Organic Chemistry: Substitution, Elimination, Alkenes, Alkynes, and Alcohols

Comprehensive review flashcards covering nucleophilic substitution (SN1/SN2), beta-elimination (E1/E2), alkene synthesis and reactions, alkyne transformations, and alcohol/ether chemistry, based on lecture notes and exam material.

How is nucleophile strength generally classified between anionic and uncharged nucleophiles?

Anionic nucleophiles are generally better electron donors than uncharged nucleophiles and are classified as strong nucleophiles. Neutral molecules like water ($H_2O$) and alcohols ($ROH$) are weak nucleophiles, while amines, sulfides, and phosphines are moderate nucleophiles.

Which halides are classified as good leaving groups in nucleophilic substitution, and why?

$Cl^-$, $Br^-$, and $I^-$ are good leaving groups because they are the most stable conjugate bases of strong acids. Poor leaving groups include less stable anions of weaker acids such as $F^-$ and $HO^-$.

What is the rate law equation and kinetic order for an $S_N2$ reaction?

An $S_N2$ reaction exhibits second-order kinetics, described by the rate equation $\text{Rate} = k [\text{Substrate}][Nu]$ (for example, $\text{Rate} = k [CH_3Br][HO^-]$).

Why are polar aprotic solvents preferred over protic solvents for $S_N2$ reactions?

Protic solvents form hydrogen bonds with anionic nucleophiles, encasing them and lowering their reactivity. Polar aprotic solvents (such as acetone, $DMSO$, acetonitrile, and $DMF$) dissolve salts without forming hydrogen bonds to nucleophiles, leaving them unshielded and highly reactive.

How does steric hindrance in the haloalkane substrate affect the relative rate of an $S_N2$ reaction?

Steric hindrance decreases access to the electrophilic carbon. The relative rate order is $H_3CX\text{ (methyl)} > RH_2CX\text{ (}1^\circ\text{ alkyl)} > R_2HCX\text{ (}2^\circ\text{ alkyl)}$. In $3^\circ$ haloalkanes ($R_3CX$), access is completely blocked, making $S_N2$ impossible.

What stereochemical change occurs at a chiral center during an $S_N2$ substitution?

An inversion of configuration occurs because the nucleophile attacks the electrophilic carbon from the backside opposite to the leaving group, converting an $(R)$ configuration to an $(S)$ configuration, or vice versa.

What is the rate-determining step and rate equation of an $S_N1$ reaction?

The rate-determining step is the slow, unimolecular cleavage of the $C-X$ bond to form a carbocation intermediate ($R^+$). The rate depends only on substrate concentration: $\text{Rate} = k [\text{substrate}]$ (e.g., $\text{Rate} = k [t\text{-}BuBr]$).

What is the order of relative stability of alkyl carbocations, and why?

$3^\circ > 2^\circ > 1^\circ > \text{methyl}$. Stability increases with the number of attached alkyl groups due to their electron-donating inductive effect stabilizing the empty $p$ orbital of the $sp^2$-hybridized carbocation center.

Which types of carbocations exhibit the highest stability beyond simple alkyl substitution?

Carbocations with resonance stabilization exhibit the highest stability: allylic carbocations, benzylic carbocations, and structures stabilized by lone pairs of adjacent heteroatoms (such as a protonated carbonyl).

What are 1,2-hydride and 1,2-alkyl shifts in carbocation intermediates?

They are intramolecular rearrangements where a less stable carbocation converts to a more stable carbocation. In a 1,2-hydride shift, a hydrogen atom with its pair of electrons ($H:^-$) migrates to the adjacent carbocationic center. In a 1,2-alkyl shift, an alkyl group migrates with its electron pair.

What stereochemical outcome is expected for an $S_N1$ reaction at an asymmetric stereocenter, and why?

Racemization occurs. The intermediate carbocation adopts a planar trigonal geometry ($sp^2$), allowing the nucleophile an equal probability of attacking from either face, yielding an equimolar pair of enantiomers (a racemic mixture).

What stereoelectronic arrangement is strictly required for an $E2$ elimination mechanism?

An anti-coplanar arrangement of the $H-C-C-X$ system is required, meaning the $\beta$-hydrogen and the leaving group $X$ must reside in the same plane on opposite sides ($180^\circ$ dihedral angle) to allow proper orbital overlap during the concerted elimination.

What is Zaitsev's rule in $\beta$-elimination reactions?

Formulated in 1875 by Aleksander Zaitsev, it states that the major product in the $\beta$-elimination of a haloalkane is the more highly substituted alkene, which possesses higher thermodynamic stability.

Why does an $E2$ reaction of a secondary haloalkane with sodium ethoxide ($EtONa$) yield the Zaitsev product, while potassium tert-butoxide ($t\text{-}BuOK$) or $NaOC(C_2H_5)_3$ favors the less substituted alkene?

Small, strong bases like $EtONa$ or $NaOCH_3$ can access more hindered secondary hydrogens to yield the thermodynamically more stable, more substituted alkene. Bulky, sterically hindered bases preferentially abstract the more accessible, less sterically hindered primary ($1^\circ$) hydrogen at the $\beta'$ position.

How does the unimolecular $E1$ mechanism proceed and how is its rate expressed?

The $E1$ mechanism begins with the slow, rate-determining loss of the leaving group to form a carbocation intermediate (identical to $S_N1$), followed by fast proton removal by a weak base/solvent from the $\beta$-carbon. The rate law is first order: $\text{Rate} = k [\text{substrate}]$.

How do the IUPAC $(E)$ and $(Z)$ stereochemical descriptors differ in alkenes?

Using the Cahn-Ingold-Prelog priority rules at each $sp^2$ carbon: if the two higher-priority groups are located on the same side of the double bond, the configuration is $(Z)$ (from zusammen); if they are on opposite sides, the configuration is $(E)$ (from entgegen).

What are the IUPAC formulas and names for the three common alkenyl substituent groups: methylene, vinyl, and allyl?

Methylene is $H_2C=$, vinyl is $H_2C=CH-$, and allyl is $H_2C=CH-CH_2-$.

What is Markovnikov's rule for electrophilic addition of hydrogen halides ($HX$) to unsymmetrical alkenes?

Published by Vladimir Markovnikov in 1870, it states that addition of an acid $HX$ to an unsymmetrical alkene adds the hydrogen to the double-bond carbon already bearing more hydrogen atoms, and the halogen $X$ to the carbon bearing fewer hydrogens (proceeding via the more stable carbocation).

What intermediate explains the anti stereoselectivity observed in the addition of $Cl_2$ or $Br_2$ to alkenes?

A cyclic halonium ion intermediate (chloronium or bromonium ion). In the second step, the halide counter-ion performs a backside nucleophilic attack ($S_N2$-like) on the three-membered ring, resulting in anti addition.

What is a halohydrin, and what governs its regiochemical formation from an unsymmetrical alkene?

A halohydrin is a 1,2-haloalcohol formed by reacting an alkene with halogen ($X_2$) in water. Water acts as the nucleophile in the second step, selectively attacking the more substituted carbon of the cyclic halonium ion because that carbon holds greater partial positive charge.

What are the regiochemical and stereochemical outcomes of the hydroboration-oxidation of alkenes?

Hydroboration-oxidation gives anti-Markovnikov regiochemistry (the $-OH$ group attaches to the less substituted carbon) and syn stereoselectivity, as the boron and hydrogen add simultaneously to the same face of the double bond.

For what development did Herbert C. Brown receive the Nobel Prize in Chemistry in 1979?

Herbert C. Brown was awarded the 1979 Nobel Prize in Chemistry for developing the use of boron- and phosphorus-containing compounds into important reagents in organic synthesis, including hydroboration reactions.

What reagent and stereochemical pathway are involved in the syn-dihydroxylation of alkenes to form 1,2-diols (glycols)?

Osmium tetroxide ($OsO_4$), followed by reduction with aqueous sodium bisulfite ($NaHSO_3, H_2O$). It proceeds via a cyclic osmate intermediate, ensuring syn stereoselective addition to yield a cis-1,2-diol.

How do peroxycarboxylic acids ($RCO_3H$) react with alkenes, and what is the stereochemical feature of the oxirane ring formed?

Peroxycarboxylic acids (such as peracetic acid or $mCPBA$) transfer an oxygen atom to the alkene in a concerted syn addition, producing epoxides (oxiranes) that retain the relative stereochemical configuration of the starting alkene.

What sequence of reagents is used for the ozonolysis of alkenes, and what intermediate stages occur?

Treatment with ozone ($O_3$) at low temperature forms an initial molozonide that rearranges to an ozonide. Reductive workup with zinc and water ($Zn, H_2O$) or dimethyl sulfide ($(CH_3)_2S$) cleaves the ozonide into carbonyl compounds (aldehydes and/or ketones).

What relationship exists between the heat of hydrogenation and alkene thermodynamic stability?

A lower (less exothermic) heat of hydrogenation indicates higher thermodynamic stability. More substituted alkenes release less heat upon catalytic hydrogenation, proving they are thermodynamically more stable than less substituted double bonds; trans alkenes are more stable than isomeric cis alkenes.

Why is N-bromosuccinimide ($NBS$) used in allylic brominations instead of elemental molecular bromine ($Br_2$)?

$Br_2$ in high concentration undergoes competing electrophilic addition to double bonds and is toxic. Solid $NBS$ in the presence of light or heat maintains a constant, very low concentration of $Br_2$ and bromine radicals ($Br\cdot$), promoting clean radical allylic substitution.

What causes the addition of $HBr$ to an alkene in the presence of peroxides ($ROOR$) to produce an anti-Markovnikov bromoalkane?

The reaction shifts to a radical chain mechanism. Alkoxy radicals ($RO\cdot$) generate a bromine radical ($Br\cdot$), which adds to the double bond to generate the more stable, more highly substituted alkyl radical intermediate, placing $Br$ on the less substituted carbon.

Why are terminal alkynes significantly more acidic ($pK_a \approx 25$) than internal alkynes or alkanes ($pK_a \approx 50\text{--}60$)?

The terminal alkyne hydrogen is attached to an $sp$-hybridized carbon ($50\%$ $s$-character). The higher $s$-character holds electron density closer to the carbon nucleus, strongly stabilizing the resulting carbanion (acetylide anion).

Why does attempting to synthesize 2,2-dimethyl-3-hexyne by reacting 1-butynyl anion with 2-bromo-2-methylpropane fail?

2-Bromo-2-methylpropane is a tertiary ($3^\circ$) haloalkane. The alkynyl anion acts as a strong base rather than a nucleophile because backside attack in an $S_N2$ pathway is completely blocked by steric hindrance, resulting in $E2$ elimination instead.

What are the product differences when hydrating a terminal alkyne via acid catalysis ($H_2SO_4, HgSO_4$) versus hydroboration-oxidation ($BH_3\cdot THF$, then $H_2O_2, NaOH$)?

Acid-catalyzed hydration follows Markovnikov's rule to give an enol that tautomerizes into a methyl ketone. Hydroboration-oxidation gives anti-Markovnikov addition of water, yielding an enol that tautomerizes into an aldehyde.

How can an internal alkyne be selectively reduced to an $(E)$-alkene versus a $(Z)$-alkene?

Reduction with sodium metal in liquid ammonia ($Na, NH_3\text{ (liq)}$) gives the $(E)$-alkene (trans) via anti stereoselectivity. Hydrogenation with molecular hydrogen ($H_2$) over a poisoned Lindlar catalyst gives the $(Z)$-alkene (cis) via syn stereoselectivity.

What do the open arrows ($\Rightarrow$) designate in a retrosynthetic scheme?

An open arrow indicates a retrosynthetic transform, moving backwards from the target molecule on the left toward the preceding precursors or commercially available starting materials on the right.

What order of boiling points is observed among hexane, 1-pentanol, 1,2-butanediol, and 1,2,3-propanetriol, and why?

$\text{hexane } (68\,^\circ\text{C}) < 1\text{-pentanol } (138\,^\circ\text{C}) < 1,2\text{-butanediol } (195\,^\circ\text{C}) < 1,2,3\text{-propanetriol } (290\,^\circ\text{C})$. While their molecular weights are comparable, each additional hydroxyl group introduces more intermolecular hydrogen bonding, significantly raising the boiling point.

What is the Williamson ether synthesis, and which substrates yield the best results?

It is an $S_N2$ reaction between a metal alkoxide ($RO^-Na^+$) and a primary haloalkane ($R'CH_2X$) or halomethane ($CH_3X$) to produce an unsymmetrical or symmetrical ether ($ROR'$). Secondary and tertiary haloalkanes fail because they undergo $E2$ elimination.

How does the stereochemical outcome of converting a chiral alcohol to an alkyl tosylate compare to its subsequent reaction with a nucleophile?

Formation of an alkyl tosylate ($ROTs$) from an alcohol and $TsCl$ in pyridine occurs with retention of configuration because the $C-O$ bond is not broken. Subsequent nucleophilic attack on the tosylate proceeds by an $S_N2$ mechanism with inversion of configuration.

What functional group is formed when a primary alcohol is oxidized by pyridinium chlorochromate ($PCC$) or $IBX$ versus chromic acid ($H_2CrO_4$)?

Mild oxidants like $PCC$ or $IBX$ oxidize primary alcohols selectively to aldehydes. Strong oxidants like chromic acid ($H_2CrO_4$), $CrO_3$, or $KMnO_4$ oxidize primary alcohols directly to carboxylic acids.

Why can tertiary ($3^\circ$) alcohols not be oxidized under typical chromic acid or $IBX$ conditions?

Tertiary alcohols lack an $\alpha$-hydrogen atom on the carbon bearing the hydroxyl group, which is required for base elimination of the reduced metal/oxidant byproduct in the second step of the oxidation mechanism.

What is the correct IUPAC name and stereochemical configuration for Question 1 of Midterm Exam 2?

$(2R,3R)\text{-2-bromo-3-chlorobutane}$.

What are the conjugate base structures and relative acidities of p-toluenesulfonic acid ($TsOH$) and methanethiol ($CH_3SH$)?

$TsOH$ is a strong sulfonic acid with $pK_a \approx -3$ whose conjugate base is the highly stabilized tosylate anion ($TsO^-$). Methanethiol ($CH_3SH$) is a sulfur alcohol analogue with $pK_a \approx 10$, making it substantially more acidic than typical alcohols ($pK_a \approx 16\text{--}18$).