Cyclodextrins

Last update: 5/13/2003

Content:

Structure
Nomenclature
Reviews
Properties
History
Synthesis
Complexation
Reactivity
Regioselective derivatization
CD derivatives
Practical use of CDs
Commercial availability
Prices

Structure

CD structure (.gif)

cyclic oligomers of α-D-glucopyranose (Glc)
glycosidic bond α(1->4)
⁴C₁ conformation of Glc
number of Glc units:
- usual CDs: 6-8
- rare CDs: 5, 9-13

Nomenclature

Schardinger's dextrins
α, β, γ-cyclodextrins (CD, CyD, CDx)
cyclohexaamylose, cyclomaltohexaose
cyclo-α(1->4)-glucohexaoside, cyclo[D-Glcpα(1->4)]6

Reviews:

Chem. Rev. 1998, 98, Issue 5. online
Connors, K.A.: The Stability of Cyclodextrin Complexes in Solution. Chem. Rev. 1997, 97, 1325. online
Wenz., G. Angew. Chem. IEE 1994, 33, 803.

Properties

formation of inclusion (host/guest) complexes with lipophilic compounds
- α-CD - aliphatic chains (e.g. decanol)
- β-CD - small aromatic compounds (e.g. toluene)
- γ-CD - larger molecules (e.g. pyrene, fullerene)
solubility: H₂O (relatively low), DMF, DMSO, pyridine
low toxicity
biodegradability

	α	β	γ
number of Glc	6	7	8
M_r	972	1135	1297
solubility H₂O [g/100mL]	14.5	1.85	23.2
pK_a	12.33	12.2	12.08
+ x H₂O	6, 7.57	11, 12	7-13
inner diameter [nm]	0.45-0.57	0.62-0.78	0.79-0.95
outer diameter [nm]	1.37	1.53	1.69
height [nm]	0.79	0.79	0.79
cavity volume [nm³]	0.174	0.262	0.472
cavity volumes [mL]:
per 1 mol	104	157	256
per 1 g	0.1	0.14	0.2

History

1891 Discovery, Villiers
1903 Descriptions of properties, Shardinger
1957 Complexation ability of CDs widely accepted; Cramer, French
1981 1. International Symposium on CDs, Szejtli
1987 Total synthesis, Ogawa
1994 Total synthesis of cyclo[D-Glcp(1->4)]₅

Synthesis

Enzymatic conversion of starch (CGTases), selective precipitation of complexes

	precipitating agent	yield%
α-CD	1-decanol	40
β-CD	toluene	50-60
γ-CD	cyclohexadec-8-en-1-ol	40-50

Complexation

stoichiometry (guest : CD): 1:1 > 1:2, 2:1, 2:2
formation speed T_1/2 ~ 0.001 - 1 ms
complexes stability constants: 10² - 10⁵ M^-1

K_s[M^-1]	50	200	500	1000	2000	10000
% of complexed guest	18	46	69	92	91	98

substrate unspecific complexation
ternary complexes with lower alcohols, amines, nitriles
complexes stable only in water solution
compounds suitable for complexation
- >5 atoms (C,P,N,S)
- solubility in water <10 mg/mL
- b.t. <250°C
- <5 condensed cycles
- M_r 100-400

Reactivity

as non reducing oligosaccharides
influence of Cn symmetry
large number of isomers
higher stability under acidic conditions
reactions on OH groups
- alkyl halides, epoxides
- acyl derivatives, isocyanates
- derivatives of inorganic acids (RSO₃Cl, PO_xCl_y, R_xSiCl_y, ...)
- Br₂, Ph₃P
- Mitsunobu
cleavage of C(1)-O-C(4) bonds:
- hydrolysis (β-CD + 1.15 M HCl, 80°C: T_1/2 = 1.6h)
- reductive cleavege (BF₃.Et₂O/Et₃SiH)
cleavage of C(1)-O(5) bonds: 9-borabicyklo[3.3.1]nonyl TfO/EtBH₂
cleavage of C(2)-C(3) bonds: NaIO₄ (-> crown ether analogs)
oxidation of CH₂(6) to COOH (NO₂ or Pt/O₂)

Regioselective derivatization

mono-arylsulfonation
- 6-O: TsCl, py
- 2-O:
  - m-nitrophenylbenzensulfonyl chloride, NaOH, H₂O, DMF
  - 1-NsCl, NaOH, H₂O
  - 1. Bu₂SnO, 2. TsCl, DMF
- 3-O: - 2-NsCl, NaOH, H₂O, CH₃CN
mono-alkylation

NaH (1 ekv.), DMF, RI
NaOH, H₂O + oxiranes, RI, RBr

disubstituted derivatives
- bridging with reagent with two functional groups (arenedisulfonyl chlorides)
- chromatografic separation

CD derivatives

Reasons for preparation
- modification of solubility
- modification of complexation abilities (stability constant, guest selectivity)
- introducing groups with specific functions (e.g. catalytic)

Most important derivatives
- RAMEB - randomly methylated β-CD
- HPBCD - hydroxypropyl-β-CD
- HEBCD - hydroxyethyl-β-CD
- DIMEB - heptakis(2,6-dimethyl)-β-CD
- TRIMEB - heptakis(2,3,6-trimethyl)-β-CD
- EPC - CD crosslinked with epichlorhydrine

Practical use of CD

Areas of use

pharmacy
food
cosmetics
agrochemistry
analytical chemistry
catalysis, enzyme models
chemosensors

Utilized properties

change of physical and chemical properties caused by complexation:
- solubilization of liphophilic compounds with low solubility in water (e.g. drugs - prostaglandins, piroxicam)
- speeding up solubilization - bioavailability
- stabilization of reactive compounds
- fixation of volatile compound, protection of hygroscopic compounds
- elimination of bad taste or smell (e.g. garlic oil containing lotion)
- converstion of liquids into solids
- creating mixtures of compound otherwise incompatible
- dilution of compounds (dosage of drugs,...)
- separation of compound in the form of complexes (precipitation from solutions, absorbtion on CD polymers, ...)
- controled release of compounds (drugs, fragrances)
- change of UV, NMR,... spectra

UV a VIS spectrometers

spectra of complexed compounds in water solution, due to hydrophobic CD cavity, similar to spectra measured in organic solutions

Fluorescent spectrometers

increase of fluoresecnce intensity caused by hydrophobic environment in the cavity
prevention of contact with quenchers
hindered rotation - decreased solvent relaxation
increase of detection limit caused by increased solubility
increase of intensity of chemiluminiscence

NMR

signal shifts coused by complexation
chiral shift reagents

Electrochemical analysis

Ion selective electrodes
CE - Separation of regioisomers, diastereoisomers, enantiomers

Afinity chromatography

α-CD + β-amylase, β-CD + α-amylase, ...

TLC, HPLC, GC

separation of homologs, isomers , enantiomers

mobile phase additive
stationarny phase or its component
CDs, polymer CDs (ECP, CDPU, CDP), alkyl, acyl derivatives bonded to silica
Koenig - pentylated CDs (chiral, GC)

Armstrong - Cyklobond (chiral, HPLC, spacer) 1985, 2,6-dipentyl-3-trifluoroacetyl (chiral, GC)

Commercial availability

Cyclolab

http://www.cyclolab.hu

α, β, γ-CD
Me derivatives (TRIMEB,DIMEB,RAMEB, ...)
complexes with CD a CD-der. polymers CD CM, Et, All, Bu, TBDMS ethers

Sigma-Aldrich

http://www.sigmaaldrich.com

α, β, γ-CD
more than 200 derivatives

TCI

http://www.tokyokasei.co.jp

Wacker-Chemie

http://www.wacker.com
α, β, γ-CD (CAVAMAX^®)
CD derivatives (CAVASOL^®)
- HP-β-CD,
- HE-β-CD,
- RAMEB
- per-Ac-β-CD
- β-CD polymer

Prices 2003 ($) (Sigma-Aldrich / TCI)

	1 g	1 kg
α-CD	12.40 / 2.30	6000 / 1800
β-CD	1 / 0.35	1000 / 150
γ-CD	50 / 5	70000 / 3000

In larger quantities much lower.