Chapter 13–16 Notes: NMR, Ethers/Epoxides/Sulfides, Organometallics, Aldehydes & Ketones

Nuclear Magnetic Resonance (NMR)

• Purpose of NMR in organic spectroscopy

  • Information about the number and types of atoms in a molecule; choice of isotope to examine.
  • Common isotopes relevant to NMR: 1H, 13C (and other nuclei not covered here). Many nuclei have spin: I = 1/2 is the focus for the slides.
  • NMR complements IR spectroscopy (which reveals bond types) by counting atoms and distinguishing environments and is particularly useful for identifying products and isomers.

• Key concepts introduced in these notes

  • Spin concepts:
  • Spin quantum number for electrons is 1/2, giving two allowed spin states: +1/2 and −1/2.
  • Nuclei with odd mass number or odd atomic number can be viewed by NMR; this course focuses on I = 1/2 isotopes.
  • External magnetic field:
  • Without an external field: spins are random.
  • With an external field: spins align with (lower energy) or against (higher energy) the field.
  • Frequency dependence on element/isotope:
  • The absorbed radiation frequency depends on the nucleus and its environment; different nuclei and isotopes absorb at different frequencies.
  • For 1H, 13C, 2H (deuterium) specific frequencies at a given field, e.g. at 7.05 T:
  • $^{1}H$: approx. 300 MHz
  • $^{2}H$: approx. 46.1 MHz
  • $^{13}C$: approx. 75.4 MHz
  • Solvent choice is important to avoid overlapping peaks in the spectrum.
  • Common solvents for 1H NMR: CDCl3, CCl4, D2O; for 13C NMR, often similarly chosen to avoid interfering signals.
  • External field strengths (examples you’ll see in NMR labs):
  • Earth’s field: ≈ 40 μT; pacemaker safety limit ≈ 0.5 mT; kitchen magnet ≈ 10 mT; MRI ≈ 1.5–3 T; research NMR ≈ 7.05–23.5 T.

• 1H and 13C NMR spectroscopy basics

  • 1H NMR:
  • Provides information on the number of signals, their integration (height/area) which corresponds to the number of equivalent hydrogens, the chemical shift (δ) which relates to the environment of each hydrogen, and splitting (coupling) which is due to attached spin-active nuclei.
  • 13C NMR:
    • Similar information about the number of signals and environment of carbons.
    • In practice, spectra are usually run with 1H decoupling, so each carbon appears as a singlet (no splitting by attached hydrogens).
    • 13C chemical shift range is broad, typically around oxed{0 ext{ to } 200 ext{ ppm}}, often spread out ~150–200 ppm for easy counting.
    • Each 13C signal can be split by attached 1H according to the n+1 rule, but decoupling removes this for routine spectra.
  • Signal interpretation basics:
  • Equivalent hydrogens: hydrogens in the same chemical environment give the same signal; their integrations add up for that signal.
  • Non-equivalent hydrogens: give distinct signals.
  • 1H NMR: Equivalent hydrogens in alkenes and stereochemistry
  • Alkenes exhibit restricted rotation about the C=C bond, leading to stereoisomerism that can affect hydrogen equivalence.
  • Testing equivalence: replace H with another atom (X) and observe whether the resulting compound remains the same; this helps determine equivalence.

• 1H NMR: Equivalent hydrogens, stereochemistry, and topicity

  • In the exam/storyline, a concept called equivalence and stereochemistry is highlighted: homotopic, enantiotopic, and diastereotopic relationships.
  • Note: In-class homework covers this topic, but it is stated that it will not be on the exam (for this course). The idea parallels the alkene test described above.

• Practical 1H NMR considerations

  • Signal counting and integration practice problems help you determine how many signals to expect and their relative proton counts.
  • Typical tasks include: given a molecule, deduce the number of signals and assign integration to each signal; assume no coincidental overlap unless specified.

• Chemical shift estimation guidelines (quick references)

  • Benzylic protons (adjacent to a benzene ring): oxed{ ext{approximately } 2.0 ext{ to } 2.5 ext{ ppm}}
  • Ketones α to C=O: oxed{ ext{approximately } 2.1 ext{ to } 2.6 ext{ ppm}}
  • Alkene vinylic protons (sp2 C–H): typically in the range of oxed{4.5 ext{ to } 6.5 ext{ ppm}} depending on substitution.
  • General aliphatic protons: 0.5–2.5 ppm depending on substitution and electronegativity of neighboring atoms.
  • For 13C NMR:
  • Carbonyl carbons (C=O): typically around 160–210 ppm depending on the functional group.
  • Sp2/sp3 carbons: ranges vary; carbonyls are downfield, aliphatic carbons upfield.

• Practice problems (summary of approach)

  • Determine the number of 1H NMR signals by identifying chemically distinct proton environments.
  • Assign signal integrations based on the number of equivalent hydrogens in each environment.
  • Use chemical shift ranges to place signals in their typical regions (e.g., carbonyls, alkenes, benzylic positions).
  • For complex splitting, consider coupling with neighboring protons (n + 1 rule) and coupling constants.

• 13C NMR spectroscopy: key differences from 1H NMR

  • 13C nuclei are far less sensitive than 1H; signals are weaker and fewer in number for a given sample.
  • 13C spectra are typically run with 1H decoupling; thus, carbon signals appear as singlets.
  • The wide chemical shift range helps in counting distinct carbons and identifying functional groups.

• Additional notes on splitting and coupling (1H NMR)

  • Signal splitting arises from coupling to nearby magnetically active nuclei; the intensity pattern follows Pascal’s Triangle for simple n+1 couplings.
  • Coupling constants (J-values) depend on the chemical environment and can be used to infer stereochemistry and dihedral angles.
  • Common coupling patterns include singlets, doublets, triplets, quartets, sextets, and more complex patterns like doublet of doublets, triplet of doublets, etc.
  • Bond rotation can influence splitting: many single bonds rotate freely with J ≈ 7 Hz; alkenes lack free rotation (Jgem ≈ 5 Hz; Jtrans ≈ 15 Hz; Jcis ≈ 10 Hz).
  • Fast exchange (e.g., O–H, N–H) can broaden or collapse splitting due to rapid proton exchange.

• 1H NMR practice (illustrative problems)

  • Problems involve matching signals (multiplicity and integration) to 2D structural fragments and assigning them to positions in the molecule.
  • Typical outputs include a mapping of signal type (singlet, doublet, triplet, quartet, etc.) to proton environments in the structure.

• 13C NMR practice (illustrative problems)

  • Similar practice to 1H NMR but focusing on counting distinct carbons and recognizing splitting patterns (although decoupled to singlets).

• Quick glossary of terms to know for NMR

  • Chemical shift (δ): position of NMR signal on the ppm scale relative to a standard.
  • Integration: area under a signal proportional to the number of nuclei giving rise to that signal.
  • Coupling constant (J): the frequency of splitting between coupled signals, measured in Hz.
  • Equivalence: hydrogens or carbons in the same chemical environment give the same signal.
  • Homotopic / enantiotopic / diastereotopic: types of equivalence relationships that affect splitting and signal count in certain contexts.

Ethers, Epoxides, and Sulfides (Chapter 11)

• Nomenclature and examples

  • Ether: generic –R–O–R′. Examples: Diethyl ether (Et2O), Ethyl methyl ether, methoxy substituted systems.
  • The term “Ether” also appears in complex systematic naming (e.g., very long chain ethers with multiple substituents).

• Physical properties

  • Boiling points and hydrogen bonding differences:
  • Ether molecules lack O–H bonds, so their hydrogen-bonding capabilities are weaker than alcohols, leading to lower boiling points.
  • Solubility in water correlates with the ability to hydrogen-bond with water.
  • Example trend: Diethyl ether has relatively lower boiling point than alcohols of similar carbon count but can have appreciable water solubility due to dipole interactions.

• Methods to make ethers

  • Williamson ether synthesis (SN2):
  • Nucleophile: alkoxide (O−) and alkyl halide (R–X).
  • Typical outcome: R–O–R′ formed; E2 side reactions are a concern with strongly basic conditions.
  • Acid-catalyzed dehydration of alcohols:
  • Can form symmetric ethers more readily;
  • Often limited for making asymmetric ethers due to competing reactions and rearrangements.
  • Substitution using two alcohols (one nucleophile, one electrophile): SN2/SN1-like processes, typically best for symmetric ethers.
  • Acid-catalyzed addition of alcohols to alkenes (hydration style):,
  • Works better for more substituted alkenes that can form stable carbocations.
  • Limitations and caveats:
  • Acid-catalyzed dehydration is poor for making asymmetric ethers.
  • E2 competition in Williamson synthesis with hindered substrates.

• Epoxides and related chemistry

  • Epoxides are three-membered cyclic ethers; they can be formed via several routes:
  • Internal SN2 of halohydrins (base-induced cyclization).
  • Oxidation of alkenes with peroxyacids (e.g., MCPBA) to form epoxides.
  • Sharpless asymmetric epoxidation
  • A catalytic system (Ti(OiPr)4) with tert-butyl hydroperoxide (tBuOOH) and chiral tartrate-derived ligands to achieve enantioselective epoxidation.
  • Demonstrates enantioselective oxygen delivery to alkenes.
  • Other methods:
  • Internal SN2 of halohydrins, oxidation routes, and asymmetric epoxidation strategies.
  • Ring opening of epoxides
  • Nucleophilic opening (base or nucleophiles): nucleophile attacks the least substituted carbon (SN2-like).
  • Acid-catalyzed opening: nucleophile attacks the more substituted carbon (more carbocation character).
  • Protecting groups—Silyl ethers
  • Protecting a hydroxyl group as a silyl ether prevents it from reacting during a transformation.
  • Common groups include OTMS (trimethylsilyl) and OTBS (tert-butyldimethylsilyl).
  • Reactivity differences arise from bulky groups; OTMS is less bulky and easier to remove; OTBS is more bulky and harder to remove.
  • Deprotection: commonly with aqueous acid or fluoride sources (e.g., TBAF, Bu4NF).

• Practical synthesis considerations

  • Ether formation strategies depend on substrate type (primary, secondary, tertiary) and desired selectivity (symmetric vs asymmetric ethers).
  • Epoxide chemistry provides routes to stereocontrolled transformations and subsequent functionalization via ring-opening reactions.

Organometallics (Chapter 15)

• Key reagent families

  • Grignard reagents: RMgBr
  • Organolithiums: RLi
  • Cuprates (Gilman reagents): R2CuLi
  • These reagents have different nucleophilicity/basicity and reactivity profiles.

• Bond character and reactivity

  • C–M bonds show varying degrees of ionic character depending on the metal:
  • Example approximate ionic character (percent): C–Li ≈ 60%, C–Mg ≈ 52%, C–Al ≈ 40%, C–Zn ≈ 36%, C–Cu ≈ 24%.
  • Nucleophilic behavior:
  • Organomagnesiums and organolithiums act as very strong bases and nucleophiles; they can be highly reactive under basic conditions.
  • Cuprates (R2CuLi) are less ionic and can behave as nucleophiles, enabling coupling-type reactions (often called cross-coupling).

• Reactivity as nucleophiles (epoxide addition and substitution)

  • Grignard reagents and organolithiums generally do not reliably perform SN2 substitutions; they are strong bases and can lead to side reactions.
  • Cuprates can participate in substitution-like couplings with certain substrates.
  • In presence of protic species (OH or NH), Grignards and organolithiums behave as very strong bases (pKa ≈ 50–60): this can cause deprotonation rather than nucleophilic substitution.
  • Cuprates are less ionic and can act as bases but behave differently than Grignards; acid-base interactions can hinder reactions.
  • Attempting acidic epoxide opening with organomettallic reagents often fails due to stability and reactivity considerations.

• Retrosynthesis and strategic use (Grignard/epoxide pairings)

  • Grignard reagents can couple with epoxides to form extended carbon frameworks; this is a useful disconnection strategy in synthesis planning.

• Dihalocarbenes and Simmons–Smith reaction

  • Dihalocarbenes (e.g., from reagents like CH2I2) can form carbenoids that transfer a CH2 unit to alkenes.
  • Simmons–Smith reaction uses CH2I2 with Zn(Cu) to generate a methylene donor for cyclopropanation of alkenes (syn-addition).
  • This is a powerful method to construct cyclopropane rings in a stereospecific manner.

• Practical notes and practice problems

  • The course includes practice problems on retrosynthesis with Grignard reagents and epoxides to form targeted products.
  • The emphasis is on planning nucleophilic additions and subsequent transformations using organometallics.

Aldehydes and Ketones (Chapter 16)

• Nomenclature and precedence rules

  • Aldehydes: suffix -al (RCHO).
  • Ketones: suffix -one (RCOR′).
  • Examples: Butanal, pentan-2-one, 3-oxobutanal, etc.
  • Common prefixes for special carbonyl-containing fragments: form-, acet-, benz-, etc. (e.g., formaldehyde form-, acetone, acetaldehyde, benzaldehyde).
  • Precedence rules: among functional groups, some have higher priority; carboxylic acids > aldehydes > ketones > alcohols > amino groups > thiols.
  • When multiple functional groups exist, the suffix/prefix chosen depends on the highest-priority group present.

• General reactivity of the carbonyl group

  • Nucleophilic addition to carbonyls proceeds via a tetrahedral intermediate and can be irreversible, equilibrium-controlled, or both depending on nucleophile and conditions.
  • Common reagents to form carbon-carbon and carbon-heteroatom bonds include Grignard reagents, organolithiums, acetylide anions, and cyanide (–CN).

• Addition of carbon nucleophiles to carbonyls

  • Nucleophiles such as Grignard reagents (CH3MgBr), organolithiums (CH3Li), alkynyl anions (e.g., CH3C≡C−), and cyanide (CN−) can attack the carbonyl carbon to form alcohols after workup.
  • The reactivity and selectivity depend on the nucleophile strength and the carbonyl compound (aldehydes vs. ketones).

• Hydride reductions: addition of hydrogen nucleophiles

  • Common hydride donors:
  • LiAlH4 (LAH): very reactive; broad reactivity; less selective.
  • NaBH4: milder; good selectivity; reduces aldehydes and ketones, generally leaves other functional groups intact.
  • All aldehydes and ketones are reduced by these reagents; other carbonyl groups (e.g., esters, carboxylic acids) respond differently or require specific conditions.

• Hydration and oxygen nucleophiles

  • Hydrate formation mechanism (acid-catalyzed): aldehydes hydrates readily in water to give geminal diols; ketones hydrate less readily.
  • General principle: hydrate formation is often under the principle of microscopic reversibility; the hydrated form can be favored in aqueous solution for aldehydes.
  • Hydrates: R–CH(OH)–OH (diol form on the carbon).
  • If water is present in aqueous solution, aldehydes can be >99.9% hydrated in some cases; ketones hydrate to a lesser extent (e.g., 0.14% in tBu cases shown).
  • Hydrates are in dynamic equilibrium with the carbonyl compound in aqueous environments.
  • Hemiacetals and acetals (oxygen nucleophiles):
  • Hydration forms hydrates; attack by alcohols leads to hemiacetals; further reaction under acid catalysis can form acetals.
  • Hydrate/acetal formation is reversible; acetals can be used as protecting groups for carbonyls.

• Alcohol nucleophiles and hemiacetals/acetals

  • In the presence of alcohols, aldehydes/ketones can form hemiacetals (one OR group and one OH on the same carbon).
  • Under acidic conditions, hemiacetals can be converted to acetals (two OR groups on the same carbon).
  • Intramolecular versions can form cyclic acetals (acetal protecting groups) more readily; basic conditions favor hemiacetal formation only.
  • Acetals serve as protecting groups for carbonyl compounds in multi-step syntheses.

• Acetals as protecting groups

  • Acetals can be used to mask carbonyls during reactions that would otherwise affect the carbonyl.
  • Cyclic acetals can be formed and later deprotected to regenerate the carbonyl
  • Practical note: selective protecting/deprotecting requires choice of conditions to avoid unwanted side reactions.

• The Wittig reaction – carbon nucleophile with a twist

  • Purpose: convert carbonyl compounds to alkenes via reaction with phosphoranes (ylides).
  • Key components:
  • Ylide: phosphorane species (e.g., Ph3P=CHR).
  • Wittig salt: the quaternary phosphonium salt precursor.
  • E/Z geometry: the reaction can produce alkenes with E or Z geometry depending on the ylide whether it is stabilized or non-stabilized.
  • Typical procedure:
  • Form ylide with strong base (e.g., n-butyllithium) to generate the phosphorane ylide.
  • React with an aldehyde or ketone to form the corresponding alkene after workup.
  • Stereochemical outcomes:
  • Non-stabilized ylides tend to give Z-alkenes.
  • Stabilized ylides (e.g., with electron-withdrawing groups) tend to give E-alkenes.

• Horner-Wadsworth-Emmons (HWE) variation

  • A variation of Wittig using phosphonate esters (P(OMe)3) that typically gives the same type of alkene as the Wittig reaction but can offer different selectivity to obtain predominantly E-alkenes with certain ylides.
  • Advantage in the lab: sometimes easier to isolate the product and tune stereochemistry.

• Addition of hydrogen nucleophiles – Hydride reductions (revisited)

  • Hydride reducing agents:
  • LiAlH4 (LAH) – strong reducer, broad scope, less selective.
  • NaBH4 – milder, more selective toward aldehydes and ketones; generally does not reduce esters, amides, or carboxylic acids without forcing conditions.

• Catalytic and selectivity considerations in carbonyl reductions

  • Metal catalysts can influence which functional groups get reduced; rhodium (Rh) catalysts may selectively hydrogenate alkenes/alkynes without touching other carbonyls, whereas other transition metals may reduce multiple functional groups.

• Summary of carbonyl chemistry implications

  • Understanding whether a carbonyl will react with a given nucleophile under specific conditions is essential for planning synthetic routes.
  • Hydrates and acetals/ hemiacetals offer protection strategies and influence the course of reactions under acidic or basic conditions.

• Pericyclic and additional methods mentioned

  • Dihalocarbene chemistry and Simmons–Smith cyclopropanation provide specialized tools for building rings and three-membered units from alkenes.
  • Carbenes in general can engage in cyclopropanation and related transformations.

• Stop point for Exam 1 (Spring 2025)

  • The slides indicate a stop for an exam review session at this point.