Organic Chemistry: Stereochemistry & Spectroscopy

A chiral molecule is non-superimposable on its mirror image. A CHIRAL CENTER (stereocenter) is typically a carbon with FOUR DIFFERENT substituents (sp³, tetrahedral geometry). To identify: check each sp³ carbon — does it have 4 different groups? If yes, it’s a stereocenter. A molecule can be chiral without a stereocenter (e.g., allenes, biaryls) but this is less common.

Step 1: Assign PRIORITY to the 4 substituents by atomic number (higher atomic number = higher priority). Rank 1 (highest) to 4 (lowest). Step 2: If tied at first atom, go outward to the next atom of difference (first point of difference wins). Step 3: Orient the molecule so priority #4 points AWAY from you (into the page). Step 4: Trace a path from 1→2→3. CLOCKWISE = R (rectus). COUNTERCLOCKWISE = S (sinister). Tie-breakers: Double bond = two single bonds to that atom (phantom duplicate atoms).

By atomic number: I(53) > Br(35) > Cl(17) > S(16) > O(8) > N(7) > C(6) > H(1). Common group priorities (high to low): –I > –Br > –Cl > –OH > –NH₂ > –COOH > –CHO > –CH₂OH > –C₆H₅ > –C≡CH > –CH=CH₂ > –CH₂CH₃ > –CH₃ > –H Multiple bonds: C=O counts as C bonded to O,O (two phantom O atoms). C≡C counts as C bonded to C,C,C.

Enantiomers: Non-superimposable mirror images. They have OPPOSITE R/S configurations at ALL stereocenters. SAME properties: melting point, boiling point, solubility, Rf value, IR spectrum, NMR spectrum, density — identical in achiral environments. DIFFERENT properties: Optical rotation (equal magnitude, opposite sign: one is +, other is –), behavior with chiral reagents/enzymes/receptors, and retention time on chiral HPLC columns.

Optical activity: The ability of chiral compounds to rotate plane-polarized light. Measured with a polarimeter. Dextrorotatory (+) or (d): Rotates light clockwise. Levorotatory (–) or (l): Rotates light counterclockwise. Specific rotation: [α]_D = α/(c × l) where α = observed rotation (degrees), c = concentration (g/mL), l = path length (dm). IMPORTANT: (+)/(–) designation has NO correlation to R/S configuration. Must be determined experimentally.

Diastereomers: Stereoisomers that are NOT mirror images. They have the same connectivity but differ in configuration at ONE OR MORE (but not all) stereocenters. Properties: DIFFERENT melting point, boiling point, solubility, Rf, NMR, specific rotation — they are different compounds with different physical and chemical properties. Examples: cis/trans isomers, (2R,3R) vs (2R,3S) tartaric acid. Maximum stereoisomers for n stereocenters = 2ⁿ (but may be fewer if meso forms exist).

A meso compound has chiral centers but is ACHIRAL overall because it possesses an INTERNAL MIRROR PLANE (plane of symmetry). Identification: Look for a molecule with 2+ stereocenters where one half is the mirror image of the other half. The stereocenters have opposite configurations (one R, one S) that cancel out. Example: (2R,3S)-tartaric acid — has two chiral centers but an internal mirror plane → achiral, optically inactive. Meso compounds are NOT optically active (specific rotation = 0). They reduce the expected 2ⁿ stereoisomers.

A racemic mixture (racemate, ±, dl, or rac): A 50:50 mixture of two enantiomers. Properties: - Optically INACTIVE (rotations cancel: [α] = 0) - May have different melting point than pure enantiomer (racemic crystals pack differently) - Labeled as (±) or rac- Resolution: Separating a racemic mixture into pure enantiomers. Methods: chiral HPLC, diastereomeric salt formation, enzymatic resolution.

Convention: Carbon chain is drawn vertically with C1 (most oxidized carbon) at TOP. - HORIZONTAL lines = bonds coming TOWARD you (out of page, wedges) - VERTICAL lines = bonds going AWAY from you (into page, dashes) Rules for manipulation: 1. Can rotate 180° in the plane (still same molecule) 2. CANNOT rotate 90° (changes configuration!) 3. Can swap any two groups — one swap = enantiomer, two swaps = same molecule To determine R/S: If lowest priority group is on a vertical line (going back), read 1→2→3 directly. If on horizontal (coming forward), the answer is OPPOSITE of what you read.

View the molecule along a C–C bond axis. Front carbon = dot (intersection of 3 bonds). Back carbon = circle. - STAGGERED conformations: Bonds on front and back are offset (60° dihedral). Lower energy. - ECLIPSED conformations: Bonds align (0° dihedral). Higher energy (torsional strain). For butane along C2–C3: - ANTI: Two largest groups (methyls) are 180° apart. LOWEST energy staggered conformation. - GAUCHE: Two largest groups are 60° apart. Higher energy than anti by ~0.9 kcal/mol (steric strain) but still staggered. - Eclipsed: Highest energy. Totally eclipsed (methyls at 0°) is the global maximum.

1. TORSIONAL STRAIN (Pitzer strain): Resistance to bond eclipsing. Results from electron repulsion in eclipsed bonds. Even H/H eclipsing costs ~1 kcal/mol. 2. STERIC STRAIN (van der Waals strain): Repulsion between electron clouds of bulky groups that are too close. Gauche butane interaction ≈ 0.9 kcal/mol. 3. ANGLE STRAIN (Baeyer strain): Deviation from ideal bond angles (109.5° for sp³). Significant in small rings: cyclopropane (60°, very strained), cyclobutane (90°, strained), cyclopentane (108°, nearly ideal).

Cyclohexane adopts a chair conformation to minimize strain (all angles ≈ 111°, all H’s staggered). Each carbon has one AXIAL position (pointing straight up or down, parallel to ring axis) and one EQUATORIAL position (pointing outward, roughly in the plane). Alternating pattern: If one carbon has axial-up, the adjacent carbon has axial-down. 6 axial + 6 equatorial = 12 total H positions. Ring flip: Converts all axial to equatorial and vice versa. Axial-up becomes equatorial-down and vice versa.

1,3-Diaxial interactions: Steric repulsion between an AXIAL substituent and the two axial hydrogens (or groups) on the same face of the ring, located on C3 and C5 (1,3-relationship). Analogous to gauche interactions in Newman projections. Equatorial preference: Equatorial substituents point outward and avoid these 1,3-diaxial interactions. Larger groups have stronger equatorial preference: - –CH₃: 1.7 kcal/mol (equatorial favored) - –CH₂CH₃: 1.8 kcal/mol - –C(CH₃)₃ (t-butyl): 4.9 kcal/mol (essentially locks the ring) - –OH: 0.9 kcal/mol - –F: 0.3 kcal/mol

1. Draw both chair conformations (ring flip interconverts them). 2. Place substituents: In one chair, determine if each is axial or equatorial. 3. Ring flip: Axial becomes equatorial and vice versa. 4. The MORE STABLE chair has the LARGER group EQUATORIAL. 5. If both groups are on the same carbon: gem-disubstituted. 6. Trans-1,2: one axial + one equatorial in BOTH chairs (diequatorial exists in one chair). 7. Cis-1,2: both axial or both equatorial. Remember: cis = same side of ring plane, trans = opposite sides.

The boat conformation is an alternative non-planar conformation of cyclohexane. It is ~7 kcal/mol HIGHER in energy than the chair due to: 1. FLAGPOLE interactions: H’s on C1 and C4 point inward and clash sterically (like the bow and stern of a boat). 2. ECLIPSING strain: 4 pairs of eclipsed C–H bonds along the sides. The twist-boat is slightly more stable than the true boat (~1.5 kcal/mol lower) because it partially relieves flagpole and eclipsing interactions. The chair is still the most stable by far.

Step 1: For each carbon of the C=C, identify the two substituents and assign CIP priorities (higher atomic number = higher priority). Step 2: Compare the positions of the HIGHER-priority group on each carbon: - Z (zusammen, ‘together’): Higher-priority groups on the SAME side of the double bond. - E (entgegen, ‘opposite’): Higher-priority groups on OPPOSITE sides. Cis/trans only works for 2 groups total; E/Z works for ALL alkenes (even tri- and tetrasubstituted).

cis/trans and Z/E can disagree when priority assignments differ from visual ‘same side’ assessment. Example: 1-bromo-2-chloroethene. Br and Cl on the same side = cis visually, but CIP priority: on C1, Br > H; on C2, Cl > H. Both higher-priority groups (Br and Cl) are on the same side → Z. Here cis = Z. BUT: In (Z)-1-bromo-1-chloro-2-methylpropene, visual ‘cis’ may not match Z if you track the wrong groups. ALWAYS use CIP priorities, not visual intuition.

O–H (alcohol): 3200–3600 cm⁻¹, BROAD O–H (carboxylic acid): 2500–3300 cm⁻¹, VERY BROAD (overlaps C–H region) N–H (amine): 3300–3500 cm⁻¹, MEDIUM (1° amine: 2 peaks, 2° amine: 1 peak) C–H (sp³): 2850–3000 cm⁻¹ C–H (sp²): 3000–3100 cm⁻¹ C–H (sp, alkyne): ~3300 cm⁻¹, SHARP C≡N (nitrile): ~2200 cm⁻¹, SHARP C≡C (alkyne): ~2150 cm⁻¹, SHARP (may be absent if internal & symmetric) C=O (carbonyl): ~1700 cm⁻¹, STRONG and SHARP (most diagnostic peak in IR) C=C (alkene): ~1650 cm⁻¹, MEDIUM

C=O stretch position varies by functional group: - Acid chloride: ~1800 cm⁻¹ - Acid anhydride: ~1800 and ~1750 cm⁻¹ (TWO C=O peaks!) - Ester: ~1735–1750 cm⁻¹ - Aldehyde: ~1720–1740 cm⁻¹ (also has 2 C–H stretches at 2720 and 2820 cm⁻¹ — Fermi resonance doublet) - Ketone: ~1705–1720 cm⁻¹ - Carboxylic acid: ~1710 cm⁻¹ (plus very broad O–H) - Amide: ~1630–1690 cm⁻¹ (lower due to strong N resonance donation) Conjugation LOWERS the C=O frequency. Ring strain RAISES it.

ALCOHOL: Broad O–H stretch at 3200–3600 cm⁻¹. NO carbonyl peak near 1700 cm⁻¹. CARBOXYLIC ACID: VERY broad O–H stretch from 2500–3300 cm⁻¹ (so broad it overlaps C–H region — distinctive ‘haystack’ shape). PLUS strong C=O at ~1710 cm⁻¹. AMINE: N–H stretch at 3300–3500 cm⁻¹. 1° amine shows TWO peaks (symmetric and asymmetric N–H stretch). 2° amine shows ONE peak. 3° amine shows NO N–H peak. Also look for C–N stretch at 1020–1250 cm⁻¹.

¹H NMR provides 4 types of information: 1. CHEMICAL SHIFT (δ, ppm): Position of signal — indicates electronic environment (shielded vs deshielded). 2. INTEGRATION: Area under peak — proportional to NUMBER of H’s giving that signal. 3. SPLITTING PATTERN: Multiplicity (n+1 rule) — tells you how many H’s are on adjacent carbons. 4. NUMBER OF SIGNALS: Tells you how many chemically distinct types of H’s exist. Equivalent protons give ONE signal. Symmetry reduces the number of signals.

TMS (reference): 0.0 ppm Alkyl (R–CH₃, R₂CH₂): 0.8–1.5 ppm Allylic (C=C–CH): 1.5–2.5 ppm α to C=O (O=C–CH): 2.0–2.5 ppm N–CH: 2.2–2.9 ppm O–CH (ether, alcohol): 3.3–4.0 ppm Vinylic (C=C–H): 4.5–6.5 ppm Aromatic (Ar–H): 6.5–8.0 ppm Aldehyde (RCHO): 9.0–10.0 ppm Carboxylic acid (RCOOH): 10–12 ppm (broad, exchangeable) Alcohol (R–OH): 1–5 ppm (variable, exchangeable, often broad) Amine (R–NH): 0.5–3 ppm (variable, exchangeable)

The n+1 rule: A proton with n equivalent neighboring protons (on adjacent carbons) is split into (n+1) peaks. Multiplicities: 0 neighbors → singlet (s) 1 neighbor → doublet (d) 2 neighbors → triplet (t) 3 neighbors → quartet (q) 4 neighbors → quintet 5 neighbors → sextet 6 neighbors → septet (heptet) Intensity ratios follow Pascal’s triangle (e.g., triplet = 1:2:1, quartet = 1:3:3:1). Protons split EACH OTHER (coupling is mutual). Equivalent protons do NOT split each other. OH and NH protons usually appear as broad singlets (rapid exchange).

Coupling constant (J): The distance in Hz between peaks in a multiplet. Mutually coupled protons have the SAME J value. Typical J values: - Geminal (2-bond, ²J): 0–12 Hz - Vicinal (3-bond, ³J): 6–8 Hz (typical), depends on dihedral angle (Karplus equation) - Trans-alkene: ³J = 12–18 Hz - Cis-alkene: ³J = 6–12 Hz - Aromatic (ortho): ³J = 6–10 Hz - Long-range (4+ bonds): Usually 0–3 Hz J values help distinguish cis vs trans alkenes and confirm connectivity.

ALDEHYDE: Signal at δ 9.0–10.0 ppm (distinctive downfield singlet or doublet if α-H present). Only 1H. CARBOXYLIC ACID: Very broad signal at δ 10–12 ppm (exchangeable, disappears with D₂O shake). AROMATIC: Signals at δ 6.5–8.0 ppm. Integration indicates number of aromatic H’s. Monosubstituted benzene: 5 ArH. Para-disubstituted: 4 ArH showing characteristic two doublets (AA’BB’ pattern).

D₂O shake: Add D₂O to the NMR sample. Exchangeable protons (O–H, N–H, S–H) are replaced by deuterium (D). Since deuterium is NMR-invisible in a ¹H experiment, those peaks DISAPPEAR from the spectrum. Use: Confirms which peaks are from OH, NH, or COOH groups. If a peak disappears after D₂O shake, it’s an exchangeable proton. This helps distinguish between overlapping peaks in the 1–5 ppm region (where OH can appear).

1. MOLECULAR ION (M⁺): The highest significant m/z peak = molecular weight of the compound. Also called the parent ion. 2. BASE PEAK: The tallest (most abundant) peak in the spectrum. Not necessarily M⁺. 3. FRAGMENTATION PATTERN: How the molecule breaks apart → reveals structural information. 4. NITROGEN RULE: Odd molecular weight → odd number of nitrogen atoms. Even MW → zero or even number of N. 5. Isotope patterns: Br (M and M+2 in ~1:1 ratio), Cl (M and M+2 in ~3:1 ratio) are diagnostic.

Common fragmentations (loss of fragments from M⁺): - Loss of 15 → loss of CH₃ (methyl) - Loss of 17 → loss of OH - Loss of 18 → loss of H₂O (alcohols) - Loss of 28 → loss of CO (aldehydes, ketones) or C₂H₄ (ethylene) - Loss of 29 → loss of CHO (aldehyde) or C₂H₅ - Loss of 31 → loss of OCH₃ (methyl ester/methyl ether) - Loss of 45 → loss of OC₂H₅ (ethyl ester) - McLafferty rearrangement: Carbonyls with a γ-hydrogen → loss of alkene, gives m/z = enol fragment. α-Cleavage next to carbonyl is very common in ketones and aldehydes.

NITROGEN RULE: Organic compounds with an ODD molecular weight contain an ODD number of nitrogen atoms (1, 3, 5...). Even MW → 0 or even number of N. Reason: N has odd valence (3) and even atomic weight (14). ISOTOPE PATTERNS: - Bromine: M and M+2 peaks in approximately 1:1 ratio (⁹Br and ⁸¹Br are nearly equal abundance). - Chlorine: M and M+2 peaks in approximately 3:1 ratio (³⁵Cl:³⁷Cl = 3:1). - Two Br atoms: M, M+2, M+4 in 1:2:1 ratio. - Sulfur: Small M+2 peak (~4% of M) from ³⁴S. No significant M+2 → no Cl, Br, or S.

Systematic approach: 1. MS: Determine molecular weight (M⁺) and molecular formula. Apply nitrogen rule. Check isotope patterns for Cl/Br. 2. Calculate DEGREES OF UNSATURATION from molecular formula. 3. IR: Identify functional groups. Key peaks: broad OH (3200–3600), C=O (1700), N–H (3300–3500), C≡N (2200), very broad COOH (2500–3300). 4. ¹H NMR: Count types of H (number of signals). Integration → number of H per signal. Chemical shifts → identify functional groups. Splitting → connectivity (n+1 rule). 5. ¹³C NMR (if available): Number of unique carbons. DEPT to identify CH₃, CH₂, CH, quaternary C. 6. Propose a structure consistent with ALL data. Verify by checking that every spectral feature matches.