Handout 1A: Amino Acids - Electronics and Acid-Base Chemistry

Amino Acids: Overall Structure

• a.a’s are difunctional compounds that contain both an amine and a carboxylic acid functionality

• acid has priority in naming

• carbons b/w the functional groups designated ⍺, β, γ, δ, etc. starting from the carbonyl

• 20 common a.a’s found in proteins (all ⍺-amino acids)

  • differ in R group/side chain

Chirality

• glycine is achiral

• other 19 common amino acids are chiral; each contains a stereogenic center at the ⍺-carbon

  • all are in “L” configuration; when drawn in Fischer Projection w/ the most oxidized carbon (CO₂H) at the top, R group at the botoom, the NH₂ is on the left

• threonine and isoleucine have a second stereogenic center within their side chains

Fischer Projections

• vertical lines go into the page (dashes)

• horizontal lines come out the page (wedges)

• a switch of the two substituents leads to the opposite configuration (R → S, S → R, changes enantiomer)

• two switches and you are back where you started

Amino Acids: R vs S Configuration

• the ⍺-carbon of cysteine has R configuration

• other 18 common acids have S configuration

Acid-Base Properties of Amino Acids

• when CB/CA = 1, pK_a = pH

• when pH < pK_a, CA dominates

• when pH > pK_a, CB dominates

• when the pH is one pH unit above the pK_a, there is 10x more CB present than CA

pK_a, Ka Definitions

pK_a: indicates how readily an acid donates a proton

• lower pK_a = stronger acid

K_a: acid dissociation constant

• larger K_a = stronger acid

• smaller K_a = weaker acid

Simpel Amino Acids

• side chain is neither acidic nor basic

• exist as zwitterions in neutral aqueous solution (contain both + and - charges)

• pK_a carboxylic acid = 2.3

• pK_a ammonium = 9.6

Why is the pK_a of an a.a lower than acetic acid (4.74)

• the amino group makes the carboxyl group more acidic by stabilizing its CB (zwitterionic state)

• NH₃⁺ pulls electron density away from COO^- (spreads out - charge)

  • electronically stabilizing

• inductive effect

• resonance and sterics do not come into play

Factors that might affect a reaction

• sterics: physical crowding around reactive site can block reactants from approaching each other

• electronics: distribution of electron density in a molecule, EDG or EWG can stabilize/destabilize charges or T.S

• hydrogen bonding: formation of H-bonds can stabilize reactants, intermediates or T.S (changes reactivity or orientation of molecules)

• solvation: refers to interactions b/w reactants and solvents; solvents can stabilize charged species, influence nucleophilicity/electrophilicity

Within Electronics: Induction

• induction: electron density is shifted thru σ bonds due to electronegativity differences

  • EWG stabilize (-) charge and destabilize (+) charge, EDG do the opposite

Within Electronics: Resonance

• resonance (delocalization of charge): e^- density is delocalized over multiple atoms via π system or lone pairs

  • delocalization stabilizes charged intermediates and T.S, lowers activation energy, favors resonance-stabilized products

Within Electronics: Hybridization

• hybridization: s-character of an orbital affects electron holding ability

  • more s-character (sp>sp²> sp³) hold electrons more tightly

Within Electronics: Octets

• octets (atoms like to have full octets): more stable

Within Electronics: Aromaticity

• aromaticity (achieving aromaticity accords stabilization): very stabilized by cyclic, conjugated π electron delocalization

  • rxs that form/preserve aromaticity are favored

Compare amine, pyridine, and pyrrole basicity: Amine

• N hybridization: sp³ (more p-character; e^-’s are further from the nucleus; more stable)

• (+) charges held closer to the nucleus are less stable; (-) charged have opposite effect

• pK_a = 10

• conjugate acid: ammonium

• lone pair = sp³ orbital (l.p is fully available, most basic)

Compare amine, pyridine, and pyrrole basicity: Pyridine

• N hybridization: sp²

  • e^- are held closer to nucleus

• lone pair: sp² orbital (not part of aromatic sextet)

• conjugate acid: pyridinium

  • wants to get rid of proton more than ammonium

  • more acidic than ammonium due to hybridization

• pK_a = 5

• aromatic (has resonance structures)

• Key idea: Lone pair is available but stabilized by higher s-character → less basic than amines

Compare amine, pyridine, and pyrrole basicity: Pyrrole

• N hybridization: sp²

• Lone pair: p orbital, part of aromatic sextet

• Conjugate acid: pyrrolium

• pKa (acid): ~0 (very weak base)

• Key idea: Lone pair needed for aromaticity → least basic

Why is sp² l.p held more tightly?

• an sp² l.p is held more tightly to the nucleus and thus has less affinity for a proton

  • the more s-character, the closer the orbital/electrons/charge are to the nucleus

• this is stabilizing for a (-) charge, but destabilizing for a (+) charge

• eg. the l.p og pyridine’s l.p is more stable, less basic than the l.p of an amine

Compare benzene, pyridine, and pyrrole: Benzene

• Atoms in ring: 6 carbons

• Aromatic? Yes (6 π electrons)

  • all double bands are conjugated

• Lone pairs? None

• each C is sp² hybridized

• Basicity: Essentially non-basic

• Key idea: Pure π system, no heteroatom to protonate

Compare benzene, pyridine, and pyrrole: Pyridine

• Atoms in ring: 5 carbons + 1 nitrogen

• N hybridization: sp²

• Aromatic? Yes (6 π electrons)

• Lone pair: sp² orbital, not part of aromatic sextet

• Basicity: Weak base (pKa of conjugate acid ≈ 5)

• Key idea: Lone pair is available → can be protonated without breaking aromaticity

Compare benzene, pyridine, and pyrrole: Pyrrole

• Atoms in ring: 4 carbons + 1 nitrogen

• N hybridization: sp²

• Aromatic? Yes (6 π electrons)

• Lone pair: p orbital, part of aromatic sextet

  • p-orbitals are higher energy than s-orbitals (by promoting to p-orbitals → get conjugation)

• Basicity: Very weak base

• Key idea: Protonation destroys aromaticity → strongly disfavored

Pyrrole + charge delocalization

Pyrrolium

• 14 pK_a units more acidic than ammonium due to a gain of aromaticity upon deprotonation to become pyrrole

• if pyrrole is protonated on its N, it loses aromaticity and has no resonance structures

• if it is protonated on its ⍺-carbon, it loses aromaticity and has 3 resonance structure

• it does protonate on its ⍺-carbon over the N (and over the β-carbon, which has 2 resonance structures), but pyrrolium is very acidic

Guanidine

Guanidiniums (e.g. Arg)

• have higher pK_a’s than ammoniums due to delocalization of the (+) charge (resonance)

  • the conjugate acid is stabilized and thus less acidic

• there is about 1/3 (+) charge on each N

  • there will only be a small charge on the carbon due to a lost octet on the carbon when it is charged

  • normally it is preferable to put a (+) charge on the less electroneg. atom

• in guanidinium, it is better to put (+) charge on the more electroneg. N (and maintain all octets)

Phenols (e.g Tyr)

• have lower pK_a’s than alcohols due to delocalization of the (-) charge around the ring (resonance)

  • the conjugate base is stabilized

• this breaks up aromaticity somewhat, but no octets are lost, so there is a net gain in stability of the conjugate base versus that of a simple alkoxide

Phenols Figure

Imidazole (His side chain)

• aromatic

• like pyridine, protonation does not disturb the aromaticity

  • also the l.p on the nitrogen(s) is sp²

• an imidazolium should be a bit more stable than a pyridinium from the stand point of resonance b/w the nitrogens of the immidazolium, but the extra nitrogen also inducitvely withdraws → leads to overall similar pK_a’s of imidazolium and pyridinium

Imidazole Figure

Thiols (Cys Side Chain)

• pK_a are much lower than alcohols due to lower charge density on anion

• the “hard” alkoxide anion has higher affinity for a “hard” proton

Aromatic Compounds

An aromatic compound must:

1. be cyclic

2. have one unhybridized p-orbital on every atom in the ring (in the same orientation)

3. be planar

4. have 4n+2 pi electrons in the ring (where n=0, 1, 2, 3)

   1. 4n+2 can be 2,6,10, 14

Antiaromatic Compounds

Planar, cyclic, conjugated systems with 4n π electrons. They are unstable/reactive because the MO diagram has two unparied electrons

Nonaromatic Compounds

Nonaromatic compounds fail any one of Hückel’s rules.

Isoelectric Point (pI)

• the pH at which the a.a. exists in solution predominantly as a neutral species

• for simple a.a.’s (those w/ no acidic or basic groups in their side chains)

• pI = (pK_a1 + pK_a2)/2

  • average of two pK_a’s

• if there is a potential charge in the side chain, the pI is the average of the two pK_as that yield a neutral species

Buffers

• if a.a’s are present in appreciable amounts, they can be used as buffers

• they can buffer at any pH that corresponds to one of their pK_a’s