IDM - Structure of Drugs

1. why are orbitals important: - all molecules have 3d structure -this is defined by the bonding present in the molecule - this bonding is dictated by the shape of the orbitals which combine to form the bonds present 2. what is an orbital: A region of space around the nucleus where an electron is likely to be found. - is impossible to locate precise position of electron as they aren't discrete particles but rather waves - it is possible tho to indicate a region or volume where the electron is most likely to be found - this region is the orbital 3. what is orbital hybridization: - atoms hybrise (mix) their orbitals in order to optimise the geometry and minimise the energy of the molecules in which they are included 4. explain the hybridisation in carbon 2p3: - carbon has config of 1s2 2s2 2p2 - bonding with other atoms occurs using the outer 2s2 and 2p2 electrons - but there is a mismatch in energy between the s and the p electronic levels - in order to form equivalent bonds, equivalent energy levels are needed - so the s and p orbitals hybridise (combine) to produce degenerate orbitals (orbitals with the same energy level) called sp3 orbitals - the orbitals contain 25% s character and 75% p character - the combining of the 4 sp3 orbitals give a tetrahedral shape which allows the orbitals to be as far apart from each other as possible therefore have the lowest energy 5. explain the electron arrangement in methane: - each sp3 orbital on carbon (4) contain a valence electron - hydrogen has an unhybridized S orbital containing an electron - when the 4 hydrogens combine with the carbon, the s orbital or the hydrogens overlap with the sp3 orbital of the carbon. - this overlap is a sigma bond - methane therefore has 4 sigma bonds - sigma bonds are free to rotate 6. explain the hybridization of carbon sp2: - the 2s and 2 of the 2p orbitals of carbon combine forming sp2 orbitals (3 sp2 orbitals per carbon) - the sp2 orbital give a flat(triangular) arrangement - this leaves a left over 2p orbital on the carbon - carbon has 3 sp2 orbitals each containing an electron and 1 2p orbital containing an electron - there is 33% s character and 67% P character 1/6 7. explain the electron arrangement in ethene: - ethene = 2hc=ch2 - the first bond in the double bond c=c is a sigma bond - how?: one sp2 orbital of one carbon overlaps with one sp2 orbital on the other carbon creating a sigma bond - for each carbon, 2 hydrogens bond with a valence electron causing the 1s orbital of the hydrogen and the sp2 orbital of the carbon overlap forming a sigma bond - so there are now 5 sigma bonds in total - the left over 2p orbital is on each carbon - the sideways overlap of the 2p orbitals on each carbon forms a pi bonds - the pi bond what makes the second bond in the c=c - the pi bond character above and below the bond holds it rigid so it is not free to rotate 8. Explain sp hybridization in carbon: - one 2s orbital and one 2p orbital hybridise forming a sp orbital - this leaves two 2p orbitals that each contain one valence electron - there are two sp orbitals which have a linear arrangement 9. explain the electron arrangement in ethyne, acetylene: h-cac-h - the first c-c bond is a sigma bond - how?: one sp orbital on one carbon overlaps with the sp orbital on the other carbon forming a sigma bond - one hydrogen bonds with the valence electron in the other sp orbital of the carbon which causes the 1s orbital of the H and the sp orbital of the carbon to overlap forming a sigma bond. the same happens with the other carbon and a hydrogen - therefore there are 3 sigma bonds - each carbon has two 2p orbitals. one p orbital on the carbon is arranged perpendicular to the bond axis (2py (yaxis)) - the other p orbital on the carbon is arranged in the page half coming out of the page half going in (2pz (zaxis)) - this happens on both carbons - the p orbital that are perpendicular are overlapping forming a pi bond which makes the second bond in the cac - the other p orbitals going through the page are overlapping forming a pi bond which makes the third bond in the cac 10. explain the orbitals in benzene: - C6H6 - has three double bonds and three single bonds therefore each carbon is sp2 hybridised - the 6 p orbitals which sit above and below the ring delocalise giving a pi system which covers all six carbons - this gives a flat hexagonal shape where each bond is the same length 2/6 11. what is the valence shell electron pair repulsion theory: - theory assumes that each atom in a molecule will achieve a geometry that minimizes the repulsion between electrons in the valence shell of that atom. 12. what are the bond lengths of c-c bonds: - bond length c-c: 1.54 - bond energy c-c: 347 - bond length c=c: 1.34 - bond energy c=c: 611 - bond length cac 1.20 - bond energy cac: 837 13. what is bond order: the number of electron pairs (bonds) being shared by a given pair of atoms 14. what are isomers: - molecules with the same molecule formula but different structural or spatial arrangements of the atoms within the molecule 15. what are stereoisomers: - molecules which have the same molecular and structural formula but a different arrangement of atoms in 3d space 16. what is optical isomerism: - are stereoisomers - occur when a carbon is bonded with 4 different atoms in a tetrahedral arrangement - the carbon is a chiral centre - the tetrahedral structure is asymmetric - as a result 2 tetrahedral arrangements occur in space one being a mirror image of the other and they can't be superimposed on each other - the two mirror images are optical isomers and are called enantiomers 17. what are racemic mixtures: - mixtures containing exactly 50% of each enantiomers - these mixtures are optically inactive 18. explain optical activity: - an optically active substance is one that can rotate the plane of polarised light - when a beam of plane polarised light is passed through a solution of one enantiomer, the light is rotated either to the left or to the right depending on which isomer is used - if an enantiomer rotates the light to the left it is given the prefix L and if it rotates it to the right it is given the prefix D 19. what is the equation for the specific rotation of plane polarised light: [±]•^Ä = obs / c l ±obs = observed rotation in degrees c = conc in g/ml l = cell path length in dm 3/6 20. what does enantiomerically pure mean: - a sample that contains only one enantiomer - also called homochiral 21. what are constitutional isomers: - different compounds that share the same molecular formula - they can only be interconverted by the breaking and reforming of chemical bonds which requires lots of energy 22. what is the enantiomeric excess: the difference between the percentage of two enantiomers in a mixture - if the sample is racemic the ee is 0% 23. explain the sequence rule (Cahn, Ingold, Prelog rules): 1. identify a chiral carbon 2. the atom with the highest atomic number gets the highest priority 3. label the atom with the highest priority 1 and going down to 4 4. with the lightest group pointing away (dashes)going 1234. if it is clockwise the centre is named R and if it goes counter clockwise its S - if the lowest priority is not facing away from you (dashes) you change the R/S to the opposite one 24. What are diastereomers: - when some of the chiral centres change their configuration but not all of them they are diastereomers - a molecule with R,R and a molecule with R,S is a diastereomer 25. what are meso comounds: - if there is a compound with two chiral centres and bonded to the same groups there is s plane of symmetry - so a compound with R,S and a compound with S,R is the would be the same - if there is a plane of symmetry tho 26. cis/trans isomers and diastereomers: - cis trans isomers are always diastereomers - but not all diastereomers are cis trans isomers 27. cis trans isomers: - cis: same side - trans: opposite sides 28. how to identify whether two molecules are enantiomers or the same: 1. connectivity: if they don't have the same, they are constitutional isomers stereoisomers have the same connectivity 2. check R/S for each chiral centre - if its R/S and not the same they are enantiomers 3. double check for symmetry 29. how to identify whether molecules are enantiomers, diastereomers or the same: 1. compare connectivity: if they don't have the same, they are constitutional isomers 4/6 2. determine R/S for all chiral centres: if opposite enantiomers if not diastereomers 3. double check symmetry 30. what are diastereomers: stereoisomers that are not mirror images - they differ in physical properties 31. What are conformers?: -isomers that differ in spatial arrangement but can be converted into the other isomer by rotation without breaking a bond - they are continually interconverting - only single bonds can rotate - we use newman projections to visualize conformers 32. Newman projection: A method of visualizing a compound in which the line of sight is down a carbon-carbon bond axis. - closest c = dot - furthest d = ring 33. conformers of neurotransmitter acetylcholine: -acetylcholine acts at two different receptors: nicotinic and muscarinic, both are found on nerve tissue and trigger impulses in various types of nerves and target organs - muscarine is found in the fly agaric toadstool and nicotine is an active ingredient in tobacco - acetylcholine had the ability to mimic both muscarine and nicotine - different conformers of acetylcholine were used at each receptor 34. explain conformers in ring strucutres: - smallest ring: cyclopropane, one conformer - rings with 3+ carbons: more than one conformer - 6 carbon rings have two distinct conformers 35. Conformers of cyclohexane: - two distinct conformers emerge: chair and boat - there is an energy difference of 30kjmol-1 between them - axial hydrogens: H's going straight up or down - equatorial hydrogens: hydrogens going to the side - ring flipping: when the positions of axial and equatorial hydrogen interchange within a chair conformer - chairs have no torsional strain as all he hydrogen are staggered but boat has torsional strain as its hydrogens are eclipsed - chair is more stable (has lower potential energy) than boat (has higher potential energy) 36. e/z isomerism: - basically e/z but with more than two substituents on the double bonds - priority is assigned using Cahn-Ingold-Prelog - high priority groups on opposite sides: E - high priority groups of same side = Z 5/6 37. fischer plane projections: - horizontal line = wedge - vertical line = away dash - draw a rough fischer putting the functional grps in - figure out R AND S on fischer and correct if necessary 38. why is the shape and chirality of a molecule important for pharmacists: because all our proteins are made up of amino acids and amino acids occur naturally as single enantiomers - dna is chiral as the twist only goes in one direction(right) - the drugs we make need to interact with chiral molecules in the body to elicit an effect and sometimes different enantiomers have different or opposing affects 39. explain the thalidomide disaster and how it links with enantiomers: - prescribed for morning sickness - but was seriously teratogenic (drugs given to preg mothers which causes a structural or functional change in the fetus or child) - tests on mice suggested that only one enantiomer was teratogenic and the other possessed therapeutic activity - the drug was being sold as a racemic mixture which accounts for the unwanted effects - it was discovered that the enantiomers inter-convert under physiological conditions therefore the drug was unsafe even if used as a single enantiomer 40. explain how subtle changes in molecular structure and conformation give rise to profound differences in the ability to activate receptors or bind with enzyme active sites: - one optical isomer may be able to it in a receptor site but the other isomer can't as it is a mirror image - some cases: an enantiomer may bind to one protein and the other to a different protein thus each enantiomer has different biological effects 6/6