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186 Cards in this Set
- Front
- Back
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Van der waals features
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-Induced dipole-induced dipole
-Found in lipophillic solvents (not hydrophillic) -Only significant at low temps (not high temps) -Affected by steric factors -Prevalent in hydrocarbon and aromatic systems |
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What kind of interaction has permanent dipole-dipole bond?
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Hydrogen bonds.
(p61 book) Thats why polar molecules will be soluble in water, because they possess a permanent dipole. |
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What's another name for a permanent dipole?
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polar (compound)
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What types of groups can have hydrogen bonds?
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A hydrogen covalently bonded to an electronegative:
-oxygen -sulfur -nitrogen -selenium These are all polar molecules IBLV. IBLV these can also participate in IMHB as well (eg H-bonding between themselves rather than with water).. |
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Name some atoms with high electron densities
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-nitrogen on amines
-oxygen on ethers and alcohols -sulfurs on thioethers and thiols NOTE: High electron density doesn't mean its basic (necessarily), since alcohols and thioethers are neutral. |
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Strength of bond, from lowest to highest between h-bonds, van der waals, and ionic bonds?
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van der waals < h-bonds < ionic bonds
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What type of bond is seen by organic salts dissolved in water?
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ion-dipole bonds, eg:
-cation of salt bonded to oxygen of water(permanent dipole) -anion of salt bonded to hydrogen of water(permanent dipole) |
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How do you create a conjugate acid salt in water?
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Add a basic organic compound (eg has an amine) to an aqueous acidic solvent.
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Advantage of forming ion-dipole bonds with organic salts in water?
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Increase water solubility
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If a molecule has no hydrophillic groups, but has van der waals interactions, it will dissolve best in a _____ solvent.
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lipophillic
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How do you create a conjugate base salt in water?
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Add an acidic organic compound (eg has a carboxylic acid, phenol, mono/unsubstituted sulfonamide, or unsubstituted imide) to an aqueous basic solvent.
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What are the conditions that must be considered for chemical stability "on the shelf"?
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1. Air
2. Light 3. Aqueous base 4. Aqueous acid 5. Heat 6. Moisture (water in air) |
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What conditions must be met for a carbon to be chiral? (eg two stereoisomers exist which are non superimposable mirror images of each other)
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1. Have 4 different substituents
2. No plane of symmetry |
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Metabolism (eg in vivo reactions) of alkanes?
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Relatively nonreactive in vivo, excreted from the body unchanged.
Exception is alkane -> alcohol via CYP450. CYP450 can add an OH to the omega carbon (or omega minus one carbon). (see p10, figure 2-5 for two examples) |
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Why does the boiling point increase with longer alkanes?
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More van der waals interactions between alkanes.
(see my "facts of interest" on boiling points for much more) |
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Are alkanes soluble in water?
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No, because they dont form H-bonds or ion-diopole bonds with water.
Alkanes are lipophillic. |
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Where do anesthetic alkanes go to?
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The lipid portion of the brain (which is why they act as anethetics)
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In vitro stability of alkanes?
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Stable, chemically inert on the shelf
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What's an isomer?
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Same empirical formula, but different structure
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What property do alkanes with 1 to 4 carbon atoms share?
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they're gases
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Which alkanes are liquids?
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alkanes with 5 to 20 carbons
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What kind of bonds do liquid alkanes have?
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Induced dipole-induced dipole bonds between each other.
(eg van der waals interactions) |
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Which of these are unstable in vivo:
-alkanes -halogenated alkanes -cycloalkanes |
They're all stable in vivo
(FGA cd) |
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Are alkanes acidic, basic, or neutral?
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Neutral
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In vitro stability of alkenes?
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1. Light and air sensitive -> double bond is prone to epoxidation or peroxidation(iblv peroxidation requires two alkenes).
2. Flammable (epoxides and peroxides: wiki). |
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What is the significance of forming a peroxide in terms of stability?
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Peroxides are very unstable.
They are flamable, and may explode in presence of air and a spark. |
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Unsaturated fatty acids plus water create _____ ?
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alcohols
R-Ch2-Ch=Ch-Ch2-R -> R-Ch2-C(OH)h-Ch2-Ch2-R |
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What is the rule for naming E or Z?
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Use priority rules to find the highest priority group on each side of the double bond. If they are both above or below the double bond, they're Z. If they're diagonal, they're E.
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What metabolic reactions can alkenes undergo?
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1. Hydration (of an unsat fatty acid -> alcohol)
2. Epoxidation 3. Peroxidation (cyp450, p143) 4. Reduction (add an H to each carbon on the alkene) (these are shown on p13) |
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Whats a geometric isomer?
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In general, an isomer has the same epirical formula, but a different structure, typically containing a double bond which cannot rotate. An isomer may also include a ring structure, where the rotation of bonds is greatly restricted
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What are the physical properties of alkenes?
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1. Alkenes with 2-4 carbons are gases
2. Alkenes with 5+ carbons are liquids 3. Alkenes are lipophillic 4. Have low (but increasing) boiling points (like alkanes) due to van der waals interactions only |
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Name it:
Ch2=Ch-Ch3 |
Common: Propylene
IUPAC: Propene |
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Name it:
Ch3-Ch2-C(Ch3)=Ch-Ch2-C(Ch3)3 |
IUPAC: 3,6,6-trimethyl-3-heptene
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Whats an unsaturated fatty acid?
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A chain of hydrocarbons with one or more alkenes
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Name it:
Ch2=C(Ch3)-Ch3 |
Common: iso-butylene
IUPAC: 2-methylpropene |
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When is E/Z used over trans/cis?
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For tri and tetra substituated alkenes (where 3 or 4 groups attached to double bond differ)
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Whats an epoxide?
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A cyclic ether (a triangle with one oxygen and two carbons)
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What are the geometric isomers of:
-propene -pentene -hexene |
-cyclopropane (reactive: explosive)
-cyclopentane (reactive: highly flammable) -cyclohexane (nonreactive) (all have same empirical formula, no free rotation around C to C bonds, but different structure) |
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Difference between:
axial-trans-1,2-dimethyl-cyclohexane and equatorial-trans-1,2-dimethyl-cyclohexane |
Axial conformation is the high energy conformation, equatorial is low energy conf.
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Are alkenes acidic, basic, or neutral?
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Neutral
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Are alkenes water soluble or lipophillic?
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Lipophillic
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Properties of cycloalkanes?
(include acid/base/neutral, sol, in vitro/vivo stability, and anything important to know) |
-Neutral
-Lipophillic -In vitro: stable for most part, exceptions are cyclopropane (explosive), and cyclopentane (flammable)) -In vivo: possible reactive in acid? (P1 review doc) |
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Aromatic stability in vitro?
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Stable
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Aromatic are lipophillic or hydrophillic?
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Lipophillic
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Aromatic metabolism?
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1. Very prone to aromatic hydroxylation (epoxidation followed by oxidation to an alcohol) by CYP450
2. Then (likely) phase 2 conjugation of hydroxyl groups (glucuronidation, sulfonation, methylation) 3. (me) Wherever the first OH is added the second and third are added ortho and para to it. It might be possible to hydroxylate every available position? Professor says benzenes cant be hydroxylated, so perhaps these in vivo rxns are for aromatics already substituated, as seen in fig 4-2, p17. |
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What does aromatic hydroxylation increase or decrease?
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1. Increases molecules water solubility
2. Usually causes rapid removal of molecule from body 3. May increase the drug activity (in a few cases) |
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What's are the phase 2 conjugations for aromatics?
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Glucuronidation and sulfonation (requires OH off aromatic).
Methylation (of OH) because phenols can do it (me). Glucuronidation and sulfonation increase the molecules water solubility and excretion from body, methylation decreases its water solubility and excretion. p18, 29 Lemke |
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What's a aromatic heterocyclic ring?
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An aromatic ring containing noncarbon ring atoms, like O, N, or S.
(wiki) |
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In vitro stability of heterocyclic aromatic ring?
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light and air sensitive
(Rubric doc) |
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What type of bonding occurs with halogenated hydrocarbons?
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Just van der waals interactions.
(no h-bonding, even though halogen has a permanent dipole (you would need an electropositive atom next to it IBLV)) |
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Properties of halogenated hydrocarbons?
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1. Highly lipophillic
2. Low boiling points 3. Chemically nonreactive (with some exceptions) 4. Prolonged half-life |
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What are the exceptions to the chemical nonreactivity of halogenated hydrocarbons?
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1. Monohaloalkanes are flammable.
2. Polyhalogenated compounds, with addition of heat and oxygen can create a reactive/toxic compound, eg chloroform -> phosgene (p 20 Lemke) |
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Metabolism of halogenated hydrocarbons?
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Not readily metabolized, kidney cant easily excrete them since they're very lipid soluble, therefore potentially more toxic.
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Properties of alcohols?
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1. Intermolecular h-bonding (due to permanent dipole on oxygen(-) and hydrogen(+)
2. Relatively high BP (due to IMHB). 3. Water sol (due to h-bonding with water). 4. Neutral polar (attached halogens can increase the acidity). |
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What placement of the hydroxyl group makes an alcohol more water soluble?
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If the hydroxyl is centered on the molecule, rather than at the end.
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Whats the in vitro stability of an alcohol?
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Relatively stable, although rarely the following are possible:
1. Primary alcohol can be oxidized to an aldehyde, then to a carboxylic acid. 2. Secondary alcohol oxidized to a ketone. 3. Tertiary alcohol is stable to mild oxidation (carbon has no more hydrogens left to oxidize). Book strongly implies that these rxns require an oxidizing agent stronger than air. (p23 Lemke) |
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Metabolism of alcohol?
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Oxidized by ADH (alcohol dehydrogenase) primarily, and CYP450:
-primary alcohol -> aldehyde -> carboxylic acid -secondary alcohol -> ketone -tertiaries are stable Alcohols also undergo glucuronidation and sulfation, not methylation. |
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How is an ester created?
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a carboxylic acid + an alcohol
(via a dehydration rxn) (see wiki) |
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Properties of phenols?
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1. intermolecular h-bonding
2. high BP 3. high water sol 4. acidic (weak acids) |
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What happens with the addition of an alkyl or halogen to a phenol?
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1. water sol greatly decreases
2. acidity increases (pka dec) with halogen substit (IBLV) 3. acidity decreases (pka inc) with alkyl substituents (because alkyls are e- donating groups, this decreases resonance stabilization of ring, resulting in less ion-dipole bonding to water) |
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Why are phenols acidic and alcohols arent?
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because the phenolate anion formed after loss of H is resonance stabilized by the aromatic ring (e- sink)
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Why is the BP and water solubility noticibly better for phenols than with an equivalent alcohol (eg cyclohexanol)?
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Because phenols have both dipole-dipole bonding and ion-dipole bonding with water (dipole-dipole in neutral form, and ion-dipole as anion/phenolate).
Same goes for intermolecular attaction between phenols to inc BP. |
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How do you make a salt with a phenol?
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Using a strong base (NaOH or KOH).
You end up with phenolate and Na+ (or K+). Phenols are nonreactive in a weak base. |
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why do we formulate a drug as a salt?
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1. this greatly increases water sol
2. for a drug to be biologically active it must be soluble |
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Are all salts water soluble?
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No, salts can be either water soluble or insoluble(if they dont dissociate from each other).
In general, salts made from NaOH, KOH, Nh4+OH−(ammonium hydroxide) are water soluble, while heavy metal salts like CaOH, MgOH, ZOH, ALOH are not water soluble. Insoluble salts can precipitate (which is not good for drugs) |
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in vitro stability of phenols?
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1. oxidized by air and light to p-quinone or o-quinone
2. turns yellow 3. must be protected in amber container or with antioxidants |
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Metabolism of phenols?
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1. Hydroxylation (figure shows ortho or para, others?) using CYP450, increases water sol (phase 1 rxn).
2. Glucuronidation of OH, inc water sol (phase 2 rxn). 3. Sulfation of OH, inc water sol (phase 2 rxn). 4. Methylation of OH (to lesser extent), decreases water sol (phase 2 rxn). |
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How to you make an ether?
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1. alcohol + alcohol
2. alcohol + phenol |
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Properties of ethers?
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1. Neutral
2. Low BP 3. Poor water sol (weakly hydrophillic). (oxygen of ether to H of water). Smaller ethers have better water sol than longer ethers. |
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In vitro stability of ethers?
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Stable, chemically almost inert.
Exception: low MW ethers are unstable in air (classnotes). Exception: liquid ethers is formation of a peroxide, that may lead to an alcohol and an aldehyde (or ketone). This can be prevented by adding copper as an antioxidant. (p31 Lemke) |
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Metabolism of ethers?
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Mostly excreted unchanged.
Possible ("O-demethylation") dealkylation of methyl or ethyl group, but typically when other side of oxygen is aromatic. Forms an alcohol(phenol typically), and an aldehyde. Example: dealkylation of methoxybenzene (or ethoxybenzene) to form formaldehyde (or acetaldehyde). Requires CYP450. Hydroxyl can then be conjugated (classnotes). (p32 Lemke) |
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In vitro stability of a THIOETHER?
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In light and air, can be oxidized to a sulfoxide, and then a sulfone:
RSR -> R(S=O)R -> R(S=O)2R |
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Are aldehydes neutral?
Are ketones neutral? |
Yes
Both are also polar (due to the carbonyl group) |
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Physical properties of ketones and aldehydes?
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1. Exist in equilibrium with the enol form (less so for aldehydes).
2. Water soluble/hydrophillic. 3. Higher BP, h-bonding, and solubility than comparable sized ethers, but decreases rapidly with more carbons as well |
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In vitro stability of ketones?
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Relatively nonreactive.
Exception: α,β unsaturated ketones are light sensitive (P1 review doc). α,β unsat ketone -> secondary alcohol (classnotes) |
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In vitro stability of aldehydes?
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1. Liquid aldehydes are rapidly oxidized by air to carboxylic acids in vitro (protection is required).
2. Small aldehydes can bond to each other as cyclic trimers, or as a straight chain polymer. (p35 Lemke) |
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Chemical reactions of ketones?
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ketone + alcohol + acidic medium => hemiketal.
hemiketal + alcohol + acidic medium => ketal. Note: If asked about the stability of a hemiketal(or ketal), the reverse pathway will be the products. Not sure if this is in vitro or just a chemical rxn thats possible. (p36 Lemke) |
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Chemical reactions of aldehydes?
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aldehyde + alcohol + acidic medium => hemiacetal.
hemiacetal + alcohol + acidic medium => acetal. Note: If asked about the stability of a hemiacetal (or acetal), the reverse pathway will be the products. Not sure if this is in vitro or just a chemical rxn thats possible. (p35/6 Lemke) |
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Metabolism of aldehydes?
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1. Readily oxidized to a carboxylic acid by these non-CYP450 enzymes:
-ADH -Xanthine oxidase -Aldehyde oxidase 2. Reduction to a primary alcohol (lesser). (p37 Lemke) |
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Metabolism of ketones?
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1. Oxidation to a carboxylic acid
2. Reduction of ketones (in general, but especially for a,b unsaturated) to a secondary alcohol using ADH (alcohol dehydrogenase). (P1 review doc, p37 Lemke). |
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What is a hemiacetal (and hemiketal) unstable in?
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Any aqueous condition, regardless of pH
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What is an acetal(and ketal) unstable in?
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only unstable in aqueous acid.
(theyre stable in a neutral or aqueous base) |
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example of a hemiacetal?
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glucuronic acid
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In vitro "change" of aldehydes and ketones.
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Equilibrium to ENOL form.
Aldehyde <-> primary alcohol Ketone <-> secondary alcohol Results in higher BP. |
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Purpose of adding an amine to a drug compound?
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1. increase its water solubility, and therefore biological activity
2. binds drug to a specific site in body |
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Basicity of amines?
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Basic (secondary > tertiary > primary)
This assumes that all the attached groups are e- donating. (tertiary has more steric hindrance than primary, but three times more e- donators) Amines are polar as well. (p41 Lemke) |
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BP of amines?
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Relatively low for primary and secondary.
Lower for tertiary. (p39 Lemke) |
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Solubility of amines?
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primary > secondary > tert (all 3 are sol)
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What factor(s) determines the basicity of an amine?
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1. if the groups attached to N are electron donating (amine is more basic), if they're electron withdrawing (amine is less basic)
2. tertiary amines provide some steric hindrance to the H3O+ in an acid soln, dec basicity |
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when an amine is in acidic soln, what forms?
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salt
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which is LESS basic: alkyl amines or aromatic amines?
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aromatic amines 10^6 times LESS basic than alkyl amines
(due to e- sink, they're resonance stabilized and cant be donated easily) |
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Example of an aromatic amine?
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Aniline: C6H5Nh2
An example of an amine attached to an e- withdrawing group (resonance stabilization of amines electrons). |
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compare adding an e- withdrawing group to aniline, versus adding one to phenol, at ortho, meta, and para positions
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adding to para has biggest impact for aniline and phenol.
adding to meta has less impact than adding to para (for both). adding to ortho is unpredictable (for both). e- withdrawing groups added to aniline make it even less basic, while adding them to phenol makes it more acidic |
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What are common acids used to prepare salts from basic drugs?
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1. Pamoic acid
2. Hydroxynaphthoic acid 3. Maleic acid 4. Citric acid 5. Succinic acid 6. Hydrochloric acid 7. Tartaric acid 8. Sulfuric acid "PhMcShts" |
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What do you get by adding a base to an amine salt?
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the free amine may precipitate when its H is removed
(R-NH3+ -> RNH2) |
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Which acids form water insoluble amine salts?
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1. Pamoic acid
2. Hydroxynaphthoic acid |
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Why would we want to form water insoluble salts?
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to keep a drug in the intestinal tract by preventing its absorption, because salts that dont dissociate/separate cant be absorbed
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Points to know about dealkylation of amines?
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1. Tert amines -> secondary
2. Secondary -> primary 3. No dealkylation of primary 4. Alkyl group removed at each step becomes an aldehyde or ketone 5. Only small alkyls are removed (methyl, ethyl,propyl) methyl (and ethyl) -> aldehyde propyl -> ketone 6. Catalyzed by CYP450 |
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Points to know about deamination of amines?
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Primary amine -> aldehyde or ketone:
1. Only with primary alkyl amines (NH2 attached to a carbon chain). 2. Carbon attached to NH2 must have at least one H). 3. If carbon is at end, the (remaining) chain becomes an aldehyde (carbon that was attached to N gets oxidized to a carbonyl). 4. If carbon is not at end, chain becomes a ketone 5. Deamination enzymes are typically MAO or DAO 6. Example is deamination (and inactivation) of norepinephrine |
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Points to know about methylation of an amine?
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1. Primary and secondary amines.
Primary amine -> secondary amine. Secondary amine -> tertiary amine. 2. Lesser rxn. 3. A phase 2/conjugation (wiki) Example: methylation of norepinephrine to epinephrine (Ch3 is added to norepi's nitrogen). Does methylation dec solubility? |
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Points to know about conjugaton of amines?
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1. Only primary and secondary amines (no tertiary conjugations).
2. Includes glucuronidation, sulfonation, methylation, and acetylation . 3. These are all phase 2 conjugations. 4. Glucuronidation and sulfation inc water solubility. 5. Acetylation dec water sol and reqs acetyl CoA. 6. Glucuronidation affects primary and secondary amines. 7. Acetyalation (primary and secondary aryls, not sure about alkyls). 8. Sulfonation affects primary and secondary amines. 9. Methylation (primary and secondary). |
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whats the difference between regular ammonium salts and a quaternary salt?
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1. quats have 4 carbon substituents (no H's) to N
2. non-quats can revert back with addition of a base 3. quats are stable ionic compounds with very good water sol |
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example of a quaternary ammonium salt?
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TEA sulfate:
N(C2H5)4+ and SO4- |
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Points to know about acetylation of an amine?
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1. Primary and secondary aromatic/aryl amines.
2. An acetyl group (Ch3C=O) is added to N (attachment is at the carbonyls carbon). 3. Decreases the compounds water solubility. (p46 Lemke) |
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In vitro reactions with primary, secondary, tertiary amines?
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Primary: Stable
Secondary: Stable Tertiary: Unstable in air and light (forms an N-oxide) |
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In vivo reactions for primary amines?
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1. Deamination (primary alkyl, MAO/DAO)
2. Methylation (lesser, phase 2) 3. Glucuronidation (phase 2) 4. Sulfonation (phase 2) 5. Aryl Acetylation |
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In vivo reactions for secondary amines?
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1. Dealkylation (CYP450)
2. Methylation (phase 2) 3. Glucuronidation (phase 2) 4. Sulfonation (phase 2) 5. Aryl acetylation (phase 2) |
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In vivo reactions for tertiary amines?
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1. Dealkylation (cyp450).
2. Tertiary amine + O -> R3N+O− (an amine oxide or N-oxide, catalized by FMO, p143) |
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Where does an in vitro base come from?
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H2O can act as a base if the acid is strong enough
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Where does an in vitro acid come from?
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CO2 + H2O -> H2CO3 -> HCO3- + H+
(H2CO3 is carbonic acid btw) |
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What log P value signifies the compound is hydrophillic or lipophillic?
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log P < +0.5 is hydrophillic/water soluble
log P > +0.5 is is lipophillic (log P of +0.5 = 3.3% water solubility) |
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What must a compound have to be optically active?
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1. chiral center
2. NO plane of symmetry (eg terpin, a bowtie, has a PoS, and therefore is not optically actice) |
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Whats the most important enzyme in the CYP450 family?
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CYP450 3A4
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properties of a cyclopropane?
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1. unstable
2. explosive 3. high ring strain 4. used as general anethetic |
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Presentation order?
(can delete this after class ends) |
1. compound name
2. name each functional group (ketone, acetal, etc) 3. acidity/basicity/neutrality of each functional group 4. stability in vitro (air, heat, moisture, light, aqueous acid/base) (since stability overrides solubility discuss this first) 5. discuss groups that make molecule soluble (if compound is unstable, discuss solubility of products of instability) 6. stability in vivo/metabolism 7. IUPAC nomenclature 8. use of compound and general info |
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in vitro and in vivo reactions involving alkenes?
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in vitro: prone to peroxidation (light and air)
in vivo: prone to peroxidation (CYP450) |
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What form of your molecule will decrease its water solubility?
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Its zwitterionic form (when the number of cations = number of anions)
Typically a nitrogen is protonated to get a cation, or an acidic group loses its H to form an anion. |
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What should you mention if you molecule has some basic and acidic groups?
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That the molecule is AMPHOTERIC
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What do quinones generate, where, and how?
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-generate radicals
-in the gut -from trapped air |
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What are esters unstable in?
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acidic and basic media.
results in cleavage of bond between the carbonyl carbon and the ester oxygen to form a carboxylic acid and an alcohol |
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In general, if you're trying to determine a compounds solubility, what should you consider first, and why?
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consider its stability first, since stability takes precedence over solubility.
If its unstable for whatever reason, its decomposition will occur before it solubilizes (or not) |
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If you add an acidic compound to a basic solvent, what is formed?
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A "basic" salt.
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If you add an basic compound to a acidic solvent, what is formed?
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A "acidic" salt.
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In vitro stabilization of thioesters?
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Hydrolysis to a carboxylic acid + thiol(R-SH)
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Types of phase 1 reactions (very general, from wiki)?
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1. Oxidation
2. Reduction 3. Hydrolysis Phase 1 reactions are in vivo (not in vitro) |
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What sites participate in phase 2 reactions (conjugation)?
Give one example. |
-OH
-COOH -SH -NH2 (eg of amino acids glutamine and glycine with carboxylic acids) |
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Are phase 2 reactions enzyme catalized?
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Of course, phase 1 and 2 are both in vivo reactions.
Phase 2 enzymes are typically: -Methyltransferase (methylation) -Sulfotransferases (sulfonation) -N-acetyltransferases (acetylation) -UDP-glucuronosyltransferases (glucuronidation) |
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Anything attached to an aromatic ring is in the same _____
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plane
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All salts are water soluble?
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No, salts of strong acids and bases are water soluble, but not heavy metal salts (eg CaOH, MgOH)
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Most drugs are water soluble?
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True
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What can phenols resonance stabilize into?
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Quinone (double bond to oxygen, and only two doubles in ring)
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Whats an ISOFORM?
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Different forms of a the same protein.
Either from related genes, alternative slicing of the same gene, or SNPs (single-nucleotide polymorphisms) |
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What can introduce a free radical into a molecule?
And how can it be prevented? |
UV light.
Antioxidants can prevent UV degradation. |
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If a molecule is _______ soluble and not _______, it will NOT be metabolized.
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If a molecule is WATER soluble and not a SALT, it will NOT be metabolized.
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What compounds are unstable in light and air?
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1. Phenols ( -> quinones)
2. Tertiary amines 3. Alkenes 4. others? |
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How much is a phenol ring worth during analytical method (in determining solubility)?
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+2.0 for ring
-1.0 for OH Total: +1.0 |
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When can you have glucuronidation of adjacent hydroxyls?
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If theyre in separate planes (one up, one down).
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Percentages used for water solubility in empirical and analytical methods?
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Empirical: 1% is water sol.
Analytical: 3.3% is water sol. |
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What antioxidants should you add to lipophillic compounds?
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Vitamin E (its lipophillic)
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What antioxidants should you add to hydrophillic compounds?
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Vitamin C (its hydrophillic)
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Why does the professor say that benzene is carcinogenic?
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Because (he says) benzene cant be hydroxylated, and therefore cant be excreted.
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What is the affect of adding a sulfonamide to a drug?
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Decreases the drug's metabolism.
(classnotes) |
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Difference between glucuronidation, sulfonation, methylation, and acetylation, in terms of attachment points?
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Glucuronidation and sulfonation require an available -OH or -SH.
Methylation and acetylation require an available -H and two electrons, typically conjugating primary and secondary amines. (this is conjecture from classnotes and book, and might be wrong) |
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Whats the priority of assigning a functional group as the parent chain (highest to lowest)?
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1. Carboxylic acid (-oic acid)
2. Ester (-oate) 3. Amide 4. Aldehyde (-al) 5. Ketone 6. Alcohol 7. Phenol (-phenol) 8. Amine 9. Alkene (-ene) 10. Alkane? (eg methoxyethane) 11. Benzene? (eg methoxybenzene) 12. Ether 13. Nitro |
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In vitro stability of alkenes?
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1. Light and air sensitive -> double bond is prone to epoxidation or peroxidation(requires two alkenes).
2. Flammable (epoxides and peroxides: wiki). |
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Basicity of amines?
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Basic (secondary > tertiary > primary)
This assumes that all the attached groups are e- donating. (tertiary has more steric hindrance than primary, but three times more e- donators) Amines are polar as well. (p41 Lemke) |
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What are the conditions that must be considered for chemical stability "on the shelf"?
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1. Air
2. Light 3. Aqueous base 4. Aqueous acid 5. Heat 6. Moisture (water in air) |
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properties of a cyclopropane?
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1. unstable
2. explosive 3. high ring strain 4. used as general anethetic |
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Solubility of amines?
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primary > secondary > tert (all 3 are sol)
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Unsaturated fatty acids plus water create _____ ?
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alcohols
R-Ch2-Ch=Ch-Ch2-R -> R-Ch2-C(OH)h-Ch2-Ch2-R |
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What factor(s) determines the basicity of an amine?
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1. if the groups attached to N are electron donating (amine is more basic), if they're electron withdrawing (amine is less basic)
2. tertiary amines provide some steric hindrance to the H3O+ in an acid soln, dec basicity |
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in vitro and in vivo reactions involving alkenes?
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in vitro: prone to peroxidation (light and air)
in vivo: prone to peroxidation (CYP450) |
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Metabolism (eg in vivo reactions) of alkanes?
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Relatively nonreactive in vivo, excreted from the body unchanged.
Exception is alkane -> alcohol via CYP450. CYP450 can add an OH to the omega carbon (or omega minus one carbon). (see p10, figure 2-5 for two examples) |
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which is LESS basic: alkyl amines or aromatic amines?
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aromatic amines 10^6 times LESS basic than alkyl amines
(due to e- sink, they're resonance stabilized and cant be donated easily) |
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What metabolic reactions can alkenes undergo?
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1. Hydration (of an unsat fatty acid -> alcohol)
2. Epoxidation 3. Peroxidation (cyp450, p143) 4. Reduction (add an H to each carbon on the alkene) (these are shown on p13) |
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What are esters unstable in?
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acidic and basic media.
results in cleavage of bond between the carbonyl carbon and the ester oxygen to form a carboxylic acid and an alcohol |
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compare adding an e- withdrawing group to aniline, versus adding one to phenol, at ortho, meta, and para positions
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adding to para has biggest impact for aniline and phenol.
adding to meta has less impact than adding to para (for both). adding to ortho is unpredictable (for both). e- withdrawing groups added to aniline make it even less basic, while adding them to phenol makes it more acidic |
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In vitro stabilization of thioesters?
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Hydrolysis to a carboxylic acid + thiol(R-SH)
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Types of phase 1 reactions (very general, from wiki)?
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1. Oxidation
2. Reduction 3. Hydrolysis Phase 1 reactions are in vivo (not in vitro) |
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What do you get by adding a base to an amine salt?
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the free amine may precipitate when its H is removed (R-NH3+ -> RNH2)
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What can phenols resonance stabilize into?
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Quinone (double bond to oxygen, and only two doubles in ring)
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In vitro stability of alkanes?
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Stable, chemically inert on the shelf
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What can introduce a free radical into a molecule?
And how can it be prevented? |
UV light.
Antioxidants can prevent UV degradation. |
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Points to know about dealkylation of amines?
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1. Tert amines -> secondary
2. Secondary -> primary 3. No dealkylation of primary 4. Alkyl group removed at each step becomes an aldehyde or ketone 5. Only small alkyls are removed (methyl, ethyl,propyl) methyl (and ethyl) -> aldehyde propyl -> ketone 6. Catalyzed by CYP450 |
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What antioxidants should you add to lipophillic compounds?
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Vitamin E (its lipophillic)
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Points to know about deamination of amines?
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Primary amine -> aldehyde or ketone:
1. Only with primary alkyl amines (NH2 attached to a carbon chain). 2. Carbon attached to NH2 must have at least one H). 3. If carbon is at end, the (remaining) chain becomes an aldehyde (carbon that was attached to N gets oxidized to a carbonyl). 4. If carbon is not at end, chain becomes a ketone 5. Deamination enzymes are typically MAO or DAO 6. Example is deamination (and inactivation) of norepinephrine |
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What property do alkanes with 1 to 4 carbon atoms share?
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they're gases
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Points to know about methylation of an amine?
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1. Primary and secondary amines.
Primary amine -> secondary amine. Secondary amine -> tertiary amine. 2. Lesser rxn. 3. A phase 2/conjugation (wiki) Example: methylation of norepinephrine to epinephrine (Ch3 is added to norepi's nitrogen). |
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What antioxidants should you add to hydrophillic compounds?
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Vitamin C (its hydrophillic)
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Points to know about phase 2/conjugaton of amines?
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1. Only primary and secondary amines (no tertiary conjugations).
2. Includes glucuronidation, sulfonation, methylation, and acetylation . 3. These are all phase 2 conjugations. 4. Glucuronidation and sulfation inc water solubility. 5. Acetylation dec water sol and reqs acetyl CoA. 6. Glucuronidation affects primary and secondary amines. 7. Acetyalation (primary and secondary aryls, not sure about alkyls). 8. Sulfonation affects primary and secondary amines. 9. Methylation (primary and secondary). |
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Which alkanes are liquids?
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alkanes with 5 to 20 carbons
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whats the difference between regular ammonium salts and a quaternary salt?
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1. quats have 4 carbon substituents (no H's) to N
2. non-quats can revert back with addition of a base 3. quats are stable ionic compounds with very good water sol |
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What is the affect of adding a sulfonamide to a drug?
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Decreases the drug's metabolism.
(classnotes) |
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Are alkenes acidic, basic, or neutral?
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Neutral
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Points to know about acetylation of an amine?
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1. Primary and secondary aromatic/aryl amines.
2. An acetyl group (Ch3C=O) is added to N (attachment is at the carbonyls carbon). 3. Decreases the compounds water solubility. (p46 Lemke) |
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Difference between glucuronidation, sulfonation, methylation, and acetylation, in terms of attachment points?
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Glucuronidation and sulfonation require an available -OH or -SH.
Methylation and acetylation require an available -H and two electrons, typically conjugating primary and secondary amines. (this is conjecture from classnotes and book, and might be wrong) |
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What in vivo reactions typically occur with tertiary amines?
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Dealkylation only (AFAIK).
p44 Lemke |
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Are alkenes water soluble or lipophillic?
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Lipophillic
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In vitro reactions with primary, secondary, tertiary amines?
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Primary: Stable
Secondary: Stable Tertiary: Unstable in air and light (interacts with oxygen somehow) |
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Which of these are unstable in vivo:
-alkanes -halogenated alkanes -cycloalkanes |
They're all stable in vivo
(FGA cd) |
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In vivo reactions for primary amines?
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1. Deamination (primary alkyl, MAO/DAO)
2. Methylation (lesser, phase 2) 3. Glucuronidation (phase 2) 4. Sulfonation (phase 2) 5. Acetylation (primary aryl for sure) |
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Properties of cycloalkanes?
(include acid/base/neutral, sol, in vitro/vivo stability, and anything important to know) |
-Neutral
-Lipophillic -In vitro: stable for most part, exceptions are cyclopropane (explosive), and cyclopentane (flammable)) -In vivo: possible reactive in acid? (P1 review doc) |
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In vivo reactions for secondary amines?
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1. Dealkylation (CYP450)
2. Methylation (phase 2) 3. Glucuronidation (phase 2) 4. Sulfonation (phase 2) 5. Aryl acetylation (phase 2) |
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Whats the priority of assigning a functional group as the parent chain (highest to lowest)?
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1. Carboxylic acid (-oic acid)
2. Ester (-oate) 3. Amide 4. Aldehyde (-al) 5. Ketone 6. Alcohol 7. Phenol (-phenol) 8. Amine 9. Alkene (-ene) 10. Alkane? (eg methoxyethane) 11. Benzene? (eg methoxybenzene) 12. Ether 13. Nitro |
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In vivo reactions for tertiary amines?
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1. Dealkylation (cyp450).
2. Tertiary amine + O -> R3N+O− (an amine oxide or N-oxide, catalized by FMO, p143) |
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Are alkanes acidic, basic, or neutral?
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Neutral
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