Stereochemistry and Conformation Flashcards
Isomers
molecules which posses the same molecular formula but are different
Constitutional isomers
molecules which possess the same molecular formula but different constitutions (connectivities)
Stereoisomers
molecules which possess the same molecular formula and the same connectivity (but are nonetheless different)
Enantiomers
stereoisomers which are mirror images of each other
Diastereomers
stereoisomers which are not mirror images of each other
Conformations
different shapes possible for a single molecule (usually related by rotations around single bonds)
Cahn-Ingold-Prelog (CIP) convention
1) label groups with decreasing priority
determined by:
atomic no. directly attached atoms
atomic no. largest atom in “second sphere”
no. largest atoms in second sphere
multiple bonds considered as 2/3 single bonds
if no difference, heavier isotope has higher priority than lighter isotope
2) position molecule such that group with lowest priority (4) is away from you
3) clockwise = R
anticlockwise = S
Optical activity
property of chiral molecules - rotate plane of polarised light and different enantiomers cause opposite directions of rotation
clockwise - dextrorotary (+)
anticlockwise - laevorotary (-)
no correlation to R/S
specific rotation
[a] = a/cl a = degree of rotation c = conc in g/dm3 l = length of path in dm
distinguish between diastereomers (syn/anti)
arrange longest carbon chain in zig-zag conformation
substituents pointing in same direction have sun relationship
substituents pointing in opposite direction have anti relationship
no. stereoisomers related to no. chiral centres
chiral entres and double bonds
general:
n chiral centres
2 options each
= 2^n stereoisomers
both stereogenic elements
rule applies the same to double bods
axis of symmetry
n-fold
rotate about axis by 360/n degrees, get the same structure
plane of symmetry
reflect through plane, get the same structure
every atom in the plane or reflects/matched by an identical atom on the other side of the plane
centre of symmetry
invert through centre
every atom is at centre or matched by an identical atom on a line through the centre
relation of symmetry and chirality
high symmetry = achiral
low symmetry = chiral
if a molecule has a plane or centre of symmetry, it will be achiral (reverse not quite true)
how can you tell if a molecule is chiral? (final answer)
cannot examine molecule in randomly-chosen conformation. look for an accessible conformation with plane or centre of symmetry (i.e. accessible achiral conformation)
if it has one, no enantiomers
CIP rules for double bonds
assign priorities at either end of bond
same side high priority group - Z
opposite sides high priority - E
separation of enantiomers techniques
- derivatives with chiral reagent - forms diastereomers. for preparative reasons make salts where possible, if the two diastereomers have different physical properties easy to separate - i.e. salts crystallise well and they will have different solubilities. add base and extract into organic solvent
- chromatography with chiral column packing. enantiomer with same chirality will interact better with column and will emerge after. typical stationary phase derived from cellulose
- action of enzyme - enzymes are chiral and only act on one enantiomer
- Simple crystallisation - curial shapes, distinguishable by handedness. impractical
conformational analysis for: ethane, butane, generalised larger acyclic molecules
Ethane: energy maxima when eclipsed - filled CH bonding orbitals overlap slightly which is always destabilising (raises energy)
minima when staggered - CH bonding orbitals overlap with empty sigma*, overlap of filled orbital with empty is always stabilising (lowers energy)
Butane: central carbon has 3 distinguishable energy minima - gauche, anti-periplanar and gauche which interconvert at RT. anti-periplanar more stable by 3 kJ mol-1. populations determined by equilibrium constant K = [anti-pp]/[gauche] = exp(-delta G/RT)
Generally - as K increases the % of less stable conformer decreases and -delta G increases
larger acyclic molecules - several conformers, interconverting, with somewhat different energies. often controlled by sterics. exceptions occur when groups attract each other e.g. H-bonding
conformational analysis: special cases
bonds to sp2 carbons and carbonyls
bonds with intermediated order
bonds to sp2 carbons: one CH bond eclipses double bond to avoid pi electrons (?), also applies to carbonyls
bonds with intermediate order:
amides - planar structure with rotation slower than single bonds, can show two peaks in NMR. secondary amides are more stable in Z conformation so only one NMR peak
esters - less double bond character character than for amides, but planar with Z preferred
Steric effects + overlap between lone pair N/O and empty sigma* from carbonyl carbon ( overlap between full and empty orbitals is always stabilising)
3-membered rings
planar
no rotation = no conformational variability
strain
internal angle 60, wants to be 109 - raises energy
reflected in heat of combustion
Baeyer strain
strain due to distorted bond angle
4-membered ring
planar, 90 degree angle
bent, smaller than 90 so baeyer strain increases
planar = eclipsed
bent = slightly staggered, lower energy
planar conformation - Pitzer strain, due to suboptimal dihedral/torsion angle w
bent preferred - lower Pitzer strain compensates increased Baeyer strain
5-membered ring
planar = 108, almost no Baeyer strain but bonds eclipsed so max Pitzer strain
envelope and twisted envelope - similar energies
cyclopentanes are flexible
6-membered rings
chair: internal angle about 108, almost no Baeyer strain
torsion angle w = 60, almost no Pitzer strain
almost strain-free
heat of combustion nearly the same as for linear hydrocarbons
twist boats are energy minima
10,000 chairs for each twist boat
7-membered ring
comfortable chair
2-fold symmetry
most stable. conformation
still some Pitzer strain
8-membered ring
boat chair
most stable conformation
avoids eclipsing interaction
significant Pitzer strain
special cases for chair substituents
- t-Bu has high preference for equatorial, axial t-Bu so bad that two opposing t-Bu flips to twist-boat
- trans-declin - conformational lock with H trans
- cis-declin - both rings can flip to give a second all-chair structure
6-membered rings in nature: carbohydrates
glucose - chair with one carbon replaced with oxygen
‘anomeric effect’ - axial bond at anomeric centre has an empty anti bonding orbital on the far side of the anomeric carbon. this sigma* overlaps nicely with the axial lone pair on the ring oxygen - stabilising effect
stabilisation is most effective if the sigma* is low in energy i.e. if the bad is to an electronegative atom. the most electronegative of substituents should therefore occupy axial position
O is more EN than H, alpha-anomers of carboyhydrate favoured
anomers = diastereomers
6-membered rings in nature: steroids
common framework has trans-declin at centre and therefore is rigid
two important examples:
cholesterol
cholic acid - cis-declin, but no ring flip possible as also contains trans-declin which holds everything in place
stereoselective reactions
stereoisomers favoured over others
stereospecific
stereisomers in a reaction form more stereoisomers
stereospecific reaction examples
- Diels-Alder - single step, so cis alkene creates cis ring etc
- Creation of a new chiral centre next to pre-existing one e.g. Grignards forming chelate with substrate (interacting with group on current chiral centra) means that conformation is held and R group can only attack one face, forming almost exclusively one diastereomer
- enantioselective reaction on achiral substrate - enantiomeric face gives equal enantiomer products
diastereotopic/enantiotopic
replacement of hydrogen gives diastereomeric products/ enantiomeric products
or addition to face e.g. aldehyde gives enantiomeric products
Problem: just one enantiomer wanted from reaction of achiral reagent - asymmetric catalysis
TS for the two reactions are enantiomeric so use a chiral reagent so that TS are diastereomic. Cant make carbon centre chiral instead add chiral ligand which binds to metal (catalytic amount). reagent which is not bound to ligand will react unselectively.
Start with very poor reagent - organozinc reagent (less reactive Grignard) as reaction is slow, then add chiral ligand which accelerates reaction
e.g. amino-alcohol which binds to Et2Zn, TS are diastereomeric so different energies, big difference means reaction is enantioselective
after reaction, amino-alcohol dissociates and repeats - catalyst
enantiomeric excess (% e.e.)
e.e = % major enantiomer - % minor enantiomer
enantiomeric vs disasteriomeric TS
enantiomers = identical energies, TS will always be mirror images
diastereomers, different energies (can be similar), TS not mirror images
CIP for enantiotopic faces of aldehyde
CIP: 1, 2, 3
anti-clockwise = Si face
clockwise = Re face
chiral molecules were obtained as single enantiomers from achiral materials examples
- Resolution, mandolin acid
- Kinetic resolution with enzyme
- Enantioselective organozinc addition with naturally-derived amino-alcohol
- Enantioselective reduction with enzyme - baker’s yeast
how did biological molecules become enantiopure
- Asymmetric physical process followed by chiral amlification e.g. polarised light destroyed one enantiomer more quickly than other
- Spontaneous symmetry breaking e.g. saturated solution forms single crystal which acts as a seed
acylation of cyclic compounds
Ac2O and pyridine - less aggressive than acyl chloride
equatorial OH reacts faster , monoacetate isolated
nucleophilic substitution of cyclic compounds
axial l.g. - no special problem, easy
equatorial l.g. - major steric hindrance of Hs, 30 times slower
elimination in cyclic compounds
equatorial l.g. - No anti-periplanar H- E2 cannot happen
axial l.g. - axial H is antiperiplanar - E2 occurs
C-H and C-X have to be anti-periplanar (like trans)
hydride reductions in cyclic compounds
subject to steric hindrance
differences can be magnified by using bulky reagents, LisBu3BH - attacks less-hindered face
cyclohexanones
axial attack is hindered - usually most important effect
nucleophiles approach carbonyl groups at 107 degrees -not hindered below
cyclohexanones flattened because C-CO are shorter. attack from the top is easier for small reducing agents for electronic reasons (O is already bless towards equatorial orientation)
cyclohexanes - subtle effects in additions
Br2 - biaxial product formed through chair-like TS, no problems
alternative attack goes through boat-like TS to give twist boat which flips to diequatorial products - more stable but slower
biaxial product favoured
also applies to epoxides - very reactive, diaxial product formed
