the inner space of molecules - nobel prize

The Inner Space of Molecules

L. Marshall, K. ParrisL. Marshall, K. ParrisD. Nemeth, B. Askew 1985D. Nemeth, B. Askew 1985

Molecular Chelating AgentsMolecular Chelating Agents

D. NemethD. NemethB. AskewB. Askew

19851985

Pyrazine and QuinoxalinePyrazine and Quinoxaline

K. S. Jeong, 1990K. S. Jeong, 1990

Barbiturates and DiketopiperazinesBarbiturates and Diketopiperazines

Receptor for 3Receptor for 3‘‘, 5, 5‘‘ Cyclic AMP Cyclic AMP

Dr. G. DeslongchampsDr. G. DeslongchampsDr. A. GalanDr. A. GalanProf. J. de Mendoza, (UAM) 1993Prof. J. de Mendoza, (UAM) 1993

Receptor for 3Receptor for 3‘‘,5,5‘‘ Cyclic AMP Cyclic AMP

Reversible Encapsulation PhenomenaReversible Encapsulation Phenomena

Anticipated:Size and Shape RecognitionReaction ChambersAsymmetric Recognition


Unanticipated : Single Molecule Solvation Isotope Effects

Binary CodingHelical Alkanes

Chiral SpacesChemical AmplificationSuper Capsules

““Tennis BallTennis Ball““

Dimeric Assembly


Synthesis

Dr. Rene WylerProf. J. de Mendoza (UAM)


NMR Spectrum of Encapsulated Guests

Guest Guest

Niel R. Branda Dr. Rene Wyler, 1994

““Tennis BallTennis Ball““Methane and Ethane Guests

Dr. Lubo Sebo Prof. Mike Pique (TSRI)

7x107x10-26-26 L L

Capsule x10Capsule x108 8 = tennis ball x10 = tennis ball x108 8 = earth = earth

““SoftballSoftball““

Dr. Robert MeissnerProf. J. de Mendoza (UAM)

Jongmin KangDr. Y. Tokunaga

3x103x10-25-25 L L

Guest Exchange

SoftballSoftball

Dr. Javier SantamariaDr. Tomás MartínDr. Göran HilmerssonDr. Stephen Craig

k1

k-1

A supramolecular substitution reaction:para cyclophane is a much better guest

Opening the SoftballOpening the Softball

4 Hydrogen Bonds 6 Hydrogen Bonds

Opposite Flaps Adjacent Flaps

Guest Exchange in the SoftballGuest Exchange in the Softball

16 HB


16 HB 10 HB


16 HB 10 HB 6 HB


16 HB 10 HB 6 HB 6 HB


16 HB 10 HB 6 HB 6 HB 10 HB


16 HB 10 HB 6 HB 6 HB 10 HB 16 HB

SoftballSoftball

Accelerated Diels-Alder Reaction

S =

Jongmin KangDr. Javier SantamariaDr. Tomas MartinDr. Göran Hilmersson

4.2 M each!3.5 x 10-25 Liters 4 x 10-3 M each

slow

k1 = 0.44 d-1

D10

SoftballSoftball

Accelerated Diels-Alder Reaction

Prof. Mike Pique (TSRI)

Resorcin[4]arene SynthesisResorcin[4]arene Synthesis

Dr. S. Högberg, KTH 1980

side view

top view

H+

Dr. C. SchalleyB. O'Leary

G

Ar = p-C6H4-n-C7H15D. J. Cram

R = n-C11H23

PyBOP, NEt3CH2Cl2, 48%

Molecular SieveMolecular Sieve

Dr. A. LuetzenDr. A. Renslo

8 x108 x10-25-25 L L

Holes permit rapid exchange of solventsHoles permit rapid exchange of solvents

Ions Inside Molecules Inside MoleculesIons Inside Molecules Inside Molecules

Dr. A. LuetzenDr. A. RensloDr. C. SchalleyB. O'Leary

J.-M. LehnM = K+, Sr2+, Ba2+

Cylindrical CapsuleCylindrical Capsule

Dr. Thomas HeinzProf. Dmitry Rudkevich

R = C11H23

1 nm

1.8

nm

Cavity of the Cylindrical CapsuleCavity of the Cylindrical Capsule

GRASPGRASP

4.2 x 10-25 L

Single guests and combinations fill the space

PackingCoefficient

= 0.48

PackingCoefficient

= 0.57

PackingCoefficient

= 0.66


Prof. Dmitry Rudkevich Dr. Sandro Mecozzi

Single Solute - Solvent InteractionsSingle Solute - Solvent Interactions

Dr. A. ScarsoDr. A. ScarsoDr. A. ShivanyukDr. A. Shivanyuk

86%86%14%14%

CH3

H2C CH3 CH3

H2CCH3

Single Solute - Solvent InteractionsSingle Solute - Solvent Interactions

Dr. A. ScarsoDr. A. ScarsoDr. A. ShivanyukDr. A. Shivanyuk

40%40%60%60%

CH3

HN CH3CH3

HN CH3

Revealed by a panel of 15 solventsRevealed by a panel of 15 solvents

Dr. A. ScarsoDr. D. Rechavi-RobinsonTheory:Prof. K. N. Houk (U.C.L.A.)

Equilibrium Isotope Effects

43% 57%

Coencapsulation of three solvent


Dr. Alex Shivanyuk Prof. P. BallesterDr. Masamichi Yamanaka

CHCl3 ClCH2 CH2Cl (CH3)2CHCl

Dr. A. Shivanyuk

Isomeric Constellations

Dr. M. Yamanaka

A binary coding scheme

chloroform

isopropyl chloride

+ C10

+ C12

+ C14

+ C15

Complexes of the Capsule with Linear Hydrocarbons

1H NMR, 600 MHz

Dr. Alessandro ScarsoDr. Laurent Trembleau

Straight Chain HydrocarbonsCoil to fit into the Capsule


Gauche conformation: 0.55 kcal/mol

2D-NOESY, 600 MHz, mixing time: 300ms

Capsule-Tetradecane Complex

Dr. AlessandroScarso

Dr. LaurentTrembleau

Chiral Spaces

Achiral SpacesAchiral Spaces

Dr. Alessandro ScarsoDr. Alexander Shivanyuk

Chiral SpacesChiral Spaces


G G

Chiral objects in achiral spaces

Asymmetric CoencapsulationAsymmetric Coencapsulation


An ensemble of environmentsAn ensemble of environments

CO2H

OHH CO2HHO

H HO2C

HOHG G G



Fixed orientations enhance recognitionFixed orientations enhance recognition

CO2H

OHH G HO2C

HOH G HO2C

HOH

G


Magnetic and steric effects coexistMagnetic and steric effects coexist


CO2HHOH

CH3

H3C

HOH

CH2O

H

CH3

CH3Cl

H

Asymmetric ExteriorsAsymmetric Exteriors


G

GGG

GG G G G

GGGGG

G ? ?

Separation of Steric and Magnetic Effects

Asymmetric ExteriorsAsymmetric Exteriors

Dr. Toru Amaya

Separation of Steric and Magnetic Effects

Chemical Amplification:A Chain Reaction

Length SelectionLength Selection

Dr. Steffi KörnerDr. Fabio TucciDr. Thomas HeinzProf. Dmitry Rudkevich

N

H2C

CH3

O H

CH3

Fits

Doesn‘t fit

N

H2C

H2C

O H

CH3

CH3

Rigid guests have no choice

Dr. J. ChenDr. S LinDr. S. Körner

Prof. S. CraigProf. D. Rudkevich

Long and short anilides formed at theLong and short anilides formed at thesame rate in solutionsame rate in solution

AcidR = Me, Et

AnilineCarbodiimide

(DCC)

R

OHO

NH2

CH3

CN

NNHO

R

CH3

NHO

NH

Anilide Urea(DCU)

Dr. J. Chen, Dr. S. LinDr. S. Körner


Chemical Amplification with Encapsulated ReagentsChemical Amplification with Encapsulated Reagents

Carbodiimide(DCC)

Anilide Urea(DCU)

AcidR = Me, Et

Aniline

CN

NNHO

R

CH3

NH2

CH3

R

OHO

NHO

NH



Sigmoidal product generation of theSigmoidal product generation of theshorter anilideshorter anilide



1.2

1.4

1.6

1.8

2

2.2

0 2000 4000 6000 8000 1 104 1.2 104 1.4 104 1.6 104

[DCC

] enca

p (mM

)

time (sec)

R = Me, squaresR = Et, triangles

CN

N

NH2

CH3

R

OHONHO

R

CH3

Product Recognition and AutocatalysisProduct Recognition and Autocatalysisof the shorter, but not longer anilideof the shorter, but not longer anilide

carbodiimide

urea + anilide

+acid

+aniline

In Solution(reactive)

Encapsulated(unreactive)

Encapsulated(unreactive)



Amplification mechanism

NH

OR

H3CNH

O

NH

C NN C NN

Dr. S. Lin

CanDisplace

DCC

1 Product2 Products3 Products

DCC + Reactants Products

CN

N

Simulation of the Chain ReactionSimulation of the Chain Reaction

Super Capsules

Tetrameric CapsuleTetrameric Capsule

Dr. Tomás MartínDr. Ulrike Obst

3x103x10-25-25 L L

Tetrameric CapsuleTetrameric Capsule

Adamantanedione

Assembles when the space is properly filled

Adamantanedione Guest

Dr. Darren JohnsonFraser Hof

Tetrameric Capsule X-RayTetrameric Capsule X-Ray

Resorcin[4]arene OctolsResorcin[4]arene Octols

Aoyama, et al 1988, 1989, 1993

Atwood, MacGillivray 1997

CHCl3

1.3 x101.3 x10-24-24 L L

Hexameric AssemblyHexameric Assembly

Dr. Alex Shivanyuk

CDCl3

R = n-Hexyl

Resorcin[4]arene Octol AssemblyResorcin[4]arene Octol Assembly

wetwet benzene benzene

Liam PalmerLiam PalmerDr. Alex ShivanyukDr. Alex Shivanyuk

22 molecules vs. entropy22 molecules vs. entropy

Hexameric AssemblyHexameric Assembly

Dr. Alex ShivanyukDr. Alex Shivanyuk


Unanticipated : Single Molecule Solvation Isotope Effects

Binary CodingHelical Alkanes

Chiral SpacesChemical AmplificationSuper Capsules

More Encapsulation PhenomenaMore Encapsulation Phenomena

Polymeric Capsules Fluorocarbons

Regioselecive ReactionsHindered Inversions, RotationsAnion Encapsulation

SupportSupport

Skaggs Institute

National Instituteof General MedicalSciences

VideosVideos

Dr. Lubomir Sebo

“ …‘guest’ and ‘host’ are words that intertwine… Converging,mixing, reciprocating. …Guests bring ideas from outside”.Don DeLillo

Mao II

Viking (Penguin) New York, 1991

Dr. Colin NuckollsFraser Hof

Dr. Tomás Martín

Chiral Tetrameric CapsuleChiral Tetrameric Capsule

3-Methylcyclohexane Guest

Chiral Tetrameric CapsuleChiral Tetrameric Capsule

Dr. Colin NuckollsFraser Hof

Dr. Tomás Martín

Chiral SoftballChiral Softball

José M. RiveraDr. Stephen L. CraigDr. Tomás Martín

Chiral SoftballChiral Softball

0 min

17 min

191 h

B+B'A+A'

B

A

BA

A+A'B+B'

(+)-pinanediol (-)-pinanediol adamantanol

José M. RiveraDr. Stephen L. CraigDr. Tomás Martín

Prof. M. Yamanaka

Diastereomeric Constellations

Functional Groups ConvergeFunctional Groups Convergeto Form an Active Siteto Form an Active Site

Receptor for AdenineReceptor for Adenine

DDG = 0.3 kcal mol-1H2O/D2O, 10 °Cm = 50 mM

Y. KatoY. KatoM. Conn,M. Conn,19901990Ka = 62 M-1

Ka = 36 M-1

Extending the Tennis BallExtending the Tennis Ball

Robert M. GrotzfeldDr. Carlos Valdés

Niel R. BrandaBrendan O‘leary

Hindered Inversion and Rotation

Jelly Doughnut or HamburgerJelly Doughnut or Hamburger

Encapsulated Benzene

Jelly Doughnut or HamburgerJelly Doughnut or Hamburger

Encapsulated Cyclohexane

Dr. A. ScarsoDr. H. Onagi

Regioselectivity


103 yrs

R.T.

1 mM1 mM

Dr. Jian ChenDr. Stephen Craig

Dr. Jian ChenDr. Stephen Craig

NOT

days

R.T.


Anion Encapsulation

-2.86 ppm

Anion EncapsulationAnion Encapsulation

Prof. Osamu HayashidaDr. Alex Shivanyuk

CHCl3

CHCl3

CHCl3

X-

Cl-Br-

BF4-

PF6-

IO4-

X- =

Guests


Dr. Alex Shivanyuk Prof. O. Hayashida


A widely separated ion pair

PF6- Et4N+

Anion and two different solventsAnion and two different solvents


Filling Space

Hacky-SackHacky-Sack

METHANE (PC~0.50) is bound,but ETHANE (PC=>.85) is not

The Smallest Dimeric Capsule

Dr. Leticia Toledo Dr. Carlos Valdes

NMR Shifts of Coencapsulated Gases


-3.6 ppm -4.4 ppm

Dr. Alex ShivanyukDr. Alessandro Scarso

H3C CH3 CH4



-3.0 ppm -2.9 ppm -4.1 ppm


H3CC

H3C

CH3

H H3C CH3 H2C CH2

H2C

LiquidsLiquids

Packing Coefficient

benzenetoluene

n-hexanemethylene chloride

chloroformdiethyl ether

acetoneacetonitrile

methanolethanol

water

0.540.540.510.540.530.510.520.530.540.550.63

In a liquid, only slightly more than half of the availablespace is physically filled by molecules.

Dr. Sandro Mecozzi



N

H2C

CH3

O H

CH3

Fits

Doesn‘t fit

N

H2C

H2C

O H

CH3

CH3



Fits Doesn’t fit

Complexes Within Complexes

Prof D. RudkevichDr. T. HeinzDr. A. ShivanyukDr. A. ScarsoLiam Palmer

Choleic Acids

from Steroids by Fieser and Fieser, 1959, p. 58.

F, 1959, p. 58.

Polymeric Capsules

Calixarene CapsuleCalixarene Capsule

Ken Shimizu

Fluorescence Resonance EnergyTransfer (FRET)

NO H

alk

ON

Y

OO

N

O

ON

H

YH

alk alkalk

N

OO O

NOH

alk alkO

NHX

N

O

NH

O

NH

O

D

A

NO HH

alkOO O

NH

alk alkO

HX

N N

ON

NX

NX

OH

HNX

OH

H

NH

O

D

NO HH

alkOO O

NH

alk alkO

HY

N N

ON

NY

NY

OH

HNY

OH

H

NH

O

A

hn

hn''

+ GUEST GUEST

hn hn'

hn' hn''

alk = C10H21X = SO2-p-C6H4-CH32D X = p-C6H4-CH3 2A Y = p-C6H4-CH3

1D

• Color change signalsassembly

• Sensitive at lowconcentrations (nM); observefree monomer

• Excellent time resolution• Study behavior at dilute

concentrations where theassembly process is “slow”

FRET offers:

Sulfonyl ureas (1D) and aryl ureas(2A) form exclusive heterodimericpairs in solution.

Polycaps: Polymeric Capsules

• Control of chemical andstereochemical preferences

• Strong association (KA 106–108 M-1)• Rapid dissociation/equilibrium• Functional: Responsive to external

signals (guest, solvent, temperature)• Modular construction leads to

structural variety

guestmonomer

polycaps

Why polymers?

NH ONH R2

O OO OR1R1 R1CH2

N H

NO

R2H

NHN

O

R2H

N HON HR2

HO

O

NH2

H2NX

PyBOPNEt3DMF

NH

ON

H

R2

O

OO

O R1

R1

R1

NHN

OR2

H

NHN

OR2

H

NH

ON

HR2

ON

HNH

ONHR2

O

OO

OR1

R1

R1

NH N

OR2

H

NH NO

R2H

NH

ONHR2

ON

HX

1H NMR: Still a Valuable Tool

CDCl3

DMF-d7

• Dilution/VT studies• Chain termination experiments• Guest encapsulation studies

Measurements include:

NH

ON

H

R2

O

OO

O R1

R1

R1

NHN

OR2

H

NHN

OR2

H

NH

ON

HR2

ON

HNH

ONHR2

O

OO

OR1

R1

R1

NH N

OR2

H

NH NO

R2H

NH

ONHR2

ON

H

R1 = C10H21R2 = tolyl

Quasielastic Light Scattering (Benedek, MIT)

CHCl3

2.2 5.1

+

+

(2.2)x(5.1)y2.2•2.2

X2.2/X5.11/2 (mmol1/2)

Rh-2

X 5.1

1/2 10

2 (nm

-2m

mol

1/2 )

terminated oligomers(x = 0, 1, 2)dimer

• KA = 2.3 x 106 M-1 in chloroform• Between 0.25–2.5 mM, DP =

10–60 (MW = 31,000–186,000)

• Persistence length ~ 4 monomers (ca. 9nm)

• c* ~ 2.7 mM

Polycaps are good models through which to study "living" polymerizations

Liquid-Crystalline Polycaps

0 5 10 15 20 25

2Q (°)5 10 15 20

~ 2.2 nm

1.6 nm

electrondiffraction

X-raydiffraction

LC Phases and Well-Ordered Fibers

30 mm

80 mm

uniformlyaligned fibers

hightensile strength

nematic phase (CHCl3)

100 mm 30 mm

organization upon shear

Rate and Equilibrium Constants

Solvent kass (M-1 s-1) a kdiss (s

-1) a KA (M-1) a

1•1 CHCl3 –b –b –b

1•2 CHCl3 2.7b ¥ 103 2.3 ¥ 10-5 1.2 ¥ 108

2•2 CHCl3 1.5 ¥ 104 6.4 ¥ 10-3 2.4 ¥ 106

1•1 C6H6 < 50 5.4 ¥ 10-5 < 106

1•2 C6H6 3 ¥ 103 5 ¥ 10-6 6 ¥ 108

2•2 C6H6 1.3 ¥ 104 2.8 ¥ 10-4 4.6 ¥ 107

aUncertainties in kdiss are ±15%, and in kass and KA are ±40%.bCompound 1 does not appear to form a well-defined dimer in CHCl3 by NMR, and itsbehavior in this work is consistent with a species that is effectively monomeric at theseconcentrations.

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0 1 104 2 104 3 104 4 104

Rel

ativ

e Fl

uore

scen

ce

Time (s)

-4

-3.5

-3

-2.5

-2

-1.5

-1

0 5 103 1 104 1.5 104 2 104

ln[in

tens

ity(fi

nal)

- int

ensi

ty(t)

]

Time (s)

Analyte Detection

aryl urea donor +valine urea acceptor(p-xylene, 150 nM)

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

380 400 420 440 460 480

50,000 equiv.40,000 equiv.25,000 equiv.20,000 equiv.10,000 equiv.5,000 equiv.

Fluo

resc

ence

Wavelength (nm)

O

KA ~ 3 x 109 M-2

Coiling

Cavity DimensionsCavity Dimensions

7.1 Å

16.5 Å

Folded and Unfolded GuestsFolded and Unfolded Guests

15.2 Å

18.0 Å

22

33

44

55

77

66

Guest Volume and Packing CoeficientGuest Volume and Packing Coeficient

181 Å3

199 Å3

215 Å3

231 Å3

262 Å3

246 Å3

43%

47%

51%

55%

62%

58%

Dr. LuboSebo

Prof.Osamu

Hayashida

Longest Encapsulated EsterLongest Encapsulated Ester

GRASPGRASP424 Å3

66

+ C10

+ C12

+ C14

+ C15

Complexes of the Capsule with Linear Hydrocarbons

1H NMR, 600 MHz



Capsule-Tetradecane Complex




Capsule-Decane Complex



Straight Chain HydrocarbonsCoil to fit into the Capsule


Gauche: 0.55 kcal/mol

Characteristics of the Hydrocarbons

Alkane Length(Å)

SurfaceArea (Å2)

Volume(Å3)

PC (%)

C10H22 extended 15.0 196 167 39

C12H26 extended 17.5 230 200 47

C12H26 coiled 13.6 207 206 48

C14H30 extended 20.0 264 235 -

C14H30 coiled 15.5 235 240 56

C14H28 coiled 16.0 239 239 56

C15H32 coiled 16.3 251 258 -

Calculated using Grasp after energy minimization of the structures

Dr. Alessandro Scarso, Byron Purse Dr. Laurent Trembleau

Tridecane

Tetraethyleneglycol

Perfluorooctane

Dr. Alessandro Scarso, Byron Purse Dr. Laurent Trembleau

Reactive Intermediates

Stabilization of Reactive SpeciesStabilization of Reactive Species

Raymond, 2000 Fujita, 2000

Heimacetal StabilizationHeimacetal Stabilization

Dr. Masamichi Yamanaka

Hexamer

Volleyball Seams


wetwetbenzenebenzene

Liam PalmerLiam PalmerDr. Alex ShivanyukDr. Alex Shivanyuk

150 M-1C 8450 M-1C 7

1,200 M-1C 6>104 M-1C 3-5

KGuest

Dr. A. Shivanyuk, Dr. M. Yamanaka

150 M-1C 8450 M-1C 7

1,200 M-1C 6>104 M-1C 3-5

KGuest

R4N+ in Hexamer

C3

C4

C5

C6

C7


17.1C 716.7C 5

14.8C 413.1C 3

DG* kcal/molGuest




-3.0 ppm -2.9 ppm -4.1 ppm


CD3

CD3

H3CC

H3C

CH3

H

CD3

CD3

H3C CH3

CD3

CD3

H2C CH2

H2C


wetwetbenzenebenzene

Dr. Alex ShivanyukDr. Alex Shivanyuk

Dr. Alex Shivanyuk


Social isomers

1

CH2CH3

CH3

H

CH2CH3

CH3

H

2

34

6‘

1‘

2‘

5‘

80% 20%

ClC

Cl

H

Cl

ClC

Cl

H

Cl

Dr. Alex Shivanyuk


Social isomers

80% 20%

1

2

3

4

6’

1’

2’5’

Dr. Alessandro Scarso

AcknowledgementsAcknowledgements

Ken ShimizuBlake HamannRon CastellanoDr. Colin NuckollsProfessor Dmitry RudkevichProfessor Byeang Hyean KimDr. Stephen CraigFraser Hof

Professor Reza GhadiriProfessor David MillarDr. Malcolm WoodDr. Teresa Fassell

AnimationsDr. Lubomir Sebo

Collaborators• Professor Tim Swager (MIT)

Dr. Holger Eichhorn (MIT)• Dr. Frank Würthner (Ulm)

Dr. Uwe Beginn (Ulm)• Dr. Andrew Lovinger

(Bell Laboratories)• Prof. J. de Mendoza

(Madrid)

Funding• The Skaggs Research Foundation• NIH• NASA

Polymeric Capsules

Molecular Assembly and Encapsulation

the inner space of molecules - nobel prize

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