Thermodynamic evaluation of aromatic CH/π interactions and rotational entropy in a molecular rotor

Article abstract of DOI:10.1021/ja512053t

A molecular rotor built with a stator formed by two rigid 9β-mestranol units having a 90° bent angle linked to a central phenylene rotator has an ideal structure to examine aromatic CH/π interactions. Energies and populations of the multiple solution conformations from quantum-mechanical calculations and molecular dynamics simulations were combined with variable-temperature (VT) ¹H NMR data to establish the enthalpy of this interaction and the entropy associated with rotation about a single bond. Rotational dynamics in the solid state were determined via VT cross-polarization magic-angle spinning ¹³C NMR spectroscopy.

Full text of DOI:10.1021/ja512053t

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Communication
Thermodynamic Evaluation of Aromatic C-H/#
Interactions and Rotational Entropy in a Molecular Rotor
Salvador Perez-Estrada, Braulio Rodriguez-Molina, Leilei Xiao, Rosa
Santillan, Gonzalo Jiménez-Osés, K. N. Houk, and Miguel A. Garcia-Garibay
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512053t • Publication Date (Web): 30 Jan 2015
Downloaded from http://pubs.acs.org on January 31, 2015
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ThermodynamicꢀEvaluationꢀofꢀAromaticꢀCH/πꢀInteractionsꢀandꢀRota-
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tionalꢀEntropyꢀinꢀaꢀMolecularꢀRotorꢀ
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SalvadorꢀPérez-Estrada, ꢀBraulioꢀRodriguez-Molina, ꢀLeileiꢀXiao, ꢀRosaꢀSantillan, ꢀGonzaloꢀJiménez-
1
1
1
Osés, ꢀK.ꢀN.ꢀHouk *ꢀandꢀMiguelꢀA.ꢀGarcia-Garibay *ꢀ
1DepartmentꢀofꢀChemistryꢀandꢀBiochemistry,ꢀUniversityꢀofꢀCalifornia,ꢀLosꢀAngeles,ꢀCaliforniaꢀ90095-1569,ꢀUSA;ꢀ
2DepartamentoꢀdeꢀQuímica,ꢀCentroꢀdeꢀInvestigaciónꢀyꢀdeꢀEstudiosꢀAvanzados,ꢀdelꢀIPN,ꢀMéxico,ꢀD.F.ꢀ07360,ꢀMéxicoꢀ
SupportingꢀInformationꢀPlaceholder
ABSTRACT:ꢀ Aꢀ molecularꢀ rotorꢀ builtꢀ withꢀ aꢀ statorꢀ
formedꢀbyꢀtwoꢀrigidꢀ9β-mestranolꢀunitsꢀhavingꢀaꢀ90oꢀ
determinedꢀ byꢀ anꢀ interplayꢀ betweenꢀ enthalpicꢀ fac-
torsꢀfavoringꢀtheꢀCH/πꢀinteractionꢀ(enthalpicallyꢀfa-
voredꢀ region)ꢀ andꢀ entropicꢀ factorsꢀ relatedꢀ toꢀ theꢀ
largeꢀnumberꢀofꢀconformationsꢀavailableꢀtoꢀtheꢀCH/πꢀ
unboundꢀ rotationalꢀ stateꢀ (entropicallyꢀ favoredꢀ re-
gion).ꢀꢀꢀ
bentꢀangleꢀlinkedꢀtoꢀaꢀcentralꢀphenyleneꢀrotatorꢀhasꢀ
anꢀidealꢀstructureꢀtoꢀexamineꢀaromaticꢀCH/πꢀinterac-
tions.ꢀEnergiesꢀandꢀpopulationsꢀofꢀtheꢀmultipleꢀsolu-
tionꢀconformationsꢀfromꢀquantumꢀmechanicalꢀcalcu-
lationsꢀ andꢀ molecularꢀ dynamicsꢀ simulationsꢀ wereꢀ
1
combinedꢀ withꢀ variableꢀ temperatureꢀ (VT)ꢀ Hꢀ NMRꢀ
dataꢀtoꢀestablishꢀtheꢀenthalpyꢀofꢀthisꢀinteractionꢀandꢀ
theꢀ entropyꢀ associatedꢀ withꢀ rotationꢀ aboutꢀ aꢀ singleꢀ
bond.ꢀ ꢀ Rotationalꢀ dynamicsꢀ inꢀ theꢀ solidꢀ stateꢀ wereꢀ
1
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determinedꢀviaꢀVTꢀCP-MASꢀ CꢀNMR.ꢀ
Theꢀdynamicsꢀofꢀisolatedꢀmolecularꢀrotorsꢀdependꢀonꢀ
theꢀnatureꢀofꢀtheirꢀpotentialꢀenergy,ꢀwhichꢀisꢀaꢀfunc-
tionꢀofꢀtheꢀinteractionsꢀbetweenꢀtheꢀrotatorꢀandꢀtheꢀ
stator.ꢀꢀWhileꢀtheꢀnumberꢀofꢀorientationsꢀaccessibleꢀ
toꢀtheꢀrotatorꢀisꢀrelatedꢀtoꢀtheꢀnumberꢀofꢀenergyꢀmin-
imaꢀ perꢀ period,ꢀ theꢀ averageꢀ timeꢀ betweenꢀ sitesꢀ de-
pendsꢀonꢀtheꢀheightꢀofꢀtheꢀbarriersꢀthatꢀconnectꢀthemꢀ
ꢀ
Figureꢀ 1.ꢀ Structureꢀ ofꢀ 1,4-bis(9β-mestranol)pheny-
leneꢀrotorꢀ1ꢀandꢀaꢀschematicꢀenergyꢀdiagramꢀshow-
ingꢀ theꢀ stabilizationꢀ ofꢀ CH/πꢀ interactionsꢀ andꢀ aꢀ re-
gionꢀwhereꢀtheꢀenergyꢀisꢀapproximatelyꢀconstant.ꢀ
Weꢀ preparedꢀ theꢀ doubleꢀ 9β-mestranolꢀ rotorꢀ 1ꢀ andꢀ
singleꢀ9β-mestranolꢀrotorꢀ6ꢀbyꢀaꢀdoubleꢀSonogashiraꢀ
crossꢀ couplingꢀ reactionꢀ ofꢀ 9β-mestranolꢀ 5ꢀ withꢀ 1,4-
diiodobenzeneꢀasꢀillustratedꢀinꢀSchemeꢀ1.ꢀꢀAꢀdetailedꢀ
descriptionꢀ ofꢀ theꢀ synthesis,ꢀ whichꢀ beginsꢀ withꢀ theꢀ
preparationꢀofꢀ9β-estroneꢀ3ꢀviaꢀtheꢀepimerizationꢀatꢀ
1
andꢀ theꢀ temperature. ꢀ Whileꢀ exploringꢀ steroidsꢀ asꢀ
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componentsꢀofꢀmolecularꢀrotors, ꢀweꢀrecognizedꢀthatꢀ
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theꢀbentꢀstructureꢀofꢀ9β-mestranolꢀ5 ꢀwithꢀaꢀcis-B/Cꢀ
o
ringꢀjunctionꢀandꢀaꢀnearlyꢀ90 ꢀbentꢀangleꢀinꢀmolecu-
larꢀrotorꢀ1ꢀ(Figureꢀ1)ꢀcanꢀbeꢀusedꢀtoꢀshieldꢀaꢀcentralꢀ
3
phenyleneꢀwithꢀaꢀrotationalꢀpotentialꢀdeterminedꢀbyꢀ
C9ꢀofꢀ9α-estroneꢀ2ꢀbyꢀaꢀliteratureꢀprocedure, ꢀisꢀde-
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weakꢀCH/πꢀinteractions. ꢀꢀAnꢀinterestingꢀfeatureꢀofꢀ1ꢀ
scribedꢀandꢀanalyzedꢀinꢀdetailꢀinꢀtheꢀSIꢀsection.ꢀꢀTheꢀ
1HꢀNMRꢀofꢀ1ꢀdisplayedꢀsignalsꢀcorrespondingꢀtoꢀtheꢀ
steroidalꢀ moietyꢀ andꢀ aꢀ broadꢀ signalꢀ atꢀ 2.98ꢀ ppmꢀ
isꢀ thatꢀ theꢀ rotationalꢀ dynamicsꢀ ofꢀ theꢀ centralꢀ phen-
yleneꢀ shouldꢀ beꢀ determinedꢀ byꢀ aꢀ relativelyꢀ shallowꢀ
CH/πꢀminimumꢀinꢀanꢀotherwiseꢀflatꢀpotential,ꢀasꢀsug-
gestedꢀ inꢀ Figureꢀ 1.ꢀ ꢀ Havingꢀ confirmedꢀ thatꢀ theꢀ ex-
pectedꢀCH/πꢀinteractionꢀgeometryꢀexistsꢀinꢀtheꢀcrys-
tallineꢀ state,ꢀ andꢀ knowingꢀ thatꢀ itꢀ canꢀ beꢀ easilyꢀ de-
tectedꢀinꢀsolutionꢀbyꢀtheꢀanisotropicꢀshieldingꢀchar-
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characteristicꢀ ofꢀ theꢀ 9β-steroidꢀ series ꢀ thatꢀ isꢀ as-
signedꢀ toꢀ H9ꢀ (forꢀ keyꢀ numberingꢀ seeꢀ Figureꢀ 1).ꢀ ꢀ Aꢀ
sharpꢀ singletꢀ atꢀ 6.53ꢀ ppmꢀ wasꢀ assignedꢀ toꢀ theꢀ aro-
maticꢀprotonsꢀofꢀtheꢀcentralꢀphenyleneꢀ(H23).ꢀꢀCom-
paringꢀ theꢀ chemicalꢀ shiftꢀ ofꢀ H23ꢀ inꢀ theꢀ bentꢀ 9β-
mestranolꢀ rotorꢀ 1ꢀ (δH23ꢀ =ꢀ 6.53ꢀ ppm)ꢀ (Figureꢀ 1)ꢀ toꢀ
thatꢀ ofꢀ aꢀ 9α-mestranolꢀ rotor ꢀ reportedꢀ previouslyꢀ
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acteristicꢀinꢀtheꢀ HꢀNMR,ꢀweꢀsetꢀoutꢀtoꢀinvestigateꢀtheꢀ
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equilibriumꢀofꢀ1ꢀinꢀsolutionꢀandꢀitsꢀrotationalꢀdynam-
icsꢀinꢀtheꢀcrystallineꢀstate.ꢀꢀOneꢀcanꢀexpectꢀthatꢀaꢀsys-
temꢀwithꢀaꢀlowꢀenergyꢀminimumꢀinꢀanꢀotherwiseꢀflatꢀ
potentialꢀ inꢀ solutionꢀ shouldꢀ displayꢀ anꢀ equilibriumꢀ
b
(δH23ꢀ =ꢀ 7.39ꢀ ppm),ꢀ thereꢀ isꢀ aꢀ considerableꢀ upfieldꢀ
shiftꢀ(Δδꢀ=ꢀ0.85ꢀppm)ꢀthatꢀcanꢀbeꢀrationalizedꢀbyꢀtheꢀ
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Journal of the American Chemical Society
strongꢀshieldingꢀeffectꢀofꢀtheꢀsteroidꢀaromaticꢀA-ringꢀ
thatꢀ isꢀ inꢀ closeꢀ proximityꢀ toꢀ theꢀ phenyleneꢀ rotator.ꢀꢀ
Notably,ꢀtheꢀrotatorꢀsignalsꢀinꢀtheꢀcaseꢀofꢀ6ꢀareꢀsplitꢀ
intoꢀtwoꢀsets.ꢀꢀOneꢀsetꢀisꢀaffectedꢀbyꢀtheꢀshieldingꢀofꢀ
theꢀsteroidꢀAꢀringꢀandꢀoccursꢀatꢀca.ꢀ6.65ꢀppmꢀandꢀtheꢀ
otherꢀ isꢀ outsideꢀ theꢀ rangeꢀ forꢀ thisꢀ effectꢀ andꢀ hasꢀ aꢀ
normalꢀchemicalꢀshiftꢀofꢀ7.21ꢀppm.ꢀ
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Schemeꢀ1ꢀ
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ꢀ
Figureꢀ2.ꢀa)ꢀX-Rayꢀmolecularꢀstructureꢀofꢀrotorꢀ1,ꢀb)ꢀ
spaceꢀ fillingꢀ modelꢀ ofꢀ aꢀ projectionꢀ alongꢀ theꢀ phen-
yleneꢀ 1,4-axisꢀ (red),ꢀ flankedꢀ byꢀ theꢀ twoꢀ steroidꢀ Aꢀ
ringsꢀandꢀc)ꢀcalculatedꢀꢀ(top)ꢀandꢀexperimentalꢀ(bot-
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tom)ꢀ CꢀNMRꢀchemicalꢀshiftsꢀofꢀphenyleneꢀcarbonsꢀ
1
3
a-dꢀinꢀtheꢀcrystalꢀofꢀrotorꢀ1.ꢀꢀForꢀfullꢀCP-MASꢀ CꢀNMRꢀ
spectra,ꢀ VTꢀ data,ꢀ lineꢀ shapeꢀ analysisꢀ andꢀ Arrheniusꢀ
plotꢀseeꢀFiguresꢀS19-S21.ꢀ
ꢀ
Reagentsꢀandꢀconditions:ꢀa)ꢀMe
b)ꢀethynylmagnesiumꢀbromide,ꢀTHF,ꢀ0ꢀ°Cꢀ–ꢀr.t.,ꢀ83%;ꢀc)ꢀ1,4-
diiodobenzene,ꢀPd(PPh Cl ,ꢀCuI,ꢀEt N,ꢀTHF,ꢀ65ꢀ°C,ꢀ54%;ꢀd)ꢀi.ꢀ
,4-diiodobenzene,ꢀ Pd(PPh Cl ,ꢀ CuI,ꢀ Et N,ꢀ THF,ꢀ 65ꢀ °C,ꢀ ii.ꢀ
TMS-CCH,ꢀ50%ꢀtwoꢀsteps.ꢀ
2 4 2
SO ,ꢀKOH,ꢀH O,ꢀTHF,ꢀ99%;ꢀ
3
)
2
2
3
1
3
)
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X-Rayꢀ diffractionꢀ qualityꢀ singleꢀ crystalsꢀ ofꢀ 1ꢀ wereꢀ
obtainedꢀ byꢀ slowꢀ evaporationꢀ ofꢀ aꢀ CH Cl -hexanes-
EtOAcꢀsolution.ꢀTheꢀmolecularꢀstructureꢀofꢀ1ꢀ(Figureꢀ
)ꢀshowsꢀtheꢀbentꢀsteroidsꢀshieldingꢀtwoꢀsidesꢀofꢀtheꢀ
2
2
2
rotatorꢀinꢀwhatꢀcanꢀbeꢀdescribedꢀasꢀanꢀanti-relationꢀ
ꢀ
withꢀ aꢀ torsionalꢀ angleꢀ C3-C17-C17’-C3’ꢀ =ꢀ 170°.ꢀ Theꢀ
1
Figureꢀ3.ꢀVT- HꢀNMRꢀofꢀdoubleꢀ9β-mestranolꢀrotorꢀ1ꢀ
1
,4-bis(ethynylphenylene)ꢀ moietyꢀ isꢀ almostꢀ linearꢀ
2 2
inꢀ CD Cl ꢀ atꢀ 500MHzꢀ showingꢀ theꢀ temperatureꢀ de-
withꢀ anꢀ angleꢀ C17-Phcentroid-C17’ꢀ =ꢀ 173°.ꢀ ꢀ Asꢀ illus-
tratedꢀinꢀFiguresꢀ1ꢀandꢀ2,ꢀoneꢀhydrogenꢀatomꢀonꢀeachꢀ
sideꢀ ofꢀ theꢀ phenyleneꢀ rotatorꢀ pointsꢀ towardsꢀ theꢀ
steroidꢀ A-ringꢀ whileꢀ theꢀ otherꢀ pointsꢀ towardsꢀ theꢀ
MeO-group.ꢀꢀTheꢀCH/πꢀinteractionsꢀcanꢀbeꢀdescribedꢀ
byꢀ theꢀ distancesꢀ H23-Ph(A)centroidꢀ =ꢀ 2.86ꢀ Å,ꢀ H23’-
Ph(A)’centroidꢀ=ꢀ3.20ꢀÅ,ꢀwithꢀtheꢀfirstꢀveryꢀcloseꢀtoꢀtheꢀ
theoreticalꢀ2.91ꢀÅ, ꢀandꢀbyꢀanglesꢀbetweenꢀC-Hꢀbondꢀ
vectorsꢀ andꢀ theꢀ ringsꢀ centroidsꢀ ofꢀ C23-H23-
Ph(A)centroidꢀ =ꢀ 153°ꢀ andꢀ ofꢀ ꢀ C23’-H23’-Ph(A)’centroidꢀ =ꢀ
pendenceꢀofꢀtheꢀH23ꢀsignal.ꢀ
fromꢀ6.55ꢀppmꢀatꢀ295ꢀKꢀtoꢀ6.32ꢀatꢀ222ꢀKꢀ(whereꢀtheꢀ
fullꢀspectrumꢀbroadened),ꢀwhileꢀtheꢀrestꢀofꢀtheꢀspec-
traꢀremainedꢀbasicallyꢀunchangedꢀ(Figureꢀ3).ꢀꢀAꢀsin-
gletꢀthatꢀintegratesꢀforꢀallꢀfourꢀaromaticꢀhydrogensꢀisꢀ
indicativeꢀ ofꢀ aꢀ temperature-dependentꢀ processꢀ thatꢀ
occursꢀ inꢀ theꢀ fastꢀ exchangeꢀ regime,ꢀ asꢀ expectedꢀ forꢀ
structuresꢀ withꢀ andꢀ withoutꢀ theꢀ CH/πꢀ interactions.ꢀꢀ
Analogousꢀ measurementsꢀ withꢀ theꢀ singleꢀ 9β-
4
a
1
48°.ꢀꢀTheꢀanglesꢀbetweenꢀtheꢀplanesꢀofꢀtheꢀcentralꢀ
2 2
mestranolꢀ 6ꢀ betweenꢀ 296-207ꢀ Kꢀ inꢀ CD Cl ꢀ alsoꢀ re-
phenyleneꢀandꢀthoseꢀofꢀtheꢀtwoꢀAꢀringsꢀhaveꢀvaluesꢀ
ofꢀ 73°ꢀ andꢀ 88°,ꢀ withꢀ theꢀ lastꢀ oneꢀ beingꢀ closeꢀ toꢀ theꢀ
idealꢀ90°ꢀforꢀanꢀaromaticꢀedge-to-faceꢀinteraction. ꢀꢀ
sultedꢀinꢀtheꢀgradualꢀupfieldꢀshiftꢀofꢀtheꢀH23ꢀaromaticꢀ
signal,ꢀwhileꢀnoꢀchangesꢀwereꢀobservedꢀinꢀtheꢀsignalꢀ
atꢀ7.21ꢀppm,ꢀwhichꢀisꢀoutsideꢀofꢀtheꢀshieldingꢀeffectsꢀ
ofꢀ theꢀ steroidꢀ Aꢀ ringꢀ (Figureꢀ S18).ꢀ Consideringꢀ thatꢀ
theꢀobservedꢀchemicalꢀshiftꢀofꢀH23ꢀisꢀaꢀweightedꢀav-
erageꢀofꢀallꢀconformersꢀatꢀequilibrium,ꢀweꢀdevelopedꢀ
aꢀsimplifiedꢀmodelꢀtoꢀcalculateꢀtheꢀenergeticsꢀofꢀtheꢀ
CH/πꢀinteractionꢀthatꢀassumesꢀaꢀfastꢀequilibriationꢀ
4
1
Variableꢀtemperatureꢀ HꢀNMRꢀexperimentsꢀwithꢀmo-
2 2
lecularꢀrotorꢀ1ꢀinꢀCD Cl ꢀconfirmedꢀstructuralꢀchang-
esꢀ thatꢀ affectꢀ theꢀ chemicalꢀ shiftꢀ ofꢀ theꢀ rotatorꢀ C-Hꢀ
group.ꢀꢀAꢀsystematicꢀshiftꢀofꢀthisꢀsignalꢀisꢀobservedꢀ
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termineꢀtheꢀweightedꢀaverageꢀvalueꢀrepresentativeꢀofꢀ
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conformerꢀII,ꢀδH23ꢀ=ꢀ6.1ꢀppm.ꢀꢀConformationalꢀanaly-
sisꢀ onꢀ theꢀ singleꢀ 9β-mestranolꢀ rotorꢀ 6ꢀ atꢀ theꢀ sameꢀ
levelꢀofꢀtheoryꢀrevealedꢀoneꢀmajorꢀconformer,ꢀwhichꢀ
providedꢀtheꢀsameꢀcalculatedꢀchemicalꢀshiftꢀforꢀH23ꢀ
asꢀ thatꢀ inꢀ compoundꢀ 1,ꢀ andꢀ anꢀ excellentꢀ agreementꢀ
forꢀ theꢀ protonꢀ withoutꢀ theꢀ CH/πꢀ interactionꢀ (δH24ꢀ =ꢀ
7.24ꢀ ppm).ꢀ Weꢀ wereꢀ ableꢀ toꢀ validateꢀ theꢀ computa-
tionalꢀ resultꢀ byꢀ comparingꢀ theꢀ calculatedꢀ andꢀ ex-
perimentalꢀ 13Cꢀ chemicalꢀ shiftsꢀ ofꢀ theꢀ centralꢀ rotorꢀ
ꢀ
Figureꢀ4.ꢀSchematicꢀrepresentationꢀofꢀtheꢀconforma-
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tionalꢀ equilibriumꢀ ofꢀ rotorꢀ 1ꢀ viewedꢀ downꢀ theꢀ longꢀ
molecularꢀ axis.ꢀ Theꢀ flankingꢀ blueꢀ barsꢀ representꢀ aꢀ
crossꢀsectionꢀofꢀtheꢀsteroidsꢀA-ringsꢀandꢀtheꢀredꢀbarsꢀ
theꢀcentralꢀphenyleneꢀrotator.ꢀTheꢀCH/πꢀinteractionꢀ
isꢀhighlightedꢀonꢀtheꢀenthalpicallyꢀfavoredꢀstates.ꢀ
usingꢀtheꢀcrystalꢀstructureꢀasꢀtheꢀinputꢀforꢀtheꢀcalcu-
lationꢀ andꢀ comparingꢀ thoseꢀ withꢀ theꢀ CP-MASꢀ 13Cꢀ
NMRꢀspectrumꢀofꢀaꢀmicroꢀcrystallineꢀsampleꢀ(Figureꢀ
c).ꢀ Variableꢀ temperatureꢀ CP-MASꢀ 13Cꢀ NMRꢀ con-
2
firmedꢀ theꢀ relativeꢀ chemicalꢀ shiftsꢀ byꢀ theꢀ siteꢀ ex-
changeꢀ lineꢀ shapeꢀ changesꢀ thatꢀ occurꢀ whenꢀ theꢀ
phenyleneꢀstartsꢀtoꢀrotateꢀ(Figureꢀ2c)ꢀwithꢀaꢀbarrierꢀ
ofꢀ14.1ꢀkcal/molꢀ(FiguresꢀS20ꢀandꢀS21),ꢀwhichꢀwasꢀꢀ
betweenꢀ twoꢀ setsꢀ ofꢀ states.ꢀ ꢀ Statesꢀ Iꢀ representꢀ con-
formationsꢀwhereꢀtheꢀCH/πꢀinteractionꢀisꢀabsentꢀandꢀ
statesꢀIIꢀdepictsꢀconformationsꢀwhereꢀtheꢀinteractionꢀ
isꢀ presentꢀ (Figureꢀ 4).ꢀ Theꢀ observedꢀ chemicalꢀ shiftsꢀ
(δobs)ꢀ areꢀ givenꢀ byꢀ theꢀ weightedꢀ averageꢀ ofꢀ theꢀ
chemicalꢀshiftꢀofꢀtheꢀmainꢀconformersꢀasꢀfollows,ꢀ
δ
I I II
obsꢀ=ꢀχ δ ꢀ+ꢀχIIδ ꢀ
whereꢀtheꢀχ
II,ꢀ whichꢀ canꢀ beꢀ usedꢀ toꢀ determineꢀ theꢀ equilibriumꢀ
constantꢀ (Keqꢀ =ꢀ χII/χ ),ꢀ freeꢀ energyꢀ (ΔG=-RTꢀ lnKeq),ꢀ
i
ꢀareꢀtheꢀpopulationsꢀofꢀconformersꢀIꢀandꢀ
I
enthalpyꢀ (ΔH),ꢀ andꢀ entropyꢀ (ΔS)ꢀ byꢀ analysisꢀ ofꢀ aꢀ
Van’tꢀHoffꢀplot.ꢀ
MDꢀsimulationsꢀinꢀexplicitꢀsolventꢀrevealedꢀmultipleꢀ
stackedꢀandꢀnon-stackedꢀconformationsꢀcoexistingꢀatꢀ
ꢀ
Figureꢀ5.ꢀSelectedꢀQMꢀcalculatedꢀconformationsꢀ1-α-Iꢀ
(analogousꢀtoꢀtheꢀcrystalꢀstructure),ꢀ1-β-IVꢀandꢀ1-β-IV’ꢀ
forꢀ 1.ꢀ ꢀ Relativeꢀ enthalpiesꢀ (ΔH)ꢀ andꢀ freeꢀ energiesꢀ
(ΔG)ꢀ inꢀ kcal/molꢀ areꢀ atꢀ theꢀ SCS-MP2/6-
311+G(2d,p)//ω-B97X-D/6-31G(d)ꢀ level.ꢀ Conformerꢀ
Boltzmannꢀ populationsꢀ (χ)ꢀ wereꢀ obtainedꢀ atꢀ 298ꢀ K.ꢀꢀ
Theꢀ calculatedꢀ chemicalꢀ shiftsꢀ forꢀ H-23ꢀ (averageꢀ ofꢀ
fourꢀprotons)ꢀareꢀgivenꢀinꢀppm.ꢀ
2
98ꢀ K;ꢀ non-symmetricꢀ conformationsꢀ differentꢀ toꢀ
thatꢀobservedꢀinꢀtheꢀsolidꢀstateꢀappearedꢀtoꢀbeꢀdomi-
nantꢀ (seeꢀ Supplementaryꢀ Information).ꢀ Inꢀ orderꢀ toꢀ
estimateꢀtheꢀrelativeꢀpopulationsꢀofꢀconformersꢀIꢀandꢀ
II,ꢀoneꢀneedsꢀtoꢀknowꢀtheirꢀcorrespondingꢀchemicalꢀ
shifts.ꢀꢀTheꢀvalueꢀforꢀH23ꢀinꢀtheꢀCH/πꢀunboundꢀstatesꢀ
Iꢀinꢀrotorꢀ1ꢀwasꢀconsideredꢀ(andꢀsubsequentlyꢀcom-
putationallyꢀ supported)ꢀ toꢀ beꢀ equalꢀ toꢀ thatꢀ ofꢀ theꢀ
non-interactingꢀ hydrogensꢀ inꢀ 6ꢀ (δH24ꢀ =ꢀ 7.21ꢀ ppm).ꢀꢀ
Withꢀregardꢀtoꢀtheꢀchemicalꢀshiftꢀofꢀtheꢀsameꢀprotonꢀ
inꢀtheꢀCH/πꢀboundꢀstateꢀII,ꢀweꢀundertookꢀaꢀcompleteꢀ
conformationalꢀanalysisꢀofꢀ1.ꢀCalculationsꢀatꢀtheꢀSCS-
MP2/6-311+G(2d,p)ꢀ levelꢀ ofꢀ theoryꢀ (seeꢀ SIꢀ forꢀ
benchmarkingꢀ resultsꢀ ofꢀ upꢀ toꢀ 29ꢀ methods)ꢀ withꢀ aꢀ
polarizableꢀ continuumꢀ solventꢀ modelꢀ indicateꢀ thatꢀ
rotorꢀ 1ꢀ preferentiallyꢀ existsꢀ inꢀ twoꢀ lowest-free-
energyꢀconformationsꢀwithꢀedge-to-faceꢀinteractions,ꢀ
furtherꢀ supportedꢀ byꢀ QMꢀ calculationsꢀ (Figureꢀ S25).ꢀꢀ
Theꢀ excellentꢀ agreementꢀ betweenꢀ experimentalꢀ andꢀ
1
3
calculatedꢀ Cꢀsignalsꢀprovidesꢀstrongꢀsupportꢀofꢀtheꢀ
1
predictedꢀ Hꢀshielding.ꢀꢀFurthermore,ꢀusingꢀtheꢀJohn-
6
son-Bovey ꢀ ringꢀ currentꢀ modelꢀ thatꢀ takesꢀ intoꢀ ac-
countꢀ theꢀ geometryꢀ ofꢀ theꢀ interaction,ꢀ weꢀ arriveꢀ atꢀ
theꢀ sameꢀ result.ꢀ Thus,ꢀ withꢀ theꢀ δ
handꢀweꢀcalculatedꢀtheꢀrelativeꢀpopulationsꢀχ
I
ꢀ andꢀ δIIꢀ valuesꢀ atꢀ
ꢀandꢀχII
I
ꢀ
andꢀtheꢀcorrespondingꢀequilibriumꢀconstantsꢀatꢀeachꢀ
ofꢀtheꢀtemperaturesꢀexploredꢀforꢀcompoundsꢀ1ꢀandꢀ6.ꢀꢀ
Van’tꢀ Hoffꢀ plotsꢀ (lnꢀ Kꢀ vsꢀ 1000/T,ꢀ Figuresꢀ S22ꢀ andꢀ
S23)ꢀ ofꢀ theꢀ correspondingꢀ equilibriumꢀ constantsꢀ
providedꢀusꢀwithꢀtheꢀvaluesꢀofꢀΔH,ꢀΔSꢀandꢀΔGꢀforꢀtheꢀ
correspondingꢀ conformationalꢀ equilibria.ꢀ Fromꢀ theꢀ
dataꢀshownꢀinꢀTableꢀ1ꢀweꢀnoteꢀthatꢀtheꢀfreeꢀenergyꢀ
1
-β-IVꢀandꢀ1-β-IV’,ꢀ(Figuresꢀ5ꢀandꢀS24)ꢀthatꢀlackꢀtheꢀ
apparentꢀsymmetryꢀobservedꢀinꢀtheꢀcrystal.ꢀTheꢀtwoꢀ
steroidsꢀhaveꢀaꢀtendencyꢀtoꢀapproachꢀeachꢀotherꢀsoꢀ
thatꢀonlyꢀoneꢀC-HꢀgroupꢀcanꢀexperienceꢀtheꢀCH/πꢀin-
teractionꢀ inꢀ solutionꢀ atꢀ anyꢀ givenꢀ time.ꢀ ꢀ Calibratedꢀ
chemicalꢀ shiftsꢀ wereꢀ obtainedꢀ forꢀ theꢀ majorꢀ con-
5
formersꢀusingꢀtheꢀGIAO ꢀmethodꢀ(TableꢀS6)ꢀandꢀtheꢀ
(
ΔG)ꢀatꢀ298ꢀKꢀslightlyꢀfavorsꢀtheꢀCH/πꢀboundꢀstateꢀII.ꢀ
calculatedꢀchemicalꢀshiftsꢀforꢀH23ꢀwereꢀusedꢀtoꢀde-
Asꢀ expectedꢀ fromꢀ statisticalꢀ entropyꢀ considerations,ꢀ
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theꢀentropyꢀtermꢀforꢀtheꢀdoubleꢀ9β-mestranolꢀrotorꢀ1ꢀ
isꢀlargerꢀthanꢀthatꢀforꢀtheꢀsingleꢀsteroidꢀstructureꢀinꢀ
,ꢀ sinceꢀ theꢀ numberꢀ ofꢀ conformationalꢀ statesꢀ thatꢀ
AUTHORꢀINFORMATIONꢀ
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CorrespondingꢀAuthorꢀ
6
houk@chem.ucla.edu;ꢀmgg@chem.ucla.eduꢀ
Theꢀauthorsꢀdeclaredꢀnoꢀconflictꢀonꢀinterest.ꢀꢀ
ACKNOWLEDGMENTSꢀ
ariseꢀbyꢀrotationꢀofꢀtheꢀphenyleneꢀringꢀandꢀtheꢀster-
oidsꢀinꢀ1ꢀisꢀgreaterꢀthanꢀthatꢀinꢀ6.ꢀTheꢀfactꢀthatꢀtheꢀ
entropyꢀfactorꢀforꢀbothꢀcompoundsꢀisꢀwithinꢀ3-5ꢀcalꢀ
-
1
-1
mol ꢀK ꢀisꢀindicativeꢀofꢀtheꢀentropyꢀcostꢀassociatedꢀ
withꢀ freezingꢀ rotationsꢀ aboutꢀ aꢀ singleꢀ bond,ꢀ asꢀ sug-
ThisꢀworkꢀwasꢀsupportedꢀbyꢀNationalꢀScienceꢀFounda-
tionꢀ (grantꢀ DMR1402682ꢀ forꢀ M.G.Gꢀ andꢀ CHE-1361104ꢀ
forꢀK.N.H.)ꢀandꢀusedꢀtheꢀExtremeꢀScienceꢀandꢀEngineer-
ingꢀDiscoveryꢀEnvironmentꢀ(XSEDE)ꢀsupportedꢀbyꢀgrantꢀ
7
gestedꢀbyꢀJencks. ꢀꢀItꢀisꢀreassuringꢀthatꢀtheꢀenthalpyꢀ
termꢀfavorsꢀstateꢀIIꢀ(1-β-IV’ꢀinꢀFigureꢀ5ꢀbeingꢀaꢀrepre-
sentativeꢀstructure)ꢀatꢀtheꢀlowestꢀtemperaturesꢀwhenꢀ
theꢀ TΔSꢀ termꢀ isꢀ minimal,ꢀ inꢀ agreementꢀ withꢀ theꢀ at-
tractiveꢀnatureꢀofꢀtheꢀedge-to-face-interaction.ꢀꢀCor-
respondingly,ꢀtheꢀrotationallyꢀCH/πꢀunboundꢀstateꢀI,ꢀ
althoughꢀ higherꢀ inꢀ enthalpy,ꢀ isꢀ favoredꢀ atꢀ higherꢀ
temperaturesꢀbecauseꢀitꢀcanꢀoccupyꢀmoreꢀrotationalꢀ
states.ꢀ Aꢀ comparisonꢀ ofꢀ thermodynamicꢀ parametersꢀ
ofꢀcompoundsꢀ1ꢀandꢀ6ꢀshowsꢀthatꢀtheꢀenergeticsꢀofꢀ
theꢀedge-to-faceꢀinteractionꢀareꢀnotꢀaꢀfactorꢀofꢀtwo,ꢀinꢀ
agreementꢀwithꢀtheꢀfactꢀthatꢀhavingꢀtheꢀtwoꢀsimulta-
neousꢀinteractionsꢀisꢀunlikely.ꢀ
0
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(
OCI-1053575)ꢀalongꢀwithꢀtheꢀUCLAꢀInstituteꢀofꢀDigitalꢀ
ResearchꢀandꢀEducationꢀ(IDRE).ꢀꢀ
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(
Tableꢀ 1.ꢀ Enthalpyꢀ andꢀ entropyꢀ valuesꢀ forꢀ theꢀ confor-
mationalꢀ equilibriumꢀ ofꢀ compoundsꢀ 1ꢀ andꢀ 6ꢀ derivedꢀ
Flores, B.; Farfán, N.; Santillan, R.; Garcia-Garibay, M. A. Org.
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1
fromꢀvariableꢀtemperatureꢀ HꢀNMR.ꢀ
a,c
Rotorꢀ
ΔHaꢀ
-1.74ꢀ
-1.01ꢀ
ΔSꢀbꢀꢀ
-5.12ꢀ
-3.29ꢀ
ΔG ꢀ
-0.21ꢀ
-0.03ꢀ
1ꢀ
2
012, 77, 9970. (d) Rodriguez-Molina, B.; Pérez Estrada, S.; Garcia-
Garibay, M. A. J. Am. Chem. Soc. 2013, 135, 10388.
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J. R.; de Koning, P. D. J. Chem. Soc., Perkin Trans. 1 2000, 1003.
6
ꢀ
a
-1
b
-1 -1 c
Units:ꢀ kcalꢀmol ;ꢀ calꢀmol ꢀK ,ꢀ Calculatedꢀatꢀ298ꢀK.ꢀ
(
4) (a) Jennings, W. B.; Farrel, B. M.; Malone, J. F. Acc. Chem. Res.
2001, 31, 885. (b) Wheeler, S. E.; Houk, K. N. Mol. Phys. 2009, 107,
49. (c) Salonem, L. M.; Ellermann, M.; Diederich, F. Angew. Chem.
Theꢀ freeꢀ energyꢀ valuesꢀ forꢀ theꢀ edge-to-faceꢀ interac-
tionꢀ reportedꢀ hereꢀ andꢀ inꢀ theꢀ literatureꢀ byꢀ Wilcoxꢀ
7
Int. Ed. 2011, 50, 4808.
(5) (a) London, F. J. Phys. Radium 1937, 8, 397–409. (b) Wolinski,
K.; Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251-8260.
-
1
8
(
ΔGꢀ=ꢀ-0.24ꢀkcalꢀmol ), ꢀJenningsꢀ(ΔGꢀ=ꢀ-0.05ꢀtoꢀ-0.67ꢀ
-
1
9
10
-1
kcalꢀmol ) ꢀandꢀHunter ꢀ(ΔGꢀ=ꢀ-0.33ꢀkcalꢀmol ),ꢀareꢀ
smallꢀ andꢀ slightlyꢀ different.ꢀ ꢀ Itꢀ isꢀ noteworthyꢀ thatꢀ
thereꢀareꢀremarkableꢀsimilaritiesꢀbetweenꢀourꢀmeas-
(
c) Cheeseman, J. R.; Trucks, G. W.; Keith, T. A.; Frisch, M. J. J.
Chem. Phys. 1996, 104, 5497-5509.
(
(
6) (a) Johnson, C. E.; Bovey, F. A. J. Chem. Phys. 1958, 29, 1012.
b) Emsley, J. W.; Feeney, J.; Sutcliffe. L. H., High Resolution
-
1
uredꢀenthalpiesꢀ(ΔHꢀ=ꢀ-1.0ꢀtoꢀ-1.7ꢀkcalꢀmol )ꢀandꢀtheꢀ
experimentalꢀ enthalpyꢀ ofꢀ theꢀ benzeneꢀ dimerꢀ re-
Nuclear Magnetic Resonance Spectroscopy, Pergamon Press: Oxford,
1965; Vol. 1, pp 595-604.
11
-1
portedꢀbyꢀKrauseꢀetꢀal. ꢀ(ΔHꢀ=ꢀ-1.6±0.2ꢀkcalꢀmol ),ꢀ
(
1
7) Page, M. I.; Jencks, W. P. Proc. Nat. Acad. Sci. U.S.A. 1971, 68,
678.
4 ,9
-1
12
a
Jennings ꢀ(ΔHꢀ=ꢀ-1.2ꢀtoꢀ-1.5ꢀkcalꢀmol )ꢀandꢀFuruta ꢀ
-
1
(
ΔHꢀ =ꢀ -1.3ꢀ kcalꢀ mol ).ꢀ Weꢀ interpretꢀ anꢀ entropyꢀ
(8) Paliwal, S.; Geib, S.; Wilcox, C. S. J. Am. Chem. Soc., 1994, 116,
4497.
-
1
-1
changeꢀinꢀtheꢀrangeꢀofꢀ-3.3ꢀtoꢀ-5.1ꢀcalꢀmol ꢀK ꢀasꢀre-
flectingꢀ theꢀ differenceꢀ betweenꢀ aꢀ smallꢀ numberꢀ ofꢀ
CH/πꢀboundꢀstatesꢀandꢀaꢀlargerꢀnumberꢀofꢀunboundꢀ
rotationalꢀstates,ꢀasꢀsuggestedꢀinꢀFigureꢀ1.ꢀꢀꢀꢀ
(
9) (a) Hamor, T. A.; Jenning, W. B.; Proctor, L. D.; Tolley, M. S. J.
Chem. Soc. Perkin Trans. 2 1990, 25. (b) Boyd, D. R.; Evans, T.S.;
Jennings, W. B.; Malone, J. F.; O’Sullivan, W.; Smith, A. Chem.
Commun. 1996, 2269. (c) Jennings, W. B.; Farrel, B. M.; Malone, J.
F. J. Org. Chem. 2006, 71, 2277.
(10) Carver, F. J.; Hunter, C. A.; Livingstone, D. J.; McCabe, J. F.;
Seward, E. M. Chem. Eur. J. 2002, 8, 2847.
Supportingꢀ Information.ꢀ Synthesesꢀ andꢀ characteriza-
tionꢀ ofꢀ newꢀ compoundsꢀ andꢀ solidꢀ stateꢀ CP-MASꢀ 13Cꢀ
analysis.ꢀ Computationalꢀ procedures,ꢀ Cartesianꢀ coordi-
nates,ꢀ electronicꢀ energies,ꢀ entropies,ꢀ enthalpies,ꢀ Gibbsꢀ
freeꢀenergies,ꢀandꢀlowestꢀfrequenciesꢀofꢀtheꢀcalculatedꢀ
structures.ꢀꢀThisꢀmaterialꢀisꢀavailableꢀfreeꢀofꢀchargeꢀviaꢀ
theꢀInternetꢀatꢀhttp://pubs.acs.org.ꢀꢀ
11 Krause, H.; Ernstberger, B.; Neusser, H. J. Chem. Phys. Lett. 1991,
1
(
84, 411.
12) Morimoto, T.; Uno, H.; Furuta, H. Angew. Chem. Int. Ed. 2007,
46, 3672.
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