Conformational AnalysisAn important aspect of organic compounds is that the compound is not static,but rather has conformational freedom by rotating, stretching and bending about bondsEach different arrangement in space of the atoms is called a “Conformer”(a less used term is a “Rotamer” if change is caused by a bond rotation)Different conformers can have vastly different energies and the relative proportionof each conformer is related to the energy difference between themCH3H3CH3CCH3Lower EnergyHHCH3HHHHHHCH3CH3CH3To observe the spatialarrangement of atomsin space, often drawconformers in aNewman projection196

Conformational AnalysisConformers will be of different energy due to strainSources of strain are generally categorized in one of three types:1) Torsional strainTorsional strain is due to interactions as groups change relative positionwith a change in torsional bond angleConsider rotation of ethaneHHHEclipsedconformationHHHEnergy 3 kcal/molHStaggered HconformationHHHHH-60 0 Further rotation willconvert eclipsedconformation back tostaggeredHHHHH60 120 torsional angleEclipsed is higher inenergy than staggereddue to increasedtorsional strain180 240 197

Conformational Analysis2) van der Waals strainAnother source of strain is when groups are placed in positions closerthan the sum of their van der Waals radiiConsider rotation of butanetotallyeclipsedeclipsedH3C CH3H CH3HEnergyHHCH3HHHH“totally eclipsed”conformation (which haslargest groups eclipsing eachother) is higher in energy thanother eclipsed conformations“gauche” conformation ishigher in energy than anti(both are “staggered”conformations)HHgaucheanti0 HCH3CH3HCH3-60 HCH3HHH60 120 torsional angle180 240 198

Conformational AnalysisThe difference in energy thus affects the amount of each conformer presentn-ButaneHCH3HHHMole FractionCH3HCH3CH3HMajority ofcompound is in theanti conformation,hardly any ineclipsedconformationHHTorsional AngleW.L. Jorgensen, J.K. Buckner, J. Phys. Chem., (1987), 91, 6083-6085199

Conformational Analysis3) Angle strainA third source of strain is due to angle strain(molecules that are forced to have a bond angle far from ideal [ 109.5 for sp3])A large source of strain for ring compoundsRing SizeCycloalkaneTotal RingStrain(Kcal/mol)Ring Strainper ododecane3.80.3Strain is large for small rings, but reaches minimum at 6-membered ring200

Conformational AnalysisThis angle strain is due to forcing the electron density in bonds at angles that are not idealHave observed this effect with cyclopropaneObserve same “bent” bond effect inwhere the 3 carbons are forced to be coplanarcyclobutane, here the 4 carbons need not bein the same plane but the angle strain wouldstill be largeThe electron densitytruly does form“bent” bonds,bonding electrondensity is not alonginternuclear axisAs rings become larger, however, would not expect this type of “bent” bondsdue to lower angle strainD. Nijveldt and A. Vos, Acta Cryst., 1988, B44, 296-307A. Stein, C.W. Lehmann, P. Luger, J. Am. Chem. Soc.,1992, 114, 7687-7692201

Conformational AnalysisThe angle strain becomes lowest with a 6-membered ring due to the ability to form aconformer that has nearly perfect torsional angles and a lack of ring strainH 120 HHHHHHHHHHHHPlanar cyclohexane(120 C-C-C,All hydrogens eclipsed)Conformers of cyclohexaneHHHH HHHHHHHHChair conformationHHHHHHHHHH111.4 HChair cyclohexane(nearly tetrahedral C-C-C,no hydrogens eclipsed)Remove hydrogensHHH HHHHHHHTwist-boatconformationHHHHHHHHHHHHBoat conformation202

Conformational AnalysisThe chair conformation has a low torsional strain as seen in a Newman projectionHH2CCCHHHHCH2HTherefore cyclohexane is the moststable ring size due to low angleand torsional strain compared toother ring sizesHHNearly perfect staggered alignmentHHHHH2 HCCH2 HHHStill have some gauche interactions, but energy is low for this conformation203

Conformational AnalysisCCCCHalf-chairEnergyBoat10.8 Kcal/molTwist-BoatChairKey point – there are two distinct chair conformations for a cyclohexane that can interconvertThe energy of activation for the interconversion is 10.8 Kcal/mol204

Conformational Analysis6-Membered rings are observed frequently in biological moleculesHOHOHOROOHD-glucoseOHSteroid ring y drugs also contain six-membered rings205

Conformational AnalysisThe Axial and Equatorial Positions have Different Spatial RequirementsThere are two chair conformations, a substituent moves fromequatorial to axial in a chair-chair interconversionstericsHHHYY is equatorialYHHH(called A strain,or A1,3 strain)Y is axialBigger Y substituent has more steric interactions in an axial position than equatorialThe chair conformation which has the Y group equatorial is therefore more stable206

Conformational AnalysisDue to the difference in energy between placing a substituent in the axial versus equatorialposition, the two chair conformations are no longer equal in energyCH3CH3ΔG (ax/eq) (Kcal/mol) 1.74 for a methyl groupΔG will be larger as the size of the substituent increasesCan therefore determine the exact equilibrium between the two conformers using Gibb’sΔG -RT ln KThe equilibrium thus is 19.5 at room temperature,favoring the equatorial position for the methyl groupAn easy approximation for equilibrium and rate:(Without needing to calculate using exact formula at room temperature)K 10(3/4)ΔGWould yield K 20.1k 10(13-3/4)ΔG207

Conformational AnalysisThe A value will change as the size of the substituent changesRRRA1,3 (kcal/mol)KCH31.7419.5CH2CH3CH(CH3)2C(CH3)3* As groups get larger, the A value increases208

Conformational AnalysisThe substituent in the axial position is disfavored due to steric interactions with 1,3 hydrogens(reason it is sometimes called A1,3 strain)1,3 interactionHHCH3HHHHHWith a methyl substituent,a hydrogen is directedtoward 1,3 hydrogensAs substituent becomes larger, steric interactions with 1,3 hydrogens increaseH CH3HHHHHHHCH3With an ethyl substituent, if the extraCH3 is pointed toward 1,3 hydrogenscan rotate to move away(sterics similar to methyl)HHHCH3CH3H CH3HCH3CH3With an isopropylWith a t-butyl substituent,substituent, can stillhowever, must have CH3have conformer with Htoward 1,3 hydrogenstoward 1,3 hydrogens209

Conformational AnalysisWith cyclohexanones, substituents at the 2-position prefer equatorialORROpreferredMainly due to lower A1,3 strain (similar to a normal methyl cyclohexane),but also due to an alkyl group preferring to be eclipsed with ketone (which has lower steric size)Analogous to open chain ketone compoundsROORH HHOHCH3H CH3HR CH3Most stable210

Conformational AnalysisThe ketone functionality in cyclohexanone also affects remote substituentsOCH3H3 COA1,3 value is 1.3, compared to 1.74 for a methyl substituent on cyclohexaneCH3HCH3HA 1.74A 1.3OCH3HOHKetone is positioned awayfrom axial CH3, therefore lesssterics than with hydrogensWhen a halogen is located at the α-position in cyclohexanone,need to also consider dipolar interactions (called α-Haloketone Effect)Dipoles cancel each otherMore stable in apolarsolventsOClDipoles reinforce each otherMore stable in polar solventsCl O211

Heteroatoms in RingWhen a heteroatom is placed in a cyclohexane ring,the bond lengths and bond angles changeAs the C-O bond lengthshortens in 1,3-Dioxane,the axial 1,3 hydrogens becomecloser in space, thereforegreater van der Waals strainCyclohexaneOO1,3-DioxaneGroupCH3C(CH3)3A1,3 Dioxane2 positionA1,3 Dioxane5 positionA1,3Cyclohexane1.74212

Anomeric EffectWe learned previously that in sugar compounds the hemiacetal form can close in two forms(called α and β anomers)anomeric effect favors this α HCH2OHOHHOHOOOHHOHβ-D-glucopyranoseWhenever an electron withdrawing substituent is next to an oxygen in a pyran ring,the EWG prefers to be in an axial position (called anomeric effect)Anomeric effect is commonly seen with alkoxy or halogen substituentsThe axial position is favored due to lower dipole(similar to α-haloketone effect seen earlier)Due to this dipole effect,the preference for axial position is generally greater in nonpolar solvents213

Anomeric EffectThe anomeric effect can also be explained in a molecular orbital explanationOOClClfavoredH2COH2CHCH2CH2 ClClHClExperimentally it is known that as the EWcapability of substituent at 2-positionincreases, the C-X bond length increases(and C-O bond length decreases)OClσ* orbitalOnly when the EWG is in the axial positioncan the lone pair on oxygen align to fill the σ*orbital (thus break the bond)OCl214

ReactivityUnderstanding the differences in energy with conformational analysisallows prediction of relative rates of compoundsWe will focus on reactivity differences in ring compounds(mainly cyclohexane derivatives)Remember that the answer to any rate question must deal with the difference in energybetween the starting material structures and the transition state structure(the structure of the product does not affect the rate)EaΔGReaction CoordinateImpacts rate of reactionImpacts thermodynamics ofreaction215

ReactivityConsider the acetylation of cyclohexanolOH3 COHOOOCH3OCH3The t-Butyl group locksconformationWould cis-4-tButylcyclohexanol or trans-4-tButylcyclohexanol react faster?OHOH3 COHOOCH3This is a relative rate question, needto compare the rate for each reaction(therefore energy difference betweenstarting material and transition state)216

ReactivityThe A value for a hydroxy group is 0.7 kcal/mol,therefore the axial hydroxy group is 0.7 kcal/mol less stable than the equatorialcistrans0.7Reaction CoordinatetransOHOH3 COHcisH3 C O OOOOCH3OCH3H3 C O OOOCH3217

ReactivityConsider oxidation of 4-tButylcyclohexanol, does cis or trans react faster?cistrans 0.7Reaction CoordinateBHOHCrO3OHO OCrOOHO OCrOOHOR.D.S.OH218

ReactivityCan also compare similar reactions on different size ringsA cyclohexane in a chairconformation is 6.2 kcal/mol more stable than acyclopentane in anenvelope conformation56 6.2Reaction CoordinateHOThe ketone formshould be slightly lessenergy difference dueto minimizingtorsional strainOHNaBH4OHOH219

Steric Approach ControlSteric approach control: All other things being equal,a reagent will approach from the least hindered sideConsider the reactivity of substituted cyclohexanonesHCH3OH3CLAHH3 CHH3CH3 CHWhen a hydride reacts with a ketone, thehydride approaches at the Bürgi-Dunitz angleCH3 HCH3 OHH3 COHH3C90%10%More stable productYield of products is determined by kinetic control,less stable structure is formed faster due to less sterics in the transition state(this reaction is irreversible,therefore the products cannot equilibrate to the more stable structure)220

Steric Approach ControlSteric approach control is operating under a variety of reactionswhere there is a steric difference between two possible reaction pathwaysConsider alkene reactions in bicyclic systemsPhCO3HHHOHHOWhen an electrophile reacts with a π bond,the electrophile can approach from either faceIf sterics of approach are changed, however, the product yields will also changeH3 CCH3H3CCH3PhCO3HH3 COHHCH3HHO221

Conformational Analysis! Key point - there are two distinct chair conformations for a cyclohexane that can interconvert! CC Chair! CC Half-chair! Twist-Boat! Boat! 10.8 Kcal/mol! The energy of activation for the interconversion is 10.8 Kcal/mol! E n e r g y 204