Department of Chemistry
CHEM415
SPRING QUARTER 2014
Advanced Organic Chemistry
GRADUATE COURSE
Mechanostereochemistry
and
Advanced Stereochemistry
Dennis Cao
DISCOURSE 2
Last Time
Introduction to the Course
Defining Supramolecular Chemistry
Brief Historical Overview
Chelate Effects
Cooperativity
Macrocyclic Effect
Preorganization
Overview of Weak Interactions
A Closer Look at Macrocycles
Cyclodextrins
Crown Ethers
Calixarenes
Pillararenes
Cucubiturils
Cyclophanes
Metallocycles
Macrocycles
Macrocycles provide cavities which can be tuned to meet a
desired purpose.
Remember the macrocyclic effect?
Their ability to sequester molecules
with specificity has been utilized to—
Sequester toxic pollutants
Catalyze “forbidden” reactions
Stabilize reactive species
Deliver insoluble drug molecules
Purify intractable mixtures
J. Am. Chem. Soc. 2008, 130, 12111–12122.
Cyclodextrins
A cyclodextrin (CD) is a cyclic oligosaccharide composed of
n α-D-glucopyranoside units.
2
1
Symmetric arrangement of
asymmetric units.
4
3
5
6
n = 5 to ~150 have been synthesized.
n=6
n=7
n=8
α-CD
β-CD
γ-CD
Biosynthesis
• Cyclodextrins are synthesized using a bacterial enzymatic
process which cleaves amylose.
• Cyclodextrin glucotransferase (CGTase) produces
α-, β-, and γ-CD in a specific ratio, which are then separated.
α-CD
β-CD
γ-CD
• Wacker has bioengineered α-, β-, and γ-CD specific CGTases.
http://www.chemiedidaktik.uni-wuppertal.de/disido_cy/cyen/info/01_manufacture_cy.htm
Separation of CDs
α-CD
β-CD
γ-CD
Soluble in H2O
Poorly soluble in H2O
Soluble in H2O
Complex precipitates
Complex precipitates
Complex precipitates
http://www.chemiedidaktik.uni-wuppertal.de/disido_cy/cyen/info/01_manufacture_cy.htm
Structural Features
Cyclodextrin is shaped like a bucket.
The diameters of the two faces are different.
The inner cavity is relatively hydrophobic compared to the rest
of the molecule.
Secondary Face
Primary face
CD Diameters
The varied sizes of the cyclodextrin buckets define their
supramolecular activity.
CDs complex with a vast diversity of molecules.
13.7 Å
15.3 Å
16.9 Å
5.7 Å
7.8 Å
9.5 Å
Industrial Applications
Increasing bioavailability of hydrophobic drugs—the three
common CDs are generally recognized as safe by the FDA.
Cholesterol removal—CDs will complex with cholesterol
Dietary Fiber—European Union commission verified that
consumption of α-CD after a high-starch meal lowered blood
sugar levels.
Anti-odor agent—hydroxypropyl-β-cyclodextrin
is the active ingredient in Febreze.
As a drug—hydroxypropyl-β-cyclodextrin is
currently in use as a treatment for Niemann-Pick
type C disease.
Crown Ethers
Crown ethers are cyclic macromolecules which contain
multiple ether groups.
Named n-crown-m where n is the number of atoms in the ring
and m is the number of heteroatoms in the ring.
Often bind well with cations because of the macrocyclic effect.
Earned Jean-Marie Lehn, Charles Pedersen, and Donald
Cram their Nobel Prizes.
12-Crown-4
18-Crown-6
J. Am. Chem. Soc., 1967, 89, 2495–2496.
Aza-15-Crown-5
J. Am. Chem. Soc., 1967, 89, 7017–7036.
Crown
The unbound host is flexible, but becomes rigid upon binding.
Local D3d symmetry
Crown
Charles Pedersen – Seminal Work
In 1967, Charles Pedersen, a chemist at DuPont, reported the
synthesis of 33 crown ethers.
Na+
+
51%
Combined
Yield
NaOH
+
Dibenzo-18-crown-6
Na+
Benzo-15-crown-5
His systematic studies on alkali metal cation binding with
crown ethers earned him the Nobel Prize in Chemistry in 1987.
J. Am. Chem. Soc., 1967, 89, 2495–2496.
Angew. Chem. Int. Ed. 1988, 27, 1021.
Cryptands
Cryptands are multicyclic macrobicycles and macropolycycles.
In essence they are 3D analogues of crown ethers.
Synthetically much more difficult to prepare than crown ethers.
+
K
[2.2.2]cryptand is a macrobicycle
Jean-Marie Lehn – Cryptands
Park, C. H.; Simmons. H. E. J. Am. Chem. Soc. 1968, 90, 2431–2432
Dietrich, B.; Lehn, J. M.; Sauvage, J.-P., Tetrahedron Lett. 1969, 2885–2889
Jean-Pierre Sauvage – Cryptands
6
7
8
9
m
n
0
0
1
0
1
0
1
1
9 ‫ ﬤ‬Mn+
Dietrich, B.; Lehn, J. M.; Sauvage, J.-P., Tetrahedron Lett. 1969, 2889–2892
Donald J. Cram – Macrocycles Galore
“Although we tried to interest graduate students in
synthesizing chiral crown ethers from 1968 on, the efforts were
unsuccessful. In 1970, we insisted that several postdoctoral
co-workers enter the field.”
–Nobel Prize Lecture Dec 8 1987
Angew. Chem. Int. Ed. 1988, 27, 1009.
Chiral Crown Ether
Spherand
Carcerand
An ever-popular teacher at UCLA, he entertained classes by playing guitar and
singing folk songs. – UCLA News http://www.chem.ucla.edu/news/djc.html
J. Am. Chem. Soc. 1973, 95, 2692. J. Am. Chem. Soc., 1985, 107, 3657. Science 1974, 183, 803.
Applications
Crown ethers solubilize ionic compounds in organic solvents.
The anion is “naked” instead of closely paired to the cation,
and is therefore more reactive.
Calixeranes
Calixeranes are macrocycles derived from reaction between
phenols and aldehydes.
Prefix CALIX– originates from Greek for chalice or vase.
Suffix –ARENE indicates the use of aromatic rings.
+
H+
Named ______calix[n]arene where n is the number of arene
units in the macrocycle and the prefix specifies the phenol
employed.
tert-Butylcalix[4]arene
Calixarenes
1872 Baeyer describes his first attempts.
+
H+
“Cement-like
substance”
1907 Leo Baekland files patent for Bakelite.
Over 400
Cement Patents!
1944 Alois Zinke proposes a cyclic tetramer.
+
Johann Friedrich
Wilhelm
Adolph von Baeyer
H+
+
H+
Gutsche, D. Calixarenes 1989
1970 David Gutsche coins “calixerane”.
Synthesis
The reaction actually produces a variety of linear and cyclic
products that are in equilibrium under the reaction conditions.
Huge structural diversity available.
Calix[4]arene
C-Methylcalix[4]resorcinarene
Thiacalix[4]arene
Pillararenes
Pillararenes are structural derivatives of calixarenes.
Prefix PILLAR– originates from the English word pillar.
+
Pillar[5]arene and pillar[6]arene
and other oligomers.
Two possible enantiomers arise from the flipping of the
dimethoxybenzene rings.
Ogoshi, T. et al. J. Am. Chem. Soc. 2008, 130, 5022–5023.
Cucurbiturils
+
H+
The name cucurbituril is derived from the family
which pumpkins belong to, Cucurbitaceae.
A variety of cucurbit[n]urils have been synthesized.
IUPAC Systemic Name for cucurbitur[6]uril is long:
Dodecahydro-1H, 4H, 14H, 17H-2, 16:3, 15-dimethano-5H, 6H, 7H, 8H, 9H, 10H,
11H, 12H, 13H, 18H, 19H,20H, 21H, 22H, 23H, 24H, 25H, 26H-2, 3, 4a, 5a, 6a,
7a, 8a, 9a, 10a, 11a, 12a, 13a, 15, 16, 17a, 18a, 19a, 20a, 21a, 22a, 23a, 24a,
25a, 26a-tetracosaazabispentaleno[1’’’, 6’’’:5’’, 6’’, 7’’]cycloocty[1’’, 2’’, 3’’:3’,4’]
pentaleno(1’, 6’:5, 6, 7)-cycloocta(1, 2, 3-gh:1’, 2’, 3’-g’h’)cycloocta(1, 2, 3-cd:5, 6,
7-c’d’)dipentalene-1, 4,6, 8, 10, 12, 14, 17, 19, 21, 23, 25-dodecone.
Cucurbiturils
+
H+
Brief History
1904
1981
2000
There are no firsts in Science, only many hidden gems!
Cyclophanes
“Cyclophane” is often used as a synonym for macrocycle.
A molecule “in which more than two atoms of an aromatic ring
are incorporated into a larger ring system”.
High strain systems with significant rigidity.
[2.2]Paracyclophane
[4.4]Paracyclophane
[7]Cycloparaphenylene
Hirst, E, S.; Jasti, R. J. Org. Chem. 2012, 77, 10473.
Cram, D. J., Cram, J. M. Acc. Chem. Res., 1971, 4, 204.
Cyclobis(paraquat-p-phenylene)
Phenylene
Paraquat
Metallocycles
In metallocycles, metal coordination bonds join ligands
together into a macrocycle.
Larger macrocycles and capsules that would be difficult to
achieve through covalent synthesis are more accessible.
8+
Sun, Q.-F.; et al. Science 2010, 328, 1144.
Fujita, M.; Tominaga, M.; Hori, A.; Therrien, B. Acc. Chem. Res. 2005, 38, 369.
White Phosphorous is Stable
Supramolecular capsules can stabilize unstable species and
intermediates.
Oxygen is unable to react with the encapsulated phosphorous.
Mal, P.; Breiner, B.; Rissanen, K.; Nitschke, J. R. Science 2009, 324, 1697.
A Whirlwind Tour of Macrocycles
Cyclodextrins
Crown Ethers
Calixarenes
Pillararenes
Cucubiturils
Cyclophanes
Metallocycles