Predicting pKa values (Lecture 4.2)

As you add electron-withdrawing groups or resonance stabilization to the conjugate base, what happens to the pKa?

MORE resonance/electron withdrawal = lower pKa = stronger acid

(ex. H-OH and Me-OH are weaker acids, while Ph-OH and Acetic acid are stronger acids)

As you add electron-withdrawing groups or resonance stabilization to the conjugate acid of amines, what happens to the pKb?

MORE resonance/electron withdrawal = HIGHER pKb = weaker base

Because basicity depends on the ability to use the lone pair to form a bond with a proton, why are amines less basic when EWGs are present?

Attaching an electron-withdrawing group (phenyl) to the nitrogen delocalizes those electrons into the ring. They become less available for bonding; thus, amine is a weaker base.

For alkyl groups or benzoic acids, the substitution of H with electron-withdrawing groups does what to the pKa?

Lowers the pKa = stronger acid

When going from H to CH3 to vinyl to aromatic ring, what effect occurs to pKa?

Marginal effect on pKa

Traits of Electron-withdrawing groups on aromatic rings?

- One electron withdrawing group on the aromatic ring at the ortho position shows the biggest effect, lowering pKa on a benzoic acid

- The addition of more electron-withdrawing groups at the ortho, meta, and para positions will lower the pKa for benzoic acids, but not by the same amount

For alcohols, the replacement of H with alkyl groups does what to the pKa?

- simple alkyl groups (ex. CH3) = Modest increase in pKa

- large alkyl groups (ex. cyclohexyl) = Large increase in pKa

Replacing H atoms with electron-withdrawing groups (e.g., F, CF3, NO2) does what to pKa?

*Lowers pKa (the more added, the greater the decrease in pKa)

For phenols, what does the addition of electron-withdrawing groups and electron-donating groups do to the pKa?

- electron withdrawing groups (Cl, NO2) = lower the pKa

- electron-donating group (e.g., MeO) = increases the pKa

Because the pKb value is not reported in the literature, how do you calculate a pKb value for the base from the conjugate acid and pKa?

pKa + pKb = 14

For substituted anilines, what will electron-withdrawing groups and electron-donating groups on the aromatic ring of the conjugate acid do to the pKa?

- EWGs = decrease the pKa (thus increase pKb of the base)

- EDGs = increase the pKa (thus decrease pKb of the base)

In pyridines, what will electron-withdrawing groups and electron-donating groups on the aromatic ring do to the pKb?

- EWGs = increase the pKb

- EDGs = decrease in pKb

Why aren't amides (like actemide) basic even though they have a lone pair on nitrogen?

- The lone pair on nitrogen is delocalized into resonance with the carbonyl, making it unavailable for the lone pair to form a bond with a proton

- The conjugate base is also resonance-stabilized

- Amides would behave as an acid and not a base

Does Methanesulfonamide behave as an acid or a base

Behaves as an acid

Who is the stronger EWG between sulfonyl and carbonyl?

The sulfonyl group is an even stronger electron-withdrawing group than a carbonyl, and so there is more stabilization of the conjugate base form

What would occur to a compound that gets both of its hydrogens replaced by other groups?

- The resulting compound would be neither an acid nor a base

- The resulting compound would NOT be a Bronsted acid due to NO donatable proton

- The resulting compound would NOT be a Bronsted base due to NO donatable lone pairs

- Would be neutral

What would occur to an ammonia that gets both of its hydrogens replaced by methyl groups?

- Still a base because the lone pair can be donated

How do different substituents affect acidity (pKa)?

* Groups that withdraw/delocalize electrons stabilize the conjugate base and lower pKa

- H, alkyl groups = 0

- Aryl, C=C, C=N, N=N, C≡C groups: 1st = 5 and 2nd = 2

- RC=O or ArC=O: 1st = 10 and 2nd = 5

- RSO2 or ArSO2: 1st = 15 and 2nd = 7

What are the outcomes of a compound when nitrogen is the central atom, and it is attached to either a carbonyl or sulfonyl group?

- The nitrogen is non-basic in water

- If that nitrogen has a hydrogen attached to it, then it is acidic

- If no attached hydrogen, then the nitrogen is neutral

Characteristics of Imines

- Have a C=N bond with the lone pair contained within a sp2 orbital

- The nitrogen of imines is more electronegative than the nitrogen of amines

- The lone pair of imines is not shared as readily as it is for amines

- Imines are less basic and will have pKb values ~10

Characteristics of Nitriles

- Nitriles have a C≡N bond.

- The lone-pair electrons are in an sp orbital, which is held even closer to nitrogen.

- These electrons are generally not shared readily with protons

- Nitriles will have pKb values of 14

Characteristics of Amidines

- Amidines are imino-analogs of amides.

- They have one sp2 and one sp3 nitrogen

- It is always the sp2 nitrogen that acts as a base, with a pKb value of 3 (a strong base)

The strong basicity of Amidines is the result of WHAT?

- Electrons being donated from the sp3 nitrogen(which is very weakly basic)

- Resonance stabilization of the conjugate acid

In Amidines, if an electron-withdrawing group is attached to either nitrogen, what happens to the basicity of the sp2 nitrogen?

- The basicity of the sp2-nitrogen is decreased.

- This decrease can be modest to large, depending on the groups attached to the nitrogens.

Characteristics of Guanidines

- Guanidines are imino-analogs of ureas.

- The sp2 nitrogen that is highly basic (pKb = 1), while the sp3 nitrogens are only weakly basic

In Guanidines, if an electron-withdrawing group is attached to either nitrogen, what happens to the basicity of the sp2 nitrogen?

- The basicity of the sp2-nitrogen is decreased

Characteristics of Thiols (mercaptans)

- Acidic

When are C-H groups acidic?

- C-H groups adjacent to a carbonyl are acidic, provided that there is a high enough enol content.

- Usually in water, this means that the CH should be attached to two carbonyl groups

Generic pKa Values: pKa = 1 (strong acid)

- CF3CO2H

- RSO3H

- ArSO3H

Generic pKa Values: pKa = 4

- RCO2H

- ArCO2H

Generic pKa Values: pKa = 10

Ph-OH

Generic pKa Values: pKa = 11

R-SH

Generic pKa Values: pKa = 14 (weak acid)

- ROH

- H2O

Generic pKb Values: pKb = 1 (strong base)

Guanidine

Generic pKb Values: pKb = 2

DBU (amidine base)

Generic pKb Values: pKb = 3

Pyrrolidine

Generic pKb Values: pKb = 5

- NH3

- RNH2

- R2NH

- R3N

Generic pKb Values: pKb = 7

Imidazole

Generic pKb Values: pKb = 9

Pyridine

Generic pKb Values: pKb = 10

Aniline

Generic pKb Values: pKb = 14 (weak base)

Pyrrole

Generic pKb Values: pKb = 4,5, 12 (3 basic centers)

Purine