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.

  • Cahn–Ingold–Prelog R/S Configuration Rules

    1. 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).
    2. Orient the molecule so the lowest-priority group (4) is pointing away (into the page).
    3. 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)

    1. 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.
    1. 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.
    1. 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)
    1. Nucleophile attacks C^{\delta+}.
    2. Tetrahedral alkoxide intermediate forms.
    3. 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)

    1. Hybridization of C in ethene (\ce{C2H4}) → each C forms 3 σ bonds + 1 π ⇒ sp^2.
    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.
    3. 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.