Foundations

Page 1

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 Like‌Mostly 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



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