Herbal Chemistry
Phytochemical Elements
Structure of Phytochemicals
Carbon ‘backbone’
Structure of Phytochemicals
Oxygen atoms
Structure of Phytochemicals
Hydrogen atoms
Structure of Phytochemicals
Catechin
Elements in Phytochemicals Oxygen (red)
Carbon (magenta)
Hydrogen (cyan)
Catechin, an antioxidant molecule abundant in Green Tea
Elements in Phytochemicals
Catechin, an antioxidant molecule abundant in Green Tea
Elements in Phytochemicals
Catechin, an antioxidant molecule abundant in Green Tea
Elements in Phytochemicals Nitrogen (blue) Oxygen (red)
Carbon (magenta)
Hydrogen (cyan)
Berberine, an antimicrobial molecule in Oregon Grape
Elements in Phytochemicals
Berberine, an antimicrobial molecule in Oregon Grape
Elements in Phytochemicals
Berberine, an antimicrobial molecule in Oregon Grape
Elements in Phytochemicals Sulfur (yellow) Carbon (magenta)
Nitrogen (blue)
Hydrogen (cyan) Oxygen (red)
Alliin, a sulfur compound in Garlic
Elements in Phytochemicals
Alliin, a sulfur compound in Garlic
Elements in Phytochemicals
Alliin, a sulfur compound in Garlic
Elements in Phytochemicals Oxygen (red)
Hydrogen (cyan)
Phosphorus (yellow)
Carbon (magenta)
Geranyl pyrophosphate, precursor of the monoterpenes
Elements in Phytochemicals
Geranyl pyrophosphate, precursor of the monoterpenes
Phytochemical Bonding
Bonding in Phytochemicals
Carbon forms four bonds with a tetrahedral geometry
Bonding in Phytochemicals
Carbon forms four bonds with a tetrahedral geometry
Bonding in Phytochemicals
Carbon forms four bonds with a tetrahedral geometry
Bonding in Phytochemicals
Two carbon atoms can double bond with each other, introducing a ‘stiffness’ into the molecule
Bonding in Phytochemicals
Two carbon atoms can double bond with each other, introducing a ‘stiffness’ into the molecule
Bonding in Phytochemicals
Bonding in Phytochemicals
Two carbon atoms can double bond with each other, introducing a ‘stiffness’ into the molecule
Bonding in Phytochemicals
Two carbons can also triple-bond to each other, resulting in a linear architecture
Bonding in Phytochemicals
Two carbons can also triple-bond to each other, resulting in a linear architecture
Bonding in Phytochemicals
Two carbons can also triple-bond to each other, resulting in a linear architecture
Bonding in Phytochemicals
This immune-modulating isobutylamide from Echinacea has two carbon-carbon triple bonds
Bonding in Phytochemicals
This immune-modulating isobutylamide from Echinacea has two carbon-carbon triple bonds
Bonding in Phytochemicals
The benzene ring shares electrons all around
Bonding in Phytochemicals
Resonance delocalization results in stability
Bonding in Phytochemicals 3 single bonds to hydrogens and one to another carbon
Carbon forms four bonds with a tetrahedral geometry alpha-Linolenic acid
Bonding in Phytochemicals 3 single bonds to hydrogens and one to another carbon
Carbon-carbon double bond
Carbon atoms can also double bond with each other alpha-Linolenic acid
Bonding in Phytochemicals 3 single bonds to hydrogens and one to another carbon Carbon-oxygen double bond
Carbon-carbon double bond
Carbon-oxygen single bond
Carbon can also form one or two bonds to oxygen alpha-Linolenic acid
Bonding in Phytochemicals
Oxygen forms two bonds & has two non-bonding e- pairs
Bonding in Phytochemicals
Oxygen forms two bonds & has two non-bonding e- pairs
Bonding in Phytochemicals
Acetone
Oxygen can form a double bond with carbon
Bonding in Phytochemicals Acetone
Oxygen can form a double bond with carbon
Bonding in Phytochemicals
Rarely, you’ll see oxygen with both a double & a single bond, as in the anthocyanidins
Bonding in Phytochemicals
Ammonia
Nitrogen usually forms three single bonds and has one lone pair of electrons
Bonding in Phytochemicals
Ammonia
Nitrogen usually forms three single bonds and has one lone pair of electrons
Bonding in Phytochemicals
Ammonium ion
But sometimes it can form four bonds by carrying a positive charge (NH4+)
Bonding in Phytochemicals
Ammonium ion
But sometimes it can form four bonds by carrying a positive charge (NH4+)
Bonding in Phytochemicals
Betanidin, a purple antioxidant molecule in Beets & Pokeberries, has both types of nitrogen bonds
Bonding in Phytochemicals
Betanidin, a purple antioxidant molecule in Beets & Pokeberries, has both types of nitrogen bonds
Bonding in Phytochemicals
Sulfur can form various numbers of bonds, but most commonly two, four, or six
Bonding in Phytochemicals
Sulfur can form various numbers of bonds, but most commonly two, four, or six
Bonding in Phytochemicals
Phosphorus generally forms five bonds in phytomolecules
Bonding in Phytochemicals
Geranyl pyrophosphate, precursor of the monoterpenes
Bonding in Phytochemicals
Geranyl pyrophosphate
Stereochemistry
Stereochemistry of Phytochemicals Isomers Constitutional isomers Cis-trans (geometric) isomers
Stereoisomers
Isomers with chiral carbons
Stereochemistry of Phytochemicals
* A chiral carbon
Not a chiral carbon
A carbon atom bonded to four different kinds of atoms/groups has no plane of symmetry
Stereochemistry of Phytochemicals
Non-superimposable mirror images
Stereochemistry of Phytochemicals
Non-superimposable mirror images
Stereochemistry of Phytochemicals
These two molecules are stereoisomers or enantiomers
Stereochemistry of Phytochemicals
Chiral molecules have nonsuperimposable mirror images
Achiral molecules have superimposable mirror images
Enantiomers vs. identical molecules
Stereochemistry of Phytochemicals R enantiomer
S enantiomer
X Receptor binding site
X
Receptor binding site
Why isomerism matters: receptor specificity
Stereochemistry of Phytochemicals
Stereoisomerism is common in the monoterpenes
Stereochemistry of Phytochemicals
(+)-carvone: Caraway
(-)-carvone: Spearmint
Stereochemistry of Phytochemicals
• beta-D-glucose & alpha-D-glucose are stereoisomers • The polymers they form are very different from each other: cellulose vs. starch
Stereochemistry of Phytochemicals
beta-D-glucose units link up to form cellulose
Stereochemistry of Phytochemicals
Amylose: linked alpha-D-glucose units
Stereochemistry of Phytochemicals
Amylopectin: linked alpha-D-glucose units, branched
Stereochemistry of Phytochemicals
beta-D-glucose
alpha-D-glucose
Stereochemistry of Phytochemicals
Cis (Z) & trans (E) isomers
Stereochemistry of Phytochemicals
Trans-alpha linolenic acid
Cis-alpha linolenic acid
Cis (Z) & trans (E) isomers
Stereochemistry of Phytochemicals
All-trans beta-carotene
9-cis beta-carotene
Cis (Z) & trans (E) isomers
Stereochemistry of Phytochemicals
All-trans beta-carotene
9-cis beta-carotene
Cis (Z) & trans (E) isomers
Stereochemistry of Phytochemicals
Cis (Z) & trans (E) double bonds in an isobutylamide
Polarity
Polarity • Different elements have different electronegativities (tendencies to attract electrons) • Bonds between elements with similar electronegativities are non-polar • Bonds between elements with significantly differing electronegativities are polar • If the electronegativities of two elements are extremely different, the bond is ionic
Polarity H Li Be Na Mg
Increasing electronegativity
He B
C
N O
Al Si P
F Ne
S Cl Ar
K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr • Carbon – carbon bond, non-polar: 2.55 to 2.55 • Carbon – hydrogen, non-polar: 2.55 to 2.20 (small e-neg difference, 0.35) • Carbon – sulfur, non-polar: 2.55 to 2.58 (tiny e-neg difference, 0.03) • Sulfur – sulfur, non-polar: 2.58 to 2.58 • Carbon – nitrogen, polar: 2.55 to 3.04 (diff = 0.49) • Carbon – oxygen, polar: 2.55 to 3.44 (diff = 0.89) • Sulfur – oxygen, polar: 2.58 to 3.44 (diff = 0.86) • Oxygen – hydrogen, polar: 3.44 to 2.20 (diff = 1.24)
Polarity + + +
+
+ +
• Water is very polar (O – H, 1.24) • Oxygens have partial negative charge • Hydrogens have partial positive charge • Oxygens of one molecule attract hydrogens of another • Result: hydrogen bonding in water
Ethanol is Polar Ethane is a symmetrical, nonpolar molecule
–OH group
Ethanol (grain alcohol) is a polar molecule – not electrically symmetrical
Glycerol is Highly Polar
Glycerol (glycerin) is generally used for water-soluble constituents
Glycerol is Highly Polar –OH group
–OH group
–OH group
Glycerol (glycerin) is generally used for water-soluble constituents
Polarity • Salt (NaCl) is beyond polar: it’s ionic • Electronegativity difference between sodium & chlorine: 2.23 • In water, salt breaks up into Na+ ions & Cl– ions • The atoms are no longer bonded to each other
Polarity • The main constituents of Olive oil are triglycerides (neutral fats) • Their long hydrocarbon chains are electrically neutral: insignificant charge separation: non-polar
Hexane & CO2 are Nonpolar _ _
_
+
+
+ _ _
Hexane: no charge separation; electrically neutral molecule
_
Carbon dioxide: symmetrical shape cancels out effects of charge separation
Acetone is Amphiphilic: Both Oil & Water Soluble • Has been used as a solvent for certain constituents in standardized extracts • Alternative to hexane for many oil-soluble constituents: less toxic
Functional Groups
Functional Groups • Where the action is – areas on a molecule where chemical reactions occur • Phytomolecules consist of a ‘carbon backbone’ or ‘carbon skeleton’ &… • One or more ‘functional groups’ • Many functional groups involve oxygen, as –OH or as =O • Some involve sulfur (S) or nitrogen (N) • Functional groups give a molecule some of its characteristics
Functional Groups: Amide
• Amide group: primary amide • Fairly common in phytomolecules • Extremely polar/hydrophilic
Functional Groups: Amide
• Amide group: secondary amide • Fairly common in phytomolecules • Extremely polar/hydrophilic
Functional Groups: Amide
• Amide group: tertiary amide • Fairly common in phytomolecules • Extremely polar/hydrophilic
Functional Groups: Amide
Amide group: isobutylamide
Functional Groups: Amide
Amide group: anandamide
Functional Groups: Amide
Amide group: piperine
Functional Groups: Amide
Piperine, another perspective
Functional Groups: Carboxyl
• Carboxylic acid group: ‘-oic acid’ • Common in phytomolecules • Very polar/hydrophilic
Functional Groups: Carboxyl
Carboxyl groups: citric acid
Functional Groups: Carboxyl
Carboxyl groups: citric acid
Functional Groups: Carboxyl
Carboxyl group: L-lysine
Functional Groups: Carboxyl
Carboxyl group: EPA
Functional Groups: Carboxyl
Carboxyl group: rhein
Functional Groups: Hydroxyl
• Hydroxyl or alcohol group: ‘-ol’ • Common in phytomolecules • Polar, hydrophilic
Functional Groups: Hydroxyl
Hydroxyl group: ethanol
Functional Groups: Hydroxyl
Hydroxyl groups: glycerol
Functional Groups: Hydroxyl
Hydroxyl groups: glycerol
Functional Groups: Hydroxyl
Hydroxyl groups: delphinidin
Functional Groups: Ketone
• Ketone group: ‘-one’ • Common in phytomolecules • Slightly less polar than hydroxyl group
Functional Groups: Ketone
Ketone groups: emodin
Functional Groups: Ketone
Ketone group: pulegone
Functional Groups: Ketone
Ketone group: pulegone
Functional Groups: Aldehyde
• Aldehyde group: ‘-al’ or ‘-aldehyde’ • Less common in phytomolecules • Similar polarity to ketone group
Functional Groups: Aldehyde
Aldehyde group: benzaldehyde
Functional Groups: Aldehyde
Aldehyde group: cinnamaldehyde
Functional Groups: Aldehyde
Aldehyde group: cinnamaldehyde
Functional Groups: Amine
• Amine groups: ‘-amine’ or ‘amino-’ • Common in phytomolecules • Less polar than ketones & aldehydes
Functional Groups: Amine
Amine groups: histamine
Functional Groups: Amine
Amine groups: caffeine
Functional Groups: Amine
Amine group: phenylalanine
Functional Groups: Amine
Amine group: californidine
Functional Groups: Amine
Amine group: californidine
Functional Groups: Ester
• Ester group: ‘-oate’ • Very common in phytomolecules • Less polar than amines
Functional Groups: Ester
Ester group: chlorogenic acid
Functional Groups: Ester
Ester group: chlorogenic acid
Functional Groups: Ester
Ester group: aconitine
Functional Groups: Ester
Ester groups: echimidine
Functional Groups: Acetate
• Acetate group: ‘-acetate’ or ‘acetyl-’ • Very common in phytomolecules • Polarity similar to esters
Functional Groups: Acetate
Acetate group: linalyl acetate
Functional Groups: Acetate
Acetate group: linalyl acetate
Functional Groups: Acetate
Acetate group: acetylcholine
Functional Groups: Acetate
Acetate group: acetylcholine
Functional Groups: Carbonyl • Carbonyl: carbon double-bonded to oxygen • These groups contain carbonyls: – – – – – –
Ketones Aldehydes Carboxyls Esters Acetates Amides
Functional Groups: Ether
• Ether group • Somewhat common • Only slightly polar
Functional Groups: Ether
Ether groups: digitoxin
Functional Groups: Ether
Ether groups: a cyclic ether & a methyl ether (methoxy group)
Functional Groups: Alkane
• Alkane groups (i.e. methyl, ethyl, propyl) • Very common in phytomolecules • Nonpolar hydrocarbon moieties
Functional Groups: Alkane
Alkane group: stearic acid
Functional Groups: Alkane
Alkane groups: menthol
Functional Groups: Alkane
Alkane groups: beta-sitosterol
Functional Groups: Alkene
• Alkene groups • Very common in phytomolecules • Nonpolar, reactive
Functional Groups: Alkene
• Alkene groups: • Methylene groups in myrcene
Functional Groups: Alkene
Allyl methyl disulfide
• Alkene group: • Propene (allyl) group in allyl methyl disulfide
Functional Groups: Alkene
• Alkene groups: • Double bonds within a hydrocarbon ‘tail’
Functional Groups: Alkene
• Alkene groups: • Prenyl groups in hyperforin
Functional Groups: Alkene
Hyperforin
• Alkene groups: • Prenyl groups in hyperforin
Functional Groups: Chromophore
Functional Groups: Alkene
• Alkene section in center of molecule • Chromophore: yellow/orange compound • Nonpolar antioxidant
Functional Groups: Alkene
Lutein
• Alkene section in center of molecule • Chromophore: yellow/orange compound • Nonpolar antioxidant
Functional Groups: Alkene
Lutein
• Alkene section in center of molecule • Chromophore: yellow/orange compound • Nonpolar antioxidant
Functional Groups: Alkyne
• Alkyne groups • Uncommon in phytomolecules • Nonpolar, very reactive
Functional Groups: Alkyne
PHT
Alkyne groups: PHT
Functional Groups: Alkyne
Alkyne groups: PHT
Functional Groups: Alkyne
Alkyne groups: isobutylamide
Functional Groups: Alkyne
Alkyne group: lappaphene A
Functional Groups: Alkyne
Alkyne groups: cicutoxin
Functional Groups: Phenyl
Phenyl group
Phenolic group Polyphenolic
Functional Groups: Phenyl
Phenylalanine
A phenyl group on an amino acid
Functional Groups: Phenyl
A phenolic group on an isoflavone
Functional Groups: Phenyl
A polyphenolic compound
Functional Groups: Phenyl
Procyanidin C1
A polyphenolic compound
Functional Groups: Nitrile
• Nitrile groups • Uncommon in phytomolecules • Very polar, highly reactive
Functional Groups: Nitrile
Nitrile group: prunasin
Functional Groups: Nitrile
Nitrile group: linustatin
Functional Groups: Nitrile
Nitrile group: amygdalin
Functional Groups: Nitrile
Nitrile group: amygdalin
Functional Groups: Nitrile
• Hydrocyanic acid: HCN • Released from cyanogenic glycosides • Very toxic compound
Functional Groups: ‘Thio’
Isothiocyanate
Thiocyanate
Isothiocyanate & thiocyanate groups: active metabolites of glucosinolates
Functional Groups: ‘Thio’
Isothiocyanate group in allylisothiocyanate, the active metabolite of sinigrin
Functional Groups: ‘Thio’
Isothiocyanate group in sulforaphane
Functional Groups: Sulfate
Sulfate group: polar
Functional Groups: Sulfate
Sulfate group: polar
Functional Groups: Sulfate
Sulfate group: sinigrin
Functional Groups: Sulfoxide
Sulfoxide group: polar
Functional Groups: Sulfoxide
Sulfoxide group: alliin
Functional Groups: Sulfoxide
Sulfoxide group: sulforaphane
Functional Groups: Sulfoxide
Sulfoxide group: ajoene
Functional Groups: Sulfoxide
Sulfoxide group: ajoene
Functional Groups: Thiosulfinate
Thiosulfinate group: polar
Functional Groups: Thiosulfinate
Allicin
Thiosulfinate group: allicin
Functional Groups: Thiosulfinate
Thiosulfinate group: allicin
Functional Groups: Sulfide
Sulfide group: nonpolar
Functional Groups: Sulfide
Sulfide group: diallyl disulfide
Functional Groups: Sulfide
Sulfide group: diallyl trisulfide
Functional Groups: Sulfide
Sulfide group: diallyl trisulfide
Functional Groups: Sulfide
Sulfide group: ajoene
Functional Groups: Phosphate
Phosphate group: polar
Functional Groups: Phosphate
Phosphate group: polar
Functional Groups: Phosphate
Phosphate group: phosphatidylcholine
Functional Groups: Pyrophosphate
Geranyl pyrophosphate
Pyrophosphate group composed of two phosphate groups
Functional Groups: Pyrophosphate
Geranyl pyrophosphate
Pyrophosphate group composed of two phosphate groups
Functional Groups: Epoxide
Epoxide group: polar
Functional Groups: Epoxide
Epoxide groups: violaxanthin
Functional Groups: Epoxide
Epoxide group: 23-epi-26-deoxyactein
Functional Groups: Epoxide
Epoxide group: catalpol
Functional Groups: Epoxide
Epoxide group: catalpol
Functional Groups: Epoxide
Epoxide group: didrovaltrate
Functional Groups: Methylenedioxy
Methylenedioxy group
Functional Groups: Methylenedioxy
Methylenedioxy group: apiole
Functional Groups: Methylenedioxy
Methylenedioxy group: berberine
Functional Groups: Methylenedioxy
Methylenedioxy group: methysticin
Ring Systems
Ring Systems: Cyclopropane
Cyclopropane ring
Ring Systems: Cyclopropane
Cyclopropane ring
Ring Systems: Cyclopropane
Cyclopropane ring: cycloartenol
Ring Systems: Cyclopropane
Cyclopropane ring: pyrethrins
Ring Systems: Cyclobutane
Cyclobutane ring
Ring Systems: Cyclobutane
Cyclobutane ring
Ring Systems: Cyclobutane
Cyclobutane ring: beta-caryophyllene
Ring Systems: Cyclobutane
Cyclobutane ring: alpha-pinene
Ring Systems: Cyclobutane
Cyclobutane ring: alpha-pinene
Ring Systems: Cyclobutane
Cyclobutane ring: alpha-pinene
Ring Systems: Cyclopentane
Cyclopentane ring
Ring Systems: Cyclopentane
Cyclopentane ring
Ring Systems: Cyclopentane
Cyclopentane ring: diosgenin
Ring Systems: Cyclopentane
Cyclopentane ring: nepetalactone
Ring Systems: Cyclopentane
Cyclopentane ring: nepetalactone
Ring Systems: Cyclopentane
Cyclopentane ring: capsorubin
Ring Systems: Cyclohexane
Cyclohexane ring
Ring Systems: Cyclohexane
Cyclohexane ring
Ring Systems: Cyclohexane
Cyclohexane ring
Ring Systems: Cyclohexane
Cyclohexane ring
Ring Systems: 6-Carbon Rings
Cyclohexane rings
Ring Systems: 6-Carbon Rings
Fused cyclohexane rings: ginsenoside
Ring Systems: 6-Carbon Rings
Fused cyclohexane rings: ginsenoside
Ring Systems: 6-Carbon Rings
Fused cyclohexane rings: ginsenoside
Ring Systems: 6-Carbon Rings
Fused cyclohexane rings: ginsenoside
Ring Systems: 6-Carbon Rings
Cyclohexane ring vs. benzene ring
Ring Systems: 6-Carbon Rings
Cyclohexane ring vs. benzene ring
Ring Systems: 6-Carbon Rings
Cyclohexane ring vs. Benzene ring
Ring Systems: Benzene
Resonance delocalization results in stability
Ring Systems: Phenolic
Adding an –OH group changes benzene into phenol
Ring Systems: Phenolic
This anthocyanidin contains phenolic rings
Ring Systems: 7-C & 8-C
Cycloheptane & cyclooctane rings
Ring Systems: 7-C & 8-C
Cycloheptane & cyclooctane rings
Ring Systems: 7-C & 8-C
Cycloheptane & cyclooctane rings
Ring Systems: 7-C & 8-C
7-C: chamazulene
8-C: eschscholtzidine
Ring Systems: 10-Carbon
A ten-membered ring in parthenolide
Ring Systems
Not really a carbon ring: macrocyclic PAs
Ring Systems
Not really a carbon ring: macrocyclic PAs
Ring Systems: Oxygen Heterocycles
Furan rings
Ring Systems: Oxygen Heterocycles
Furan ring: carlina oxide
Ring Systems: Oxygen Heterocycles
Furan ring: carlina oxide
Ring Systems: Oxygen Heterocycles
Furan ring: benzofuran: psoralen
Ring Systems: Oxygen Heterocycles
Furan ring: benzofuran: psoralen
Ring Systems: Oxygen Heterocycles
Furan ring: coumestrol
Ring Systems: Oxygen Heterocycles
Furan ring: coumestrol
Ring Systems: Oxygen Heterocycles
Furan ring: fructose
Ring Systems: Oxygen Heterocycles
Furan ring: fructose
Ring Systems: Oxygen Heterocycles
Oxygen heterocycles: pyran rings
Ring Systems: Oxygen Heterocycles
Pyran ring: glucose
Ring Systems: Oxygen Heterocycles
Pyran ring: sugar in a glycoside (salicin)
Ring Systems: Oxygen Heterocycles
Pyran ring: sugar in a glycoside (salicin)
Ring Systems: Oxygen Heterocycles
Pyran rings: procyanidin A7
Ring Systems: Oxygen Heterocycles
Pyran rings: procyanidin A7
Ring Systems: Oxygen Heterocycles
Pyran ring: pelargonidin
Ring Systems: Oxygen Heterocycles
Pyran ring: pelargonidin
Ring Systems: Oxygen Heterocycles
Pyran ring: pyranone: naringenin
Ring Systems: Oxygen Heterocycles
Pyran ring: pyranone: naringenin
Ring Systems: Oxygen Heterocycles
delta-lactone
ester
gamma-lactone
Oxygen heterocycles: cyclic esters: lactones
Ring Systems: Oxygen Heterocycles
delta-lactone
gamma-lactone
Oxygen heterocycles: cyclic esters: lactones
Ring Systems
Oxygen heterocycles: cyclic esters = lactones: originate from bonding of hydroxyl groups to carboxylic acid groups within the same molecule
Ring Systems: Oxygen Heterocycles
Delta-lactone: kavain
Ring Systems: Oxygen Heterocycles
Delta-lactone: kavain
Ring Systems: Oxygen Heterocycles
Delta-lactone: gentiopicrin
Ring Systems: Oxygen Heterocycles
Delta-lactone: gentiopicrin
Ring Systems: Oxygen Heterocycles
Gamma-lactone: lactucin
Ring Systems: Oxygen Heterocycles
Gamma-lactone: lactucin
Ring Systems: Oxygen Heterocycles
Gamma-lactone: convallatoxin
Ring Systems: Oxygen Heterocycles
Gamma-lactone: convallatoxin
Ring Systems: Oxygen Heterocycles
Oxygen heterocycles: dioxans
Ring Systems: Oxygen Heterocycles
Oxygen heterocycles: dioxan ring
Ring Systems: Oxygen Heterocycles
Dioxan ring: silybin
Ring Systems: Oxygen Heterocycles
Dioxan ring: silybin
Ring Systems: Oxygen Heterocycles
• Dioxin has a dioxan ring • Carcinogenic xenoestrogen • Not a phytomolecule
Ring Systems: Oxygen Heterocycles
• Dioxin has a dioxan ring • Carcinogenic xenoestrogen • Not a phytomolecule
Ring Systems: Oxygen Heterocycles
Macrocyclic ester: macrocyclic PA: senkirkine
Ring Systems: Oxygen Heterocycles
Macrocyclic ester: macrocyclic PA: senkirkine
Ring Systems: Nitrogen Heterocycles
Nitrogen heterocycles: 5-membered rings
Ring Systems: Nitrogen Heterocycles
Nitrogen heterocycles: 6-membered rings
Ring Systems: Nitrogen Heterocycles
Nitrogen heterocycles: fused 5- & 6-membered rings
Ring Systems: Nitrogen Heterocycles
Nitrogen heterocycles: fused 6membered rings & a pyrrolizidine
Ring Systems: Nitrogen Heterocycles
Nitrogen heterocycles in alkaloids
Ring Systems: Sulfur Heterocycle
Thiophene ring
Ring Systems: Sulfur Heterocycle
Thiophene ring
Ring Systems: Sulfur Heterocycle
Thiophene rings: arctinal
Ring Systems: Sulfur Heterocycle
Thiophene rings: arctinal
Solubility
Solubility • Solubility: which solvents (menstrua) will extract the desired constituents or leave undesirable ones? • Which solvent & concentration gives maximum medicinal power? • Solubility of one component changes according to what else is dissolved • Sometimes difficult to predict; must be determined by experience or laboratory analysis
Solubility • Based mainly on ‘positive’ & ‘negative’ electrical charges • Polar molecules have partially positive regions & partially negative regions • Nonpolar molecules have no ‘charge separation’ … they are electrically neutral
Extraction Media/Solvents • • • • •
Olive oil (& other ‘fixed’ plant oils) Ethanol (Everclear®, vodka, grain alcohol) Water Glycerol (glycerin) Vinegar (acetic acid)
Solubility: Water
+ +
+
+ _ _
Water is highly polar: + region of one molecule attracts – region of another molecule
+
_
+
Solubility: Ethanol (EtOH) Ethane is a symmetrical, nonpolar molecule
–OH group
Ethanol (grain alcohol) is a polar molecule – not electrically symmetrical
Solubility: Glycerol –OH group
–OH group
–OH group
Glycerol (glycerin) is highly polar; generally used for water-soluble constituents
Solubility: Olive Oil • The main constituents of Olive oil are triglycerides (neutral fats) • Also known as triacylglycerols, their long hydrocarbon chains are electrically neutral
Solubility: Supercritical CO2 • High-pressure, low-temperature process • No chemical solvents; very clean CO2 is ideal for extracting gingerols & essential oil components
Photo courtesy of FLAVEX GmbH Germany
Solubility: Supercritical CO2 _ _
_
+
+
+ _ _
_
• CO2 has oxygen atoms but… • Molecule is symmetrical • Opposite vectors cancel each other out • Overall result: a non-polar molecule
Acetone is Amphiphilic: Both Oil & Water Soluble • Has been used as a solvent for certain constituents in standardized extracts • Alternative to hexane for many oil-soluble constituents: less toxic
Solubility: Ethyl Acetate
• Used to extract terpenes in Ginkgo & other lowpolarity constituents • Less toxic than most other organic solvents • Water-immiscible but not totally non-polar: it’s an ester
Solubility: Ether
• Diethyl ether extracts constituents of very low polarity • Ethers are water immiscible
Solubility: Hexane
• Hydrocarbon: no oxygen atoms • No charge separation • Non-polar: water-insoluble
Solubility: Polarity of Solvents • Acetone: 2.88 • Glycerol: 2.68 • Water: 1.85 • Ethyl acetate: 1.78 • Acetic acid: 1.7 • Ethanol: 1.69 • Diethyl ether: 1.15 • Hexane: ~ 0 • Olive oil: ~ 0 • Supercritical CO2: ~ 0, adjusted with ethanol
The unit of polarity is D for ‘debye’; it measures the ‘dipole moment’ or the overall charge distribution in the molecule but can be
Solubility: Octanol/water Coefficient • Glycerol: - 1.76 • Ethanol: - 0.31 • Acetone: - 0.24 • Acetic acid: - 0.17 • Ethyl acetate: 0.73 • Diethyl ether: 0.89 • Hexane: 3.9 • Oleic acid (main constituent of Olive oil): 7.73
The octanol-water coefficient (Kow) indicates the relative watersolubility of a molecule: lower Kow = higher solubility in water
Solubility: D vs. Kow Polarity
(D)
Solubility
(Kow)
Acetone
2.88
Glycerol
- 1.76
Glycerol
2.68
Ethanol
- 0.31
Water
1.85
Ethyl acetate
1.78
Acetone
- 0.24
Acetic acid
1.7
Acetic acid
- 0.17
Ethanol
1.69
Ethyl acetate
0.73
Diethyl ether
1.15
Diethyl ether
0.89
Hexane
~0
Hexane
3.9
Olive oil (oleic acid)
~0
Oleic acid
7.73
[H+] > [OH-]
Acidic
[OH-] > [H+]
Neutral
Basic
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH Affects Solubility Gastric HCl Lemon juice Vinegar Tomato juice Coffee Urine Pure water Human blood Sea water Milk of magnesia Ammonia Bleach Oven cleaner
• pH = – log [H+] • Log scale means a diff. of 1 pH represents a 10-fold change in hydrogen ion concentration • Acidic: pH < 7.0 • Neutral: pH = 7.0 • Basic: pH > 7.0
pH Affects Solubility: Acids
Protonated
Ionized
pKa: pH at which molecule loses its hydrogens
pH Affects Solubility: Acids
Protonated
Ionized
pKa differs for diff. hydrogens & diff. molecules
pH Affects Solubility: Acids
Protonated
Ionized
When pH = pKa, half of the molecules are protonated
pH Affects Solubility: Acids
Protonated And half are ionized
Ionized
pH Affects Solubility: Acids
Protonated
Ionized
Ionized acids are more water-soluble
pH Affects Solubility: Acids
Protonated
Ionized
Protonated acids are more oil-soluble
pH Affects Solubility: Acids
Protonated: neutral
Ionized: negative charge
Depending on pH, acid can be protonated or charged
pH Affects Solubility: Acids
Protonated: neutral
Ionized: negative charge
Low pH: fully protonated (lots of H+ ions around)
pH Affects Solubility: Acids
Protonated: neutral
Ionized: negative charge
High pH: fully charged (not many H+ ions around)
pH Affects Solubility: Acids
To isolate acidic compounds in the lab, first the whole plant is extracted with ethyl acetate or a similar solvent
pH Affects Solubility: Acids
Next the extract is mixed with a water solution that has been basified with an inorganic base like NaHCO3
pH Affects Solubility: Acids
And the ionized acid, being water-soluble, partitions down into the aqueous layer
pH Affects Solubility: Phenolics
Phenolic compounds are weakly acidic & will be more soluble in a high-pH aqueous solution
pH Affects Solubility: Bases
For a base, protonated = ionized Depending on pH, base can be neutral or protonated
pH Affects Solubility: Bases
For a base, protonated = ionized Low pH: fully protonated (lots of H+ ions around)
pH Affects Solubility: Bases
For a base, protonated = ionized High pH: neutral (not many H+ ions around)
pH Affects Solubility: Bases
To isolate basic compounds in the lab, first the whole plant is extracted with ethyl acetate or a similar solvent
pH Affects Solubility: Bases
Next the extract is mixed with a water solution that has been acidified with an inorganic acid like dilute HCl
pH Affects Solubility: Bases
And the ionized base, being water-soluble, partitions down into the aqueous layer
pH Affects Solubility: Bases
Aromatic amines are generally water-soluble at pH below 4 because they are positively charged (protonated)
pH Affects Solubility: Bases
H+
H+
OH-
H
+
H+
OH H+
H
+
H
H
+
H+
+
OH
-
OH OH-
OH
-
OH-
-
-
OH-
OH-
H+
Many alkaloids are soluble in acidic solutions, but will precipitate from basic solutions
pH: Summary
Example: Berberine vs. Hydrastine
Berberine: more water soluble Hydrastine: less water soluble
Other Factors Affecting Solubility • Temperature (generally, heat enhances extraction) – But watch out for thermal degradation – Exception: polysaccharides (mucilages) extract very well in cold water
• Solubility of one constituent may be altered by other constituents present – Interactions between constituents – Tannins can complex with other constituents – Common ion effect
Solubility: Precipitates • Dissolved constituents can precipitate out of solution if the polarity of the solvent system changes significantly • Example: In a water extract (infusion, decoction) of Echinacea, gradual addition of ethanol will cause the polysaccharides to precipitate out of solution • Example: In an ethanolic extract of Kava, gradual addition of water will cause the kavalactones to precipitate
Polar & Nonpolar Solvents Polar Water Ethanol (grain alcohol, Everclear速, vodka, wine) Acetic acid (vinegar) Glycerol (glycerin) Methanol (wood alcohol poisonous) Acetone (polar, amphiphilic) Ethyl acetate
Nonpolar Olive oil & other fixed oils Supercritical CO2 Hexane (some toxicity) Benzene (carcinogenic) Acetone is amphiphilic; will dissolve nonpolar substances as well
Like Dissolves Likeâ&#x20AC;ŚMostly Polar Water-soluble constituents Alcohol-soluble constituents Mono- & Disaccharides Oligo- & Polysaccharides Many polyphenols (esp. glycosides) Vitamins B, C Alkaloids (usually, alcohol) Essential oils (alcohol) Resins (high % of alcohol)
Nonpolar Oil-soluble constituents Lipids Essential oils Terpenoids Carotenoids Some polyphenols (esp. aglycones) Vitamins D, E, A, K Sterols Fixed oils
End
Lisa Ganora www.herbalchem.net info@herbalchem.net 720-890-4935 Louisville, CO Š Lisa Ganora 2005