Functional Groups

• Functional groups are sets of atoms within molecules that possess distinct chemical properties, independent of the rest of the molecule
• The reactivity and interactions of these atom sets define those properties
• Functional groups are distinguished by their heteroatoms and oxidation level.
• Longer hydrocarbon chains and more functional groups make predicting chemical behavior harder

Functional Group Classification by Oxidation Level and Bonding

• Oxidation level/Number of bonds to heteroatoms:
  • One bond, Alcohol oxidation level
  • Two bonds, Aldehyde oxidation level
  • Three bonds, Carboxylic acid oxidation level
  • Four bonds, Carbon dioxide oxidation level

Functional Groups Formed with Oxygen, Nitrogen, and Other Elements

• Formed by oxygens:
  • Alcohols (-OH), Ether (-OR)
  • Aldehydes, Ketones, Acetals
  • Carboxylic acid, Esters
  • Ureas, Carbonates
• Formed with nitrogen:
  • Amines (-NH2) Imines
  • Amides*, Nitriles
  • Guanidine
• Other:
  • Alkenes, Halides, Thiols (-SH)
  • Alkynes

Alcohols

• Alcohols contain at least one hydroxy group (OH).
• The oxygen is electronegative, creating a polar group
• They can form hydrogen bonds
• If the hydrocarbon framework is small they are water-soluble
• They have significantly higher melting and boiling points than alkanes
• The pKa is around 16-20

Alcohol Types and Oxidation

• Primary alcohols can be oxidized to aldehydes and carboxylic acids.
• Secondary alcohols can be oxidized to ketones.
• Tertiary alcohols cannot be oxidized.

Ethers

• Ethers feature an oxygen atom connected to two carbon atoms via single bonds (R-O-R')
• Ethers are less polar than alcohols but are still polar groups.
• They can act as hydrogen bond donors (but not acceptors).
• They have melting and boiling points between alkanes and alcohols
• The O atom is sp3 hybridized
• The C-O bonds are chemically stable

Formation of Ethers

• Ethers are made through the dehydration of two alcohols

Thiols and Thioethers

• Thiols and thioethers are sulfur equivalents of alcohols and ethers, in which oxygen is replaced by sulfur.
• Sulfur is a period 3 element, while oxygen is a period 2 element
• Sulfur is larger with a bigger covalent radius and is less electronegative compared to oxygen.
• Bonds to C and H are weaker and longer, compressing the bond angle.
• Thiols are deprotonated more readily.
• Thiols have lower boiling points than alcohols because interactions are weaker, though still higher than alkanes

Properties of Bonds in Methanol, Methanethiol, Dimethylether, Dimethylsulphide

• Bond length:
  • Methanol (O-H) is 0.96 Å
  • Methanethiol (S-H) is 1.33 Å
  • Dimethylether (C-O) is 1.41 Å
  • Dimethylsulphide (C-S) is 1.80 Å
• Bond angle:
  • Methanol (C-O-H) is 108.9°
  • Methanethiol (C-S-H) is 100.4°
  • Dimethylether (C-O-C) is 111.2°
  • Dimethylsulphide (C-S-C) is 98.9°
• Dissociation E (X-H):
  • Methanol is 110 kcal/mol
  • Methanethiol is 87 kcal/mol
• pKa:
  • Methanol is 15.5
  • Methanethiol is 10.4

Odor and Occurrence of Thiols

• Thiols often have strong odors and are highly flammable.
• Some thiols are found in cannabis.

Thiols in Amino Acids

• Cysteine and methionine are amino acids that contain a thiol and a thioether, respectively.

Disulfide Bonds

• Disulfide bridges are created when two thiols are in oxidizing conditions
• These bridges are primarily found in proteins
• They are formed by cysteines in close proximity.
• C-S-S-C dihedral prefers configurations around 90°
• Flattening towards 0° or 180° increases reactivity
• S-S bonds are about 0.5 Å longer than C-C and about 40% weaker
• Disulphide bonds can exchange with deprotonated thiols

Amines

• Amines are nitrogen equivalents of alcohols and ethers.
• As a group V element (not group VI like O), nitrogen can form three single bonds in its neutral state.
• Amines form hydrogen bonds, though weaker than OH due to electronegativity differences
• Primary amines form more hydrogen bonds than secondary amines, which in turn form more hydrogen bonds than tertiary amines
• Solubility in water decreases from primary to tertiary amines
• Amines are often positively charged through protonation.

pKa Values of Protonated Amines

• pKa for R-NH3+ is around 10 when R=Me
• pKa for R-NH3+ is around 4.6 when R=phenyl

Aldehydes and Ketones

• Both aldehydes and ketones contain carbonyl groups (C=O)
• Ketones have the carbonyl group embedded between two carbon atoms
• Aldehydes have the carbonyl group between a carbon and a hydrogen atom
• Ketones are formed by oxidizing secondary alcohols
• Aldehydes are formed by oxidizing primary alcohols.

Carbonyl Group Features

• A carbon atom is double bonded to an oxygen atom.
• Both atoms are sp2 hybridized.
• The bond is polarized, with the carbon partially positive.
• Bond angles are around 120°.
• pKa of the aldehyde H is 17
• pKa of the H in ketones is 20.
• Aldehydes are more reactive than ketones and are soluble in water due to hydrogen bonds with the solvent.

Carboxylic Acids

• Carboxylic acids are formed by oxidizing an aldehyde with a hydroxyl group on the carbonyl carbon
• Deprotonation of the hydroxyl group occurs readily, leading to a negative charge.
• They can form hydrogen bonds in the protonated form and are soluble in water when deprotonated
• They are a key group to form other functional groups like esters and amides.

Esters and Thioesters

• Esters are made by condensing an alcohol and a carboxylic acid, using dehydration agents and acid or base catalysis
• Acyl chlorides (R-(C=O)-Cl) are often used in place of the acid to synthesize esters

Amides

• Amides can be primary, secondary, and tertiary
• They are formed by condensing a carboxylic acid and an amine
• Peptides, important biological molecules, are examples of amides
• Amides can form hydrogen bonds
• Tertiary amides can act as hydrogen bond acceptors, but not donors
• Primary amides, such as those in asparagine and glutamate side chains, can form two hydrogen bonds
• Breaking the amide bond (hydrolysis) usually occurs in very acidic or basic conditions due to the bond's stability

Boiling Points and Functional Groups

• Alkanes < Alcohols, Thiols, Amines (primary)
• Alkanes < Alcohols, Methyl ethers
• Alkanes < Alcohols, Carboxylic acids, Amides
• Alkanes < Alcohols, Esters (methanoate)
• Alkanes < Alcohols, Aldehydes, Ketones

Common Groups in Biochemistry

• Guanidine and the guanidinium cation
• Guanidine is a strong base, commonly found as the guanidinium cation with a pKa of 13.6, and is found as a functional group in arginine.
• Guanidine as denaturing agent
  • Guanidinium chloride denatures proteins and at 6M, most protein in aqueous solutions are denatured by it.
• Imidazole is a aromatic compound with two tautomeric forms, where the hydrogen can be bound to either nitrogen
  • Imidazole can act both as a base and acid (amphoteric).
  • The nitrogen without H can be protonated, while the N-H can be deprotonated.

Amino Acids with Various Functional Groups

• Includes Guanidinium, Amine, Carboxylic acids, Imidazole, Aryls, Alcohols, Thioether, Thiol, Carboxamides and Indole

Lipids and Melting Temperature

• Saturated lipids chains cause the Tm to increase

Chemical reactions summary

• Chemical reactions represent the dynamic aspects of chemistry
• Molecules change or form new molecules, by -Addition -Elimination -Substitution -Rearrangements
• More complex reactions can involve multiple of these at the same time, such as addition-elimination reactions.
• Reactions may involve changes in oxidation levels and/or acids and bases.

Activation Energy

• Is the general term used to define chemical reactions because there is typically an activation barrier that must be passed to start the reaction
• Elimination reactions specifically require activation energy because bonds must first be broken
• When molecules are close this activation energy can be from repulsion of outer electron clouds
• Overcoming this repulsion usually requires energy

Charge Attraction

• Charge attraction and orbital interactions will depend on polarity, will ultimately help to bring the molecules together

Orbital Interactions

• The interaction between orbitals determine specific reactions and mechanisms which will lead to specific products

Nucleophiles and Electrophiles

• Chemical reactions require electrons to move to break chemical bonds
• The species donating the electrons is called the nucleophile
• The species accepting the electrons is called the electrophile

Nucleophiles

• Must be attracted to positively charges species or electron-poor atoms
• Can be molecules or ions with free pairs of electrons
• Can be molecules with unsaturated bonds
• Are the Lewis Bases (electron donor)
• Examples: hydroxide, cyanide, bromide, alcohols and thiols

Electrophiles

• Oppositely, Electrophiles must be attracted to negatively charged or electron-rich atoms
• Atoms in this situation are positive or have incomplete outer shells
• Are Lewis acids (electron acceptors)
• Examples: Cations like H+, Molecules with empty orbitals and molecules with low lying anti bonding orbitals

Electrophilic Additions to Carboxyl Groups

• Carbonyl groups are most often electrophiles because there is lower energy matching between interacting orbitals that polarizes the bond between C and O
• Due to partial positive charge the bond is susceptible to being an electrophile
• LUMO π* is lower lying which will cause Nu to break the double bond

Factors that Affect Positive Charges

• The more positive the partial charge on the carbonyl group, the more likely this reaction becomes
• Similarly, the more stable the leaving group is, the better.
• The more positive the partial charge on the carbonyl group, the more likely this reaction becomes; similarly, the more stable the leaving group is, the better.

Nucleophilic Substitutions

• Similar concept as Electrophilic Additions, based on differences in orbital
• In this case a carbon becomes partially positive and a Nu will come and interact
• A "leaving group" will simultaneously be kicked off

Understanding Basic Chemistry

• The ability to predict chemical reactions is determined by core properties such as
  • Electronegativity: polarizes the bond and has no delocalization of charge
  • Geometry: can be trigonal planar
  • Stronger the nucleophile will depend on orbital properties with the electrophile
  • Depending on basic or charged nucleophiles can react differently

Leaving group stability

• Better the stability of leaving groups are are often the best choice
• Cations such as Cl- are the best leaving groups
• Poor leaving groups are often ROH
• Very poor leaving groups are often NR2