Chemistry Lecture #1 - Alcohols

Alcohols: Nomenclature, Acidity, and Reactions

  • Overview of the lecture focus
    • Naming and priority rules for alcohol-containing compounds
    • Physical properties: boiling point, polarity, hydrogen bonding, and solubility
    • Acidity of alcohols, conjugate bases, and qualitative ranking of acidity
    • Methods to generate alkoxides in the lab
    • Comparing substituent effects on acidity (phenol vs substituted benzaldehyde)
    • Synthesis of alcohols from various starting materials (SN2, SN1, hydroboration, oxymercuration, hydration)
    • Reduction of carbonyls to alcohols using borohydride and lithium aluminum hydride; mechanism and practical notes
    • Quick notes on oxidation states and redox references (NADH/NADPH, etc.)

Nomenclature, priority, and stereochemistry of alcohol-containing compounds

  • Start by identifying the parent chain and functional groups; example given: a molecule with a hexane chain that contains both an alkene (ene) and a hydroxy group (alcohol) substituent
    • Example interpretation: a hexene-hexanol with a six-member chain and an alkene at C5, alcohol at C3
  • Priority in IUPAC naming: alcohols are generally high-priority, higher than alkanes and alkenes
    • Functional groups with higher priority than alcohols include esters, ketones, aldehydes (and others) which will set the suffix and the lowest possible locant for the parent chain
    • In a molecule like 4-hydroxybutyric acid, the carboxylic acid sets the parent chain and must receive the lowest locant (the C=O of the carboxyl group is C1); the hydroxyl substituent at C4 is treated as a substituent if the carboxyl group is the principal functional group
    • When naming alcohols where the OH is not the principal group (e.g., para-hydroxybenzaldehyde), the OH is treated as a substituent hydroxyl group if a higher-priority group (like aldehyde) is present on the ring
  • R/S stereochemistry for a chiral center with substituents including an OH and alkene-containing side chains
    • CIP priorities for this example: 1) –OH (highest priority), 2) side with the alkene group adjacent to the stereocenter, 3) the other side of the molecule (rest of the chain), 4) the hydrogen
    • If the –OH is drawn on a wedge and the sequence 1→2→3 appears counterclockwise, that would be S if the hydrogen (priority 4) is back, but the actual orientation may require rotating or reorienting to ensure the lowest-priority group (the hydrogen) is pointing away from the viewer
    • There is a careful rule about viewing from the back (the 4th priority must be back) to determine R/S correctly; if not, you must reposition/view to get the correct stereochemical assignment
  • Quick reminder: if you’re unsure about R/S, consult resources (e.g., helpful online tools linked by instructors) to refresh the method

Common alcohols and their significance

  • Benzyl alcohol, tert-butanol, ethylene glycol, glycerol as representative examples
  • Common vs IUPAC names
    • Some common names are widely recognized (e.g., acetone, tert-butyl group), but you are not expected to memorize an exhaustive list of common names
  • Glycols (e.g., ethylene glycol) contain two hydroxyl groups and exhibit particularly high boiling points due to extensive hydrogen bonding
    • Ethylene glycol boiling point ~ 197ext°C197^ ext{°C} (very high relative to monoalcohols)
  • Alcohols can be used in foods and dihydroxy compounds (glycols) appear in various industrial and pharmaceutical contexts

Intermolecular forces, boiling points, and solubility in alcohols

  • Hydroxyl group creates a polarized O–H bond; oxygen is highly electronegative and hydrogen bonding can occur
    • Hydrogen bonding is a strong dipole-dipole interaction where H bonds to highly electronegative atoms (O, N, F)
    • These interactions are a major contributor to higher boiling points in alcohols and glycol derivatives
  • General trend in boiling points and intermolecular forces
    • Nonpolar molecules (e.g., propane) have low boiling points and are gases at room temperature due to weaker intermolecular forces
    • Dipole-dipole interactions and dispersion forces exist in most molecules; hydrogen bonding significantly strengthens intermolecular forces in alcohols
    • More OH groups (e.g., ethylene glycol has two OH groups) lead to more hydrogen-bonding opportunities and higher boiling points
  • Solubility in water and miscibility
    • Alcohols with shorter nonpolar carbon chains are highly soluble in water due to strong O–H interactions with water
    • Ethanol is infinitely miscible with water; as nonpolar carbon chains grow longer, solubility in water decreases
    • Polar region (hydrophilic, blue region on diagrams) interacts with water; longer hydrophobic regions reduce overall solubility
  • Application to biological membranes and vitamins
    • Phospholipid bilayers: polar heads interact with water, nonpolar tails interact with each other, forming a barrier between water compartments
    • Vitamins illustrate solubility trends: Vitamin C (water-soluble) is rich in hydroxyl groups; Vitamin A (fat-soluble) has fewer hydroxyls and more hydrophobic character

Acidity of alcohols: pKa, conjugate bases, and qualitative ranking

  • Alcohols are weak acids; typical pKa values range roughly from extpKaext(alcohol)<br/>ightarrow16ext–18ext{p}K_a ext{ (alcohol)} <br /> ightarrow 16 ext{–} 18; phenols are more acidic (lower pKa, around 9ext–109 ext{–}10)
  • Equilibrium in acid-base chemistry with alcohols
    • When a strong base deprotonates an alcohol, the conjugate base (alkoxide) forms and the equilibrium favors the stronger acid side
    • Example: hydronium (strong acid) vs an alcohol (weaker acid) leads to an equilibrium that lies toward the alcohol side (i.e., alkoxide formation is not strongly favored unless a stronger acid/base system is used)
  • Qualitative framework to compare acidity (five key factors)
    1) Charge at the conjugate base: more stable (less charged) conjugate bases favor the acid side; here all compared species are anions (−1), so this factor is not differentiating in the given example
    2) Atom type and polarizability (A in the PA/period concept): larger, more polarizable atoms stabilize negative charge better; polarizability often dominates when present
    3) Resonance stabilization: delocalization of charge lowers charge density and stabilizes the conjugate base; resonance structures are favored when available
    4) Induction: nearby electronegative atoms withdraw electron density and stabilize the conjugate base
    5) Orbital character (hybridization): greater s-character in the orbital holding the negative charge increases electronegativity stabilization; higher s-character generally stabilizes the conjugate base more
  • Ranking of acidity among four example molecules (based on qualitative analysis from the lecture)
    • Phenol (pKa ≈ 9.899.89) is the most acidic due to strong resonance stabilization of the phenoxide anion
    • Para-hydroxybenzaldehyde (p-hydroxybenzaldehyde) has an aldehyde substituent that withdraws electron density via resonance/induction; this makes the conjugate base more stabilized than aliphatic alcohols but less so than phenoxide (pKa ≈ 12.412.4)
    • tert-Butanol (pKa ≈ 15.515.5) is less acidic than ethanol in some contexts due to alkyl donation effects
    • Ethanol (pKa ≈ 1818) is the least acidic among the four (most basic conjugate base among them)
  • Important note on pKa scale
    • The pKa scale is logarithmic: a difference of 1 in pKa corresponds to a factor of 10 in acid strength; a difference of 2 corresponds to a factor of 100, etc. This is why small pKa differences can imply large changes in acidity
    • Relationship: extpK<em>a=−extlog</em>10(K<em>a)extandK</em>a=10−extpKaext{p}K<em>a = - ext{log}</em>{10}(K<em>a) ext{ and } K</em>a = 10^{- ext{p}K_a}
  • Practical takeaway
    • If you have numerical pKa values, rank acids by the lowest pKa (strongest acid) to the highest pKa (weakest acid)
    • If you don’t memorize exact pKa values, use qualitative factors (resonance, induction, hybridization, charge, and polarizability) to estimate relative acidity

Making alkoxides: base strength, mechanisms, and practical considerations

  • Why create alkoxides?
    • Alkoxide anions are strong bases and useful nucleophiles in synthesis; they can act as bases in deprotonation and as nucleophiles in substitution reactions
  • Common reductive bases and their byproducts
    • Sodium hydride (NaH): strong, relatively mild base; converts ROH to RO−Na+ with evolution of H2 gas, driving equilibrium forward by gas evolution
    • Amide bases (e.g., sodium amide, NaNH2): strong bases used to deprotonate alcohols and generate alkoxides; can be very potent
    • Ammonia as solvent/base in some contexts; hydrolysis and redox behavior can occur depending on conditions
    • Sodium metal can also be used to generate alkoxides via redox-type processes, releasing H2 gas
  • Practical note on equilibrium shifts
    • The evolution of hydrogen gas (H2) from NaH or Na metal removes a product and shifts the equilibrium toward alkoxide formation
  • Example equilibria
    • ROH + NaH → ROTNa + H2↑
    • ROH + NaNH2 → ROTNa + NH3 (depending on conditions)
  • Comparison of phenoxide formation
    • Phenoxide formation can be achieved with weaker bases (e.g., hydroxide) because phenols are more acidic than many alcohols; acidity of phenol enhances deprotonation efficiency

Resonance effects: phenoxide vs para-hydroxybenzaldehyde substituent effects

  • Conceptual comparison: phenol vs para-hydroxybenzaldehyde (para-hydroxy substituent with an aldehyde at the para position relative to OH)
  • Conjugate base stability and resonance
    • Phenoxide: resonance distributes negative charge over the ring, creating multiple resonance structures and stabilizing the anion
    • Para-hydroxybenzaldehyde: the aldehyde substituent is electron-withdrawing via resonance and induction; during conjugate base formation, resonance structures can extend toward the aldehyde substituent, further stabilizing the negative charge
    • Additional resonance forms can place negative charge onto the oxygen of the aldehyde substituent in certain resonance structures, indicating stronger stabilization than simple alkoxides
  • Electron-donating vs electron-withdrawing groups
    • Electron-withdrawing groups (like aldehydes in the para position) stabilize the conjugate base more than electron-donating groups (like alkyl groups)
    • The presence of an electron-withdrawing substituent tends to increase acidity of the phenolic OH group (in this case, para-hydroxybenzaldehyde is more acidic than simple phenol)
  • Takeaway: inductive and resonance effects from substituents influence acidity by stabilizing the conjugate base; resonance structures can create additional stabilization pathways

Reactions to make alcohols: from SN2, SN1, and addition to alkenes

  • Alcohol synthesis via substitution on alkyl halides
    • SN2 on primary halides with a strong base (e.g., hydroxide) yields primary alcohols
    • SN1 on secondary/tertiary halides with water as nucleophile yields secondary/tertiary alcohols via carbocation intermediate (solvolysis)
    • These methods were discussed as common lab approaches for making alcohols in Orgo I
  • Alkene routes to alcohols
    • Hydroboration-oxidation: syn-addition of borane followed by oxidation to give anti-Markovnikov alcohols (OH ends up on the less substituted carbon)
    • Oxymercuration-demercuration: addition of mercury(II) followed by demercuration to yield alcohols (anti-Markovnikov or Markovnikov depending on reagents and conditions; typically yields anti-Markovnikov alcohols with minimal rearrangement)
    • Acid-catalyzed hydration: addition of water across an alkene via carbocation formation; can undergo carbocation rearrangements; often less predictable
  • Practical note on selectivity
    • Oxymercuration is often preferred for predictable anti-Markovnikov alcohols with less rearrangement risk; hydroboration yields anti-Markovnikov products with good stereochemical outcomes
  • Epoxidation and diol formation (brief mention)
    • Epoxidation followed by opening or dihydroxylation (glycol formation) are other routes to vicinal diols; this is connected to the discussion of syn vs anti diol formation

Reduction of carbonyls to alcohols: borohydride and aluminum hydride routes

  • Core concept: carbonyl reduction is a gain of electrons (reduction) by adding hydrogen; oxidation state of carbon decreases when going from carbonyl (C=O) to alcohol (C–OH)
  • Mechanistic intuition for reductions
    • Aldehydes become primary alcohols upon reduction; ketones become secondary alcohols
    • In biological contexts, NADPH/NADH acts as a hydride donor; NADPH → NADP+ is effectively the oxidized form accompanying substrate reduction
  • Why you can’t just use a free hydride anion (H−) directly
    • Hydride anions are not good nucleophiles in typical organic solvents; they are strong bases but poor nucleophiles and would not do acid-base chemistry cleanly on carbonyls
  • Complex hydride reagents enable hydrogen transfer to carbonyls
    • Sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4) are common complex hydrides that deliver nucleophilic hydride to carbonyl carbons
    • In practice, borohydride is milder and more selective (often compatible with protic solvents like ethanol); LiAlH4 is stronger and less tolerant of proton sources, reducing a broader range of substrates (including esters and carboxylic acids under certain conditions)
  • Mechanism with borohydride (NaBH4)
    • Hydride transfer from borohydride to the carbonyl carbon forms a tetrahedral alkoxide intermediate (RO−) with the metal counterion
    • In solution, the resulting alkoxide is protonated (workup step) to yield the final alcohol
    • If the reaction is run under basic conditions, the alkoxide remains deprotonated until protonation occurs in the workup
  • Mechanism with lithium aluminum hydride (LiAlH4)
    • Similar hydride transfer mechanism, with aluminum substituting for boron; the mechanism is thermodynamically and kinetically analogous
  • Scope and limitations
    • Both NaBH4 and LiAlH4 reduce aldehydes and ketones selectively
    • They do not reduce esters and carboxylic acids under mild conditions (LiAlH4 can reduce esters under more forcing conditions; NaBH4 generally does not)
    • AlH4− reagents are highly reactive and require strictly anhydrous conditions; borohydride reagents are more forgiving in typical lab settings
  • Practical lab notes
    • Borohydride reductions can often be performed in protic solvents (e.g., ethanol) without immediate decomposition; workup provides the proton source to convert alkoxide to alcohol
    • The choice between NaBH4 and LiAlH4 depends on substrate scope and sensitivity of other functional groups in the molecule
  • Summary of key redox ideas related to biology and chemistry
    • Reduction (gain of electrons, H− delivery) lowers the oxidation state of the carbonyl carbon
    • Oxidation (loss of electrons) increases oxidation state; example: NADH oxidation to NAD+ in biochemical contexts
    • In many biological systems, hydride transfer is a central step in energy metabolism and biosynthesis

Quick synthesis and lab-oriented takeaways

  • When planning alcohol synthesis, choose the method based on desired product type, functional group tolerance, and stereochemical outcomes
  • For clean alcohol formation from alkenes, hydroboration-oxidation or oxymercuration is often preferred over direct acid-catalyzed hydration due to fewer rearrangements
  • For stable alcohols from halides, SN2 is typically used for primary halides, SN1/solvolysis for secondary/tertiary halides with water as nucleophile
  • For carbonyls to alcohols, NaBH4 is a good first choice for mild conditions; LiAlH4 is a strong alternative when more demanding reductions are needed

Connections to broader concepts and real-world relevance

  • Intermolecular forces and boiling points connect to process design: higher boiling points imply different separation strategies in industry
  • Hydrogen bonding and solubility principles explain why alcohols are useful solvents in organic synthesis and why solubility in water varies with chain length
  • The concepts of acidity, conjugate base stability, and substituent effects are foundational for understanding reaction mechanisms, selectivity, and pKa-dependent equilibria in organic chemistry
  • Redox chemistry and hydride transfer are central to metabolic pathways and industrial reductions; understanding these concepts helps connect textbook reactions to real-world chemistry (biochemistry, pharmaceuticals, materials science)

Key formulas and numerical references (LaTeX)

  • Equilibrium constant for acid-base reaction: K = rac{[products]}{[reactants]}
  • Acid strength and pKa relationship: extpK<em>a=−extlog</em>10(Ka)ext{p}K<em>a = - ext{log}</em>{10}(K_a)
  • Hydrogen-bonding considerations and boiling points relate to intermolecular forces, not a single formula, but the concept is driven by hydrogen bonding strength and dipole moments
  • Notation for conjugate bases in alcohol deprotonation: extROH+extBase<br/>ightleftharpoonsextRO−+extHB+ext{ROH} + ext{Base} <br /> ightleftharpoons ext{RO}^{-} + ext{HB}^{+}
  • Typical pKa ranges mentioned in the lecture (examples):
    • Phenol: extpKa<br/>oughly<br/>ightarrow9.0ext–10.0ext{p}K_a <br /> oughly <br /> ightarrow 9.0 ext{–} 10.0
    • Alcohols (general): extpKa<br/>oughly<br/>ightarrow16ext–18ext{p}K_a <br /> oughly <br /> ightarrow 16 ext{–} 18
    • Specific example values cited in the talk: 9.89,ext12.4,ext15.5,ext18.09.89, ext{ } 12.4, ext{ } 15.5, ext{ } 18.0 (exact assignment to each molecule follows the qualitative order described: phenol < para-hydroxybenzaldehyde < tert-butanol < ethanol in acidity)

Final takeaways

  • Alcohols exhibit distinct naming rules, hydrogen-bonding-driven properties, and acid-base behavior that are central to many organic transformations
  • The acidity trend across alcohols and substituted phenols can be rationalized by resonance, induction, and orbital effects; phenols are typically the strongest acids among the examples given
  • Alkoxides can be prepared using strong bases, with H2 evolution driving the equilibrium forward; weaker bases suffice for more acidic phenols
  • There are multiple robust, selective routes to convert alkenes and carbonyls into alcohols, each with its own stereochemical consequences and substrate scope
  • Reducing carbonyls to alcohols with NaBH4 or LiAlH4 demonstrates core redox chemistry: carbonyl carbon gains electrons (reduction) and the product is an alcohol after workup