Functional Groups Flashcards
Functional Groups
- A potentially reactive unit within a molecule
- Drugs typically are multi-functional molecule
- Sometimes FG are the basic framework of the molecule (Core or scaffold) or they a are appendages to the structures (substituents)
- They work together as a team, cannot be dissected
- E- are shared throughout the FG
FG within Drug Molecules affect:
- How a drug is transported
- How it binds to its receptor
- How it causes a biological response
- How it undergoes metabolism
- How it gets excreted from the body
- The drug stability during storage
FG (common carbonyl containing)
Ketone, Aldehyde, Carboxylic Acid, Ester, Carbonate, Amide, Carbamate, Urea, Lactone(cyclic ester), Lactam (cyclic amide)
FG (common nitrogen containing)
- Amine (basic, 1,2,3)
- Ammonium (can be acidic)
- Quaternary ammonium (permanent (+) charge
– Doesn’t give or accept protons - Nitro,
- Nitrile
- Imine (basic)
- Amidine (p-orbital)
- Guanidine(strongest basic FG in amine)
- Imide
- N-Acylsulfonamide
FG (common sulfur containing)
- Thiol (Mercaptan)
- Sulfide (Thioether)
- Sulfoxide
- Sulfone
- Sulfuric Acid
- Sulfonate
- Sulfate
- Sulfonamide
FG (Miscellaneous FG)
- Alcohol
- Phenol
- Enol (the En means a double bond)
- Ether
- Fluoro
- Chloro
- Bromo
- Lodo
- Trifluoromethyl
- Phenyl
- Benzyl
- Alkyl
- Alkenyl
- Alkynyl
Tautomerization
- Some FG are capable of existing in two forms
- Break bond and form another
Ketone (favored) can turn into Enol (hydrogen migrate to carbonyl oxygen to form a O-H bond - So tautomers are two structure that only differ with respect to the point of attachment of the H and the location of double bond
- The equilibrium depend on stabilities (Keto is favored compared to Enol)
Imine - Enamine
- Imine form is strongly favored - Examines are generally stable only if they lack hydrogen on N
Oxime - Nitroso
Favor oxide form
Electronic Effects
- Single bonds formed between atoms of different electronegative will be polarized
– In such bonds e- will be attracted by the more electronegative atom which will induce a small amount of (+) charge
– This will attract e- in the adjacent bond that will induce a smaller amount of (+) - This is called inductive effect and it decrease with distance
Field effect
- When polarization happen through space rather than through bonds
– Two groups of different elctronegativities need only to be close to one another for the field effect to be observed
Polar Effect
The two field effect and inductive effect together are to as Polar Effect
- As it is difficult to differentiate
- It decrease with distance from the more electronegative element
Resonance
Conduction of electrons throgh a conjugated system
- More favorable (lower in E) to disperse electron density over several atoms rather than have it concentrated at one point
- Resonance does not decrease (significantly) with distance
Conjugated System
There is alternating single and double bonds
Electron-Donating Groups
Transfer (donate) electrons density into a molecule as needed
- In response to a developing positive charge (usually)
EDG Function Groups
- Alcohols, ethers, amine, thiols, thioethers (sulfides), alkyl groups, and aromatic rings (can be e- withdrawing)
Alcohol and Ether
EDG
Delocalize the lone pair on O to develop area of + charge
- An example of resonance, and help to lower the energy of compound
- It spread out the charge over several atoms => lower the energy relative to having the charge centered on a single atom
Thiols and Thioethers (sulfides)
EDG
Work in the same way as their Oxygen analogs
- Sulfur is much larger than carbon => p-orbital overlap to form C=S is less efficient than C=O bond
- This mean that they are less efficient as EDG compared to alcohols and ethers
Amines
EDG
Same mechanism as alcohols but with N
- It’s less electronegative than O so it can tolerate positive charge better
- Amines are an excellent electron donators (better than sulfure and oxygen containing groups)
Alkyl Groups
Include substituents as methyl, ethyl, propyl, etc.
- Capable of dislocalizing adjacent positive charge by a process called hyperconjugation
– As there are no lone pairs to delocalize, the e- in adjacent C-H bonds are instead used for the same purpose
— While it cost energy to break the C-H bond, it is compensated for by dispersing the change through resonance
—- The greater the number of adjacent hydrogens, the better the EG properties (more resonance structures)
—– Methyl>Ethyl>i-propyl>t-butyl
Aromatic Rings
EDG
Use pi-electron density to help stabilize the adjacent charges by delocalizing that charge (olefins and alkynes do the same)
- Ex. In a Benzene (+) charge can be delocalized onto both oortho-prosition and para position
Electron-Withdrawing Groups
EWG
Withdraw e- density from a system; act as sink point for excess e- density
- They stabilize existing or developing (-) charge at or near point of attachment
- Many possess double or triple bonds
– All carbonyl based functional groups, cyano, nitro, sulfonyl, sulfinyl
- Imino-type functional groups
- Halides withdaw as do aromatic rings, olefins, and alkynes
Carbonyls
EWG
Withdraw e- density by two mechanisms
- Inductive effect
– The electronegativity difference between carbon and oxygen polarizes the bond; O will have partial negative and C will have partial positive (decrease with distance)
- Resonance
– e- density can be delocalized by resonance through the C=O bond which can spread the charge over several atoms
— Delocalize negative charge
Carbonyls with esters and amides
They are heteroatoms; a lone pair can be pushed into carbonyl group by resonance
- Reduces the degree of + charge that builds on the C of the carbonyl group
– This means that relative to ketones and aldehydes, esters and amide are slightly WEAKER EWG
— This mean when we end up with both a - and + sign on the structure after resonance=> weaker EWG
Only EWG when attached to substrate at carbonyl carbon
- Acetyle oxy
- Acetomide group
If position of attachment is heteroatom (any atoms that is not C or H) then it behave as weak ED substituents
Nitriles
EWG
Have a C-N triple bond
- More electronegative than C => the bond is polarized (Charge only go in one direction-toward N)
- Resonance is important to disperse excess electron density
Nitro Groups
EWG
(-NO2) are among the strongest EWG
- The N always carries a + charge (4 bonds) and one O has a - charge
Sulfoxides
Sulfure forms four bonds
- Two to neighboring groups
- A double bond to O
Sulfur larger than Oxygen
- pi-bond formation is less efficient than C=O
- This means that a significant resonance form must exist with a
– (+) charge on S (to stabilize the - charge)
– A Single bonded O having a (-) charge
Aceyl (C=O) is more e- withdrawing
Sulfones (sulfonyl)
Sulfur form 6 bonds
- Two to neighboring groups
- Two double bonds to O
As with sulfoxides (S=O) a significant resonance form exist with
- (+) charge on S
- (-) charge on a single bonded O (one of the two)
As there are two O; this mean there is an additional resonance structure = stronger e- withdrawer
- Sulfones > Acyl > Sulfoxides
Halides: Fluorine
EWG
Despite it’s very high electronegativity; a single F is only weakly EW
- it’s strong withdrawing effect is offseted by back donation (resonace) into vacant antiboding orbital
F>Cl>Br>I
Halides: Cl, Br, I
EWG
The size difference between them and C makes back donation by resonance inefficient
- They withdraw mainly by polar effect (Cl and Br)
– F > Cl > Br > I
Trifluoromethyl
EWG
CF3 is a powerful electron withdrawing
- The three F attached to one C allow the polar effect of each one to attract e- density from the other
– Prevent their lone pair from being back-donated
Aromatic Rings
- The pi-system can respond to both (+ and -) charges on adjacent carbons
– the presence of other EWG makes aromatic rings even stronger electron withdrawing group => charge is spread over more atoms
Aromatic Rings
- The pi-system can respond to both (+ and -) charges on adjacent carbons
– the presence of other EWG makes aromatic rings even stronger electron withdrawing group => charge is spread over more atoms
