MCAT Organic Chemistry

• 1 s and 3 p orbitals combine to make 4 sp³ orbitals and 4 σ bonds in an approximately tetrahedral shape, 109.5^o separation (ex. CH₄)
• 1s + 2p orbitals make 3 sp² orbitals which will make 3 σ bonds with 120^o separation in a trigonal planar shape leaving one p orbital to participate in a π bond (ex. H₂C=CH₂)
• 1s + 1p orbital makes 2 sp orbitals which make 2 σ bonds at 180^o separation in a linear shape leaving 2 p orbitals to participate in π bonds (ex. alkynes like HCΞCH)

• Used to predict the shapes of molecules
• based on the idea that electron pairs will spread out as much as possible
• Double and triple bonds act as a single contribution (so O=C=O only has 2 which will make 180^o separation and be linear)
• Lone pairs and pairs in bonds count but lone pairs are actually stronger because they are closer to the nucleus of the atom of interest
• H₂O is not linear because of the 2 lone pairs on oxygen --> bent (orbitals are approximately tetrahedral)
• NH₃ is not trigonal planar because of the lone pair on N --> pyramidal (orbitals of N are also approximately tetrahedral)
• BF₃ is trigonal planar because B does not have any lone pairs, just 3 pairs in bonds with 120^o separation

• Delocalized electrons are electrons that do not explicitly belong to any one atom or bond in a molecule
• Often π bond electrons fall into this category, especially in ionic structures
• Best example, a C₆ (benzene) ring contains 6 delocalized electrons drawn as a circle inside the ring meaning that 2 resonance structures are equally possible for the positions of the π bonds.

• a pi bond is weaker than a sigma bond (thus a double bond is not twice as strong as a single bond)
• more bonds makes the total bond shorter and stronger (even though each component is weaker)
• rigidity is increased because only single bonds rotate freely (even partial double bonds like the peptide bond prevent free rotation)
• rare quadruple bonds contain 1 sigma, 2 pi, and 1 delta bond, only form between transition metals

• Isomers have the same molecular formula but different structural formulas
• Constitutional isomers (structural isomers) have different connectivity: Positional have same fxn'l groups positioned differently & Functional have different fxn'l groups
• Geometric isomers (cis/trans; Z/E; R(D)/S(L)): have same connectivity but differ in arrangement
• Stereoisomers (enantiomers & diastereomers): have chiral carbon(s) with R(D)/S(L) designations
• Enantiomers: every chiral carbon is opposite
• Diastereomers: not all, but some chiral carbons are different

• In decreasing amounts of torsional strain (increasing stability):
• syn-periplanar - bulky groups eclipse each other
• anticlinal eclipsed - bulky groups eclipse H
• Gauche - bulky groups staggered @ 60^o
• Anti - bulky groups staggered @ 180^o
• 3 ring conformations in increasing stability:
• Boat - everything is eclipsed
• Twist boat - not completely eclipsed or completely staggered
• Chair - everything staggered
• *Technically not isomers because change due to rotation of bonds (not breaking), call them conformers

• polarized light = all EM fields in one direction
• optically active chiral centers rotate polarized light left or right (relative)
• Left rotation: (-) = l = levorotatory
• Right rotation: (+) = d = dextrorotatory

• 1) Identify chiral carbon
• 2) assign group priorities based on the molecular weight of the atoms directly bonded to carbon, then extending outward as necessary
• 3) rotate lowest priority to the back
• 4) draw an arrow pointing from highest to lowest priority, arrow turns right = (R), arrow turns left = (S)

• Definition: mixture contains equal amounts of both enantiomers (also called racemate)
• Separation (chemical): convert to diastereomers, separate based on (now) different physical properties, & convert back to enantiomers
• Separation (biological): Enzymes are highly D/L specific

• Plotted as transmittance vs wavenumber (cm^-1, correlates with frequency), dips represent absorbance
• ~3000 cm-1 usually involves an H atom (O-H, N-H, C-H)
• <~2000 cm-1 does not involve H (same atoms with higher bond order -> higher wavenumber)
• 1700 cm-1 = carbonyl
• 3300 cm-1 is either O-H, N-H, or ΞC-H (broader peaks due to H-bonding means these increase in sharpness left to right)
• <1300 cm-1 = fingerprint region unique for each compound

• Light: Red + Green + Blue -> White (none=black)
• Pigment (complimentary to light): Yellow + Cyan + Magenta -> Black (none = white)
• absorption of light -> complimentary color
• Universal Indicator (for pH): Red (very acidic) -> green (neutral) -> purple (very basic)

• pi bonding and non-bonding electrons absorb UV light and transition to anti-bonding orbitals
• Conjugated double bonds decrease energy of EM radiation absorbed -> longer wavelengths (closer to visible spectrum)

• Fragment molecule to ions with high energy electrons and separate fragments based on mass/charge (m/e or m/z) ratio by a magnetic field
• Parent peak: highest m/z ratio, not fragmented
• Base peak: most abundant species
• Isotopes: small peaks near real peaks
• Uses: MW of a molecule, Identify molecule by fragmentation patterns, or Identify heteroatoms by their characteristic isotope ratios

• Protons spin, in a magnetic field, spin lines up with lowest energy; radiowaves of a specific frequency can excite specific (equivalent) protons to "flip" by absorption called resonance
• Chemical Shift: (Resonance frequency of absorption) depends on degree of electron shielding (affected by electronegativities of nearby atoms, especially bonded atoms), More shielding (less electronegative neighbor) creates only a small shift and peak appears upfield (to the right) and vice versa
• Higher numbers of equivalent protons produce 1 signal at height n x signal for one proton
• measured relative to TMS (tetramethylsilane) standard in ppm
• Spin-spin splitting occurs when the magnetic fields of neighboring (3 bonds away) protons influence chemical shift -> split into n+1 peaks (n=# of neighboring H+); protons across double bonds split farther

• Extraction: 2 immiscible liquids (e.g. Organic and Aqueous phases)
• Distillation: Separate liquids based on boiling point
• Chromatography: Mobile phase moves along stationary phase dragging solutes along with different affinities (Gas-liquid, Paper, & thin-layer)
• Recrystallization: make a warm saturated solution and allow to cool -> recrystallize; choose a solvent where solute is soluble at high temps but not cooler temps but impurities are highly soluble at cool temps

• dependent on the presence of free radicals
• inhibited by antioxidants
• alkane + halogen + free radical initiator (UV light or Peroxides) -> alkyl halide
• more subtituted radicals are more stable (3^o >2^o >1^o> methyl) -> substitution will occur at the more substituted carbon

• Nomenclature: hydroxyl or hydroxy prefix or -ol suffix
• H-bonding -> higher boiling point, water soluble, Broad IR peak at 3300cm^-1
• R-OH pKa = 15, Ar-OH pKa=10
• More chain branching -> higher Tm but lower boiling point

• R-OH + HX ↔ R-X + H2O
• SN1: involves a carbocation intermediate (OH leaves as H2O before X- comes in); occurs if stable carbocation can be formed, usually a tertiary carbon center and a protic solvent
• SN2: involves a transition state where -OH and -X are both partially bonded to central carbon; preferable if carbocation is unstable; usually at a primary carbon center and/or in aprotic but polar solvent
• Both require a good leaving group

• Central -OH: not bonded to a terminal carbon, will be oxidized to a ketone group
• Terminal -OH: bonded to a terminal carbon, will be oxidized first to an aldehyde (weak oxidizers stop here) then to a carboxylic acid by strong oxidizers like KMnO4 or CrO3

H2SO4 (acid) and heat cause protonation of R-OH to R-OH₂⁺ which leaves creating a carbocation that will rearrange the methyl (opposite the other -OH) and the other -OH converts to =O (ketone, possibly aldehyde?)

• trimethylsilyl group (Cl-SiMe3) + R-OH → R-O-SiMe3
• Can be unprotected by removal with fluoride, R-O-SiMe3 + F- → R-OH + F-SiMe3

• R-OH + SOCl2 → R-Cl (SO2 + HCl)
• R-OH + PBr3 → R-Br (H3PO3 + R3PO3 + HBr)
• Replace -OH with halogen

• H3C-SO2-Cl + HO-R → H3C-SO2-O-R (Mesylate)
• Alcohol + Tosyl chloride (TsCl) → Tosylates
• Sulfonates (R-SO3^-) are good leaving groups

• Acid + Alcohol → Ester
• R-COOH + HO-R' → R-COO-R'

• Phosphates and Sulfonates are inorganic esters
• PBr3 + 3R-OH → H3PO3 + 3 RBr
• Intermediates are P(OR)3 and H-Br and ionized Br- replaces each R group sequentially
• SOCl2 + ROH → SO2 + HCl + RCl through a similar mechanism
• Basically using the ROH as a source of oxygen and switching halogens for oxygen

• Alcohol + Adehyde -> hemiacetal (1 equivalent) -> acetal (2 equivalents of alcohol); same for hemiketal/ketal
• Hemiacetal/ketal = C with an -OH and an Ether
• Acetal/Ketal = C with 2 ethers

• Primary amine (R-NH2) + aldehyde or ketone ->imine
• 2^o amine (R-NH-R') + aldehyde or ketone -> enamine (R"-C-C=O becomes R"-C=C-N-R&R')
• Replacing carbonyl with either double bond to N (imine) or single bond to N and double bond to neighboring C (enamine)

• ketones + halogen -> halogenation of α-Carbon
• methyl-ketone + halogen -> haloform (CHX3) + Carboxylate
• Halogenation can be partial or complete (all H replaced with X, works because neighboring O can temporarily accept the charge if alpha carbon is deprotonated)
• Second reaction occurs due to nucleophillic attack on carbonyl carbon after complete halogenation of methyl-alpha-C; b/c trihalogenated is a good leaving group

• Key feature is the acidic alpha-H+
• Example: 2 acetaldehyde (HC=OCH3) will condense to HC=O-C=CH-CH3)
• Deprotonation of acetaldehyde creates nucleophile that attacks carbonyl-C of another acetaldehyde displacing one of the carbonyl bonds to O (creating -OH^-) which will leave as water and C will double bond with central C (closer to remaining carbonyl)

• R-C=O-CH2-C=O-R' -> R-COH=CH-C=O-R'
• This experiences the tautomeric form: R-C=O-CH=COH-R' where each carbonyl is switching between keto- and enol- forms
• Structure is stabilized by intramolecular H-bonding

• Keto is the more stable, predominant form
• R-CH-C=O-R' (keto) ↔ R-C=COH-R' (Enol)

• Organometallic compounds create R- in solution which attacks C=O -> R-C-OH
• Create C-C bonds
• R-X + Li -> R-Li (and Li-X)
• R-X + BuLi -> R-Li (and BuX)
• R-Li + C=O -> R-C-OH (wherever the carbonyl was in the original molecule)

• Reduces C=O to -CH2-
• C=O + H2N-NH2 -> -CH2- + N2

• Just like organometallics -> R-
• R-X + Mg -> R-Mg-X
• R-Mg-X + C=O -> R-C-OH

• Nomenclature: aldehyde suffix -al or -aldehyde; ketones prefix keto- or oxo- suffix -one
• Physical Properties: C=O is polar, boiling points between alkanes and alcohols/carboxylic acids; IR spectrum 1700 cm-1
• General Principles: substituents contribute to steric hindrance (bulky groups around C=O block access to electrophillic C and decrease reactivity); alpha-H+ acidity means carbanions are stabilized by resonance; alpha-beta unsaturated carbonyls have resonance structures (nucleophile such as -OH easily added at beta position)

• Nomenclature: suffix -oic acid, -dioic acid
• Physical Properties: increased boiling point (H-bonding), soluble in water, IR peaks at 1700 (for C=O) and 3300 (for -OH)
• General Principles: H-bonding contributes to dimerization, pKa ≃ 5 (weak acid), substituents with an electron withdrawing group are inductive (make acid stronger); Conjugate base is resonance stabilized

• Nucleophile + R-COOH -> R-C=O-Nuc
• Example: peptide bond

• R-COOH + SOCl2 -> R-C=O-Cl (SO2 + HCl)
• carboxylic hydroxyl oxygen is a nucleophile and can attack electrophiles like the S in SOCl2 but the resulting chloride ion will attack the electrophillic C and displace the -O-S=O-Cl as SO2 and Cl-

Can be reduced to an alcohol by LiAlH4

• Spontaneous in a neutral or basic environment
• R-C=O-CH2-COO^- -> R-CO^-=CH2 + CO2 -> R-C=O-CH3 (deprotonates water)

• convert to enolizable form: R-CH2-COOH + PBr3 -> R-CH2-C=OBr
• Enolize: R-CH=COHBr
• Halogenation: R-CH=COHBr + Br2 -> R-CHBr-C=O-Br
• Revert (hydrolysis): R-CHBr-COOH

RCOOH + E⁺ -> substitution at alpha carbon

• Acid Chlorides: -oyl chloride (ex. ethanoyl chloride H3C-C=O-Cl); IR C=O @ ~1800
• Anhydrides: -oic anhydride (ex. ethanoic anhydride H3C-C=O-O-C=O-CH3); IR 2 C=O as 2 bands between 1700-1800
• Amides: -amide (ex. N-methyl ethanamide H3C-C=O-NH-Me); IR N-H @ ~3300 and C=O ~1700
• Esters: -oate (ex. methyl ethanoate H3C-C=O-O-Me); IR C=O @ 1700 and Ether (C-O) ~1200
• Physical Properties: C=O dipole interactions (no H-bonding w/o polar H) but still increase boiling point, Amides also H-bond b/c N-H group (like peptide backbone)
• Relative Reactivity: Acid Chloride (halides are a good leaving group) >Anhydride >Esters >Amides (peptide bonds, most stable b/c NR₂^- is a terrible leaving group and C-N partial double bond character)
• Steric Effects: bulky groups around C=O help protect from nucleophillic attack
• Electronic Effects: groups (like COO-) that redistribute and stabilize negative charges are good leaving groups, why anhydrides >esters
• Strain: C-N bond cannot rotate (high strain in a ring); ex. beta-lactam is a 4 member ring with 1 amide and high strain

• R-COOH + SOCl2 -> R-C=O-Cl
• *see nucleophillic attack by -COOH

• Heat: R-COOH + R'-COOH -> Anhydride + H2O
• Acid chloride + R-COOH + base -> anhydride: R'-C=O-Cl + R-COOH -> R'-C=O-O-C=O-R + HCl

• Acid chloride + alcohol + base -> ester
• R-C=O-Cl + R'-OH + base -> R-C=O-O-R'
• *Similar to esterification but with acid chloride instead of -COOH

• Acid chloride + Amine -> Amide
• R-C=O-Cl + H2N-R' -> R-C=O-NH-R'

Acid chloride + water -> -COOH + HCl

• R-C=O-X + Nucleophile -> R-C=O-Nuc
• X=Cl >anhydride >ester >amide (b/c X needs to be a good leaving group)

• Amide loses C=O: R-C=O-NH2 + Br2 + Base -> R-NH2
• Base deprotonates NH2
• Br binds negative N
• Base deprotonates NHBr
• Br leaves negative N (takes e- with it)
• Alkyl migration (nucleophillic N with 2 lone pairs of e- attacks carbonyl C, displacing R-C bond to N) creates Isocyanate O=C=N-R
• Isocyanate + base will pick up OH- then decarboxylate to NH2-R

• Ester + Alcohol -> new Ester
• R-C=O-O-R' + HO-R" -> R-C=O-O-R" + R'-OH
• Alcohol attacks carbonyl C (similar to Acid + Alcohol -> Ester reactions)

• R-C=O-O-R' + NaOH -> R-C=O-O^- Na⁺  + R'OH
• Splits Triglyceride into glycerol (R'(OH3) + fatty acids

• Leaving group must be the neutral amine, NOT NH2-
• R-C=O-NH-R' attacked by OH- becomes R-CO(^-)OH-NH-R'
• C-N electrons leave C for H in water creating R-COOH + H2N-R' and regenerating OH-

• Alpha-keto acid: (R-C=O-COOH) is 2-oxo acid (ex. alpha-ketopropanoic acid = 2-oxopropanoic acid)
• Beta-keto acid: (R-C=O-CH2-COOH) is 3-oxo acid
• Beta (Alpha)-keto esters: R-C=O-CH2-COO-R' is 3 (2) -oxo ester (ex. methyl-beta-ketobutanoate = methyl 3-oxobutanoate)
• General Principles: hydrogen adjacent to carbonyl group is more acidic and the alpha H of the beta-keto ester is even more acidic between 2 C=O

• beta-keto esters -> beta-keto acids -> enols -> ketos
• Easy because enol stabilizes rxn intermediate (not so for alpha but didn't go in to it in the review)
• Ester Hydrolysis: R-C=O-CH2-COO-R' (Acid + Heat) -> R-C=O-CH2-COOH
• Beta-keto-acid decarboxylation: -> R-COH=CH2 + CO2
• Tautomerism: enol (above) -> R-C=O-CH3 (Keto)

• Acetate: H3C-COO-
• Acetoacetate: H3C-C=O-CH2-COO-
• Ethylacetate: H3C-C=O-OEt abstract acidic H+ by base -> H2C=COH-OEt resonates to H2C^--C=O-OEt which reacts with ethylacetate (carbanion attacks electrophillic ester C) to displace OEt -> H3C-C=O-CH2-C=O-OEt
• You can use acetoacetic ester to make C-C bonds: H3C-C=O-CH2-C=O-OEt + R-X (R- substitutes on to CH2 in between 2 carbonyls); hydrolysis removes EtOH to make H3C-C=O-CRH-COOH; decarboxylation -> H3C-C=O-CH2-R + CO2

• Nomenclature: prefix amino- (ex. 2-amino propanoic acid) or suffix -amine (ex. propanamine)
• Stereochemistry: tertiary amines can be chiral but always racemic due to spontaneous inversions at room temp, quaternary amines stay chiral (no inversions)
• IR: primary R-NH2 = 2 N-H = 2 peaks ~3300; secondary R-NH-R' = 1 N-H = 1 peak ~3300; tertiary R3N = no N-H = no peak @ 3300

• Amine + acid (or derivative with a good leaving group) -> amide
• R-COOH + H2N-R' -> R-C=O-NH-R'

• Ar-NH2 + HONO -> Ar-N2+ + H2O + OH-
• * N's are triple bonded, + is localized near the aromatic ring due to 4th bond

• R-CH2-X + H2N-R' (+ base) -> R'-NH-R + HX
• Polyalkylation can add 2 or even 3 (making 4 bonds and a positive charge)

• Amine + Methyl iodide -> exhaustive methylation of the amine (3 Me and a positive charge) -> fully methylated amine is a good leaving group
• 2-amino butane + MeI -> 2-(N(Me)3)-butane -> 1-butene

• Basic: like to gain a proton, difficult for neutral amines to lose a proton, amides can lose a proton b/c carbonyl contributes to a resonance structure that places the negative on oxygen
• Stabilize adjacent carbocations: donates its lone pair to adjacent carbocation
• Substituents: aromatic amines with e- donating groups (e.g. -OH) are even more basic, Ar-NH2 with e- withdrawing groups (e.g. NO2 +) are less basic, steric effectscan reduce basicity because protonated amines are bigger which increases steric interactions, aromatic amines are weaker bases than aliphatic