Cyclodextrins
Content:
Structure
- 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:
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 |
| Mr | 972.84 | 1134.98 | 1297.12 |
| solubility H2O [g/100mL] | 14.5 | 1.85 | 23.2 |
| pKa | 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 |
| CAS RN | 10016-20-3 | 7585-39-9 | 17465-86-0 |
| Formula | C36H60O30 | C42H70O35 | C48H80O40 |
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 T1/2 ~ 0.001 - 1 ms
- complexes stability constants: 102 - 105 M-1
| Ks[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
- Mr 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, POxCly, RxSiCly, ...)
- Br2, Ph3P
- Mitsunobu
- cleavage of C(1)-O-C(4) bonds:
- hydrolysis (β-CD + 1.15 M HCl, 80°C: T1/2 = 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
- 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
- α, β, γ-CD
- more than 200 derivatives
TCI
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 | 35 / 2.30 | 6000 / 1800 |
| β-CD | 1 / 0.35 | 2300 / 150 |
| γ-CD | 300 / 5 | 260000 / 3000 |
- In larger quantities much lower.
