MHS Organic Chemistry I – Structure, Bonding & Stereochemistry
Stereochemistry
Definition & Scope
- Study of the 3-D (spatial) arrangement of atoms in molecules.
- Focuses on isomers that share identical atomic connectivity but differ in orientation in space.
- Central to understanding biological activity: many enzymes & receptors are stereospecific, so two enantiomers may show drastically different pharmacology or toxicity.
Chirality & Chiral Centers
- A molecule is chiral if it is non-superimposable on its mirror image (i.e.
lacks an internal plane of symmetry). - Chiral (stereogenic) center: most commonly a sp^3 carbon bound to four different substituents.
- Example: 2-butanol (CH3–CH(OH)–CH2–CH3) → central C^* is chiral because it is attached to CH3, CH2CH3, H, and OH.
- A molecule is chiral if it is non-superimposable on its mirror image (i.e.
Cahn–Ingold–Prelog R/S Configuration Rules
- Assign priorities (1 → 4) to groups attached to the stereocenter by atomic number (higher Z = higher priority; if tie, move outward one atom at a time).
- Orient the molecule so the lowest-priority group (4) is pointing away (into the page).
- Trace the path 1 → 2 → 3:
- Clockwise → R (Latin rectus = right).
- Counter-clockwise → S (Latin sinister = left).
Classes of Stereoisomers
- Enantiomers
- Non-superimposable mirror images.
- Possess identical physical properties: T_b,
ho, IR, NMR, except for optical rotation and behavior in chiral environments. - Have **opposite R/S configuration at *every* chiral center**.
- Diastereomers
- Stereoisomers that are not mirror images and not superimposable.
- Differ at some but not all stereocenters.
- Exhibit different physical & chemical properties (e.g.
mp, bp, solubility, reactivity) → important for separations. - Meso Compounds
- Contain stereocenters yet are globally achiral due to an internal plane of symmetry or a center of inversion.
- Optically inactive ([α]_D = 0°) even though they possess chiral centers.
- Classic case: meso-tartaric acid.
Optical Activity
- Chiral molecules rotate plane-polarized light.
- Clockwise rotation → dextrorotatory (+ or d).
- Counter-clockwise → levorotatory (– or l).
- Sign of rotation does not correlate directly with R/S (empirical measurement vs.
configurational label). - Magnitude reported as specific rotation [\alpha]^{T}_{\lambda}.
Practice Problems (suggested approaches)
- 2,3-Dibromobutane
- Draw the Fischer projection; identify stereocenters → two sp^3 carbons each bearing Br, H, CH3, CH2Br.
- Note possibility of meso form if internal symmetry exists.
- Lactic acid (CH_3–CH(OH)–COOH)
- Assign priorities: OH (1) > COOH (2) > CH_3 (3) > H (4).
- Orient, trace, and label R or S.
- Tartaric acid
- Examine two stereocenters; look for internal mirror plane → naturally occurring (L)(+)-tartaric is chiral, but meso-tartaric acid is achiral.
Key Take-Away Points
- Chirality fundamentally alters molecular recognition.
- R/S system is a precise linguistic tool to describe 3-D arrangement.
- Mastery of enantiomer/diastereomer/meso distinctions is crucial for spectroscopy, synthesis, and drug design.
Carbonyl Chemistry
General Carbonyl Group
- Structure: R_2C=O (carbonyl carbon C=O bonded to two substituents).
- Polarization:
- Carbon: \delta^+ (electrophilic; lover of electrons).
- Oxygen: \delta^- (nucleophilic; electron-rich).
- Present in numerous functional groups: aldehydes, ketones, carboxylic acids, esters, amides, acid halides.
Classification & Comparative Data
- Aldehyde (RCHO) | Ketone (RCOR') | Carboxylic acid (RCOOH) | Ester (RCOOR') | Amide (RCONH_2) | Acid chloride (RCOCl).
- General trends:
- Boiling points ↑ with ability to H-bond (acids, amides).
- Reactivity (toward nucleophiles): acid chloride > aldehyde > ketone > ester ≈ acid > amide (resonance donation decreases C^{\delta+}).
Electronic Structure
- Carbonyl carbon is sp^2 hybridized → planar (~120° bond angles).
- Resonance: C=O \leftrightarrow C^+–O^- explains electrophilicity and basicity of oxygen.
Typical Carbonyl Reactions & Mechanisms
- Nucleophilic Addition (Aldehydes & Ketones)
- Nucleophile attacks C^{\delta+}.
- Tetrahedral alkoxide intermediate forms.
- Protonation yields alcohol derivative.
Aldehydes > ketones (less steric hindrance, less electron donation from alkyl groups).
Hydration
RCHO + H2O \rightleftharpoons RCH(OH)2 (gem-diol).
Acid or base catalyzed; equilibrium usually favors carbonyl except in formaldehyde & electron-withdrawing cases.
Hemiacetal & Acetal Formation
Step 1: RCHO + ROH \rightleftharpoons RCH(OH)(OR) (hemiacetal).
Step 2: RCH(OH)(OR) + ROH \xrightarrow{\text{acid}} RCH(OR)2 + H2O (acetal).
Important in carbohydrate ring closure; acetals serve as protecting groups (stable to base, cleaved by acid).
Imine (Schiff Base) Formation
RCHO + R'NH2 \rightleftharpoons RCH=NR' + H2O (acid-catalyzed).
Imine nitrogen must be substituted (not NH_3) to avoid further reaction to enamines.
Biological role: lysine side chains forming imine links with pyridoxal phosphate.
Reduction of Carbonyls
Reagents: NaBH4 (mild, selective) & LiAlH4 (strong, reacts with esters, acids).
\text{Aldehyde} \rightarrow 1^\circ alcohol; \text{Ketone} \rightarrow 2^\circ alcohol.
Oxidation
Aldehydes → carboxylic acids via Tollens' reagent (Ag^+/NH3), Jones (CrO3/H2SO4), KMnO_4.
Simple ketones are resistant; require cleavage (e.g., \ce{KMnO4}/\Delta or ozonolysis).
Aldol Reaction (Addition & Condensation)
Base deprotonates an \alpha-H to form an enolate.
Enolate nucleophilically adds to a second carbonyl → β-hydroxy carbonyl (the “aldol”).
Subsequent dehydration (heat/base or acid) gives α,β-unsaturated carbonyl (aldol condensation product).
Variants:
• Crossed aldol: one partner lacks \alpha-H (prevents self-condensation).
• Intramolecular aldol: forms 5- or 6-membered rings efficiently.
Summary Table of Key Reactions
- Hydration: carbonyl → gem-diol (acid/base).
- Acetal: aldehyde + ROH (acid) → acetal.
- Imine: aldehyde + NH_2R (acid) → imine.
- Reduction: aldehyde/ketone → alcohol (NaBH_4, LAH).
- Aldol: 2 carbonyls → β-hydroxy (base).
Foundations of Structure & Bonding
Learning Objectives
- Grasp atomic structure & electron configuration.
- Distinguish ionic, covalent, polar covalent, non-polar bonds.
- Apply hybridization (sp, sp^2, sp^3) and VSEPR to predict geometries.
Atomic Structure Refresher
- Nucleus houses protons (+) & neutrons (0); electrons (–) occupy orbitals.
- Orbitals grouped by quantum numbers: s, p, d, f.
- Valence electrons = outermost; determine bonding capability & periodic trends.
Types of Chemical Bonds & Examples
- Ionic: complete electron transfer; lattice of oppositely charged ions (e.g., \ce{NaCl}).
- Covalent: electron sharing between nuclei.
- Non-polar (equal sharing, \Delta EN \approx 0): \ce{Cl2}.
- Polar (unequal sharing, \Delta EN > 0.5): \ce{HF}.
Lewis Structures & Formal Charge
- Show all valence e^-, bonding & lone pairs.
- Octet rule: 8 e^- around main-group atoms (exceptions: \ce{H} (2 e^-), \ce{B} (6 e^-), and expanded octets for \ce{P}, \ce{S}, etc.).
- Formal charge = \text{valence} - (\text{lone} + 1/2\times \text{bonding}) → guides resonance & reactivity.
Bond Polarity & Molecular Dipole
- Electronegativity (EN): ability to attract electrons; increases across a period, decreases down a group.
- \Delta EN > 0.5 → polar bond → partial charges \delta^+/\delta^-.
- Overall molecular polarity depends on vector sum of bond dipoles and geometry (e.g., \ce{CO2} has polar bonds but is nonpolar linear molecule).
Hybridization & Geometry
- sp: 2 e-groups, linear, 180^\circ (e.g., \ce{CO2}, acetylene).
- sp^2: 3 e-groups, trigonal planar, 120^\circ (e.g., ethene, carbonyl C).
- sp^3: 4 e-groups, tetrahedral, 109.5^\circ (e.g., methane, alcohol O).
- Hybridization concept helps rationalize bond angles, lengths, and reactivity (e.g., acidity increases sp^3 < sp^2 < sp due to s-character).
Valence-Shell Electron-Pair Repulsion (VSEPR)
- Electron groups (bonds + lone pairs) arrange to minimize repulsion.
- Lone pairs repel more strongly → bent geometry in \ce{H2O} despite tetrahedral e-geometry.
Resonance Structures
- Depict possible delocalizations of π or lone-pair electrons using curved arrows.
- True molecule = resonance hybrid; individual forms do not interconvert physically.
- Resonance lowers energy, distributes charge, affects acidity/basicity.
Practice Problems (suggested reasoning)
- Hybridization of C in ethene (\ce{C2H4}) → each C forms 3 σ bonds + 1 π ⇒ sp^2.
- Lewis & resonance for \ce{NO3^-} → 3 equivalent N–O bonds; use 3 resonance forms with N=O double bond in different positions; formal charge –1 delocalized.
- Geometry of \ce{NH3} via VSEPR → 4 e-groups (3 bonds + 1 lone pair) ⇒ tetrahedral e-geometry, but molecular geometry = trigonal pyramidal (~107^\circ).
Integrated Perspective & Implications
- Bond type, polarity, hybridization, and resonance dictate molecular shape, which in turn controls physical properties (bp, solubility) and chemical reactivity (site selectivity, mechanism pathways).
- These foundation concepts underpin stereochemistry (chirality arises from sp^3 centers) and carbonyl reactivity (planar sp^2 centers enable nucleophilic attack from either face forming stereocenters).
Ethical, Philosophical, & Real-World Connections
- Drug Safety & Regulation: Thalidomide disaster underscores necessity of enantiopure pharmaceuticals; FDA now often mandates chiral purity.
- Green Chemistry: Selective reductions (NaBH_4 vs.
LAH) minimize waste/energy. - Biochemistry & Life Origin: Homochirality (L-amino acids, D-sugars) remains a central question in origins-of-life research—ties stereochemistry to cosmochemistry.
Comprehensive Summary Points
- Chirality lies at the heart of stereochemistry; R/S nomenclature precisely defines spatial arrangement.
- Carbonyl compounds are versatile electrophiles; their planar sp^2 geometry and resonance make them reactive toward nucleophiles, redox agents, and bases (enolate chemistry).
- Core bonding models (hybridization, VSEPR, resonance) provide predictive power for shapes and reactivity patterns across all organic families.
- Mastery of these topics forms the conceptual scaffold for advanced mechanisms (e.g., Claisen, Michael, Robinson annulation) and for interpreting spectroscopic data.