality around the original alcohol. The validity of this method depends upon the ester preferring the conformation shown in Scheme . Horeau's method + One enantioiner of the 2-phenylbutyl group reacts preferentially,depending on the steric environment of the secondary alcohol. The optical rotation of the residual 2-phenylbutanoic acid reflects the absolute configuration of the alcohol. The atrolactic acid method of determining absolute stereochemistry Chiral secondory alcohol excess racemic 2-phenylbutanoic anhydride Selective esterified chiral sec.alcohol
- 20. Optical Rotatory Dispersion and Circular Dichroism • Optical rotation varies with wavelength, a phenomenon known as optical rotatory dispersion. Stereochemical information can be deduced from this. • For some compounds, such as chiral acids, the change of molecular rotation with wavelength is a plain curve in the readily accessible region of the spectrum (Figure 3.2a). • For other chiral compounds, particularly those containing a ketone, the curve shows a change of sign (Figure 3.2b),known as the Cotton effect, in a region of UV absorption. • The sign of the Cotton effect (+ve or -ve) reflects the chiral environment of the carbonyl group. The contributions of various substituents to the Cotton effect have been evaluated and the results summarized in the octant rule.
- 21. • The ketone is viewed in a specific manner (Figure 3.3a) and the space around the ketone is divided into octants by intersecting orthogonal planes. • For the majority of ketones the substituents lie in some of the four rear octants, and their contribution may be evaluated as shown in Figure 3.3b. Circular dichroism. • When the difference between the absorption of the left-handed and right handed components of circularly polarized light is plotted against wavelength, the curve shows a positive or a negative peak in the region of the Cotton effect. The sign of this curve has been correlated with the chiral environment of the absorbing group. The octant rule
- 22. NMR Methods• NMR methods have been developed for the determination of chirality. • These use chemical shift differences between esters and amides derived from chiral derivatizing agents, or use chiral shift reagents such as those based on camphor derivatives. Many of these methods have been developed in the context of resolving NMR signals in order to establish the enantiomeric excess of a new chiral centre generated by an asymmetric synthesis. • To establish the absolute stereochemistry of secondary alcohols and primary amines using the differences between the chemical shifts of the protons of (R)- and (S-2-methoxy-2-phenyl-2-(trifluoromethyl) acetate (MTPA acetates, 3.32; Scheme 3.14). The (R)- and (S)-0-methylmandelate esters of secondary alcohols are also used. The effects arise from the shielding influence of the aromatic ring. The model is shown in 3.32. The Δδ values (δs - δR) for protons adjacent to the secondary alcohol are diagnostic. They are negative for the protons oriented on the left-hand side of the MTPA plane but for those located on the right side the values are positive.
- 23. Crystallographic Methods • Modern X-ray methods utilizing heavy atom derivatives, such as those containing bromine, enabled the absolute stereochemistry of a number of natural products to be established. • However, X-ray methods can be used in the absence of a heavy atom if a derivative of the natural product is prepared using a chiral reagent of known absolute stereochernistry. • The chiral information associated with the derivative can be extended to the molecule as a whole, and the final X-ray structure gives the absolute stereochemistry of the natural product.