SELECTIVITY IN ORGANIC CHEMISTRY

Stereospecific Β· Stereoselective Β· Regiospecific Β· Regioselective Β· Chemoselective

A Β· Definitions B Β· Stereospecific C Β· Stereoselective D Β· Regiospecific E Β· Regioselective F Β· Chemoselective G Β· Comparison H Β· Quick Table
Β§A Β· Master Definitions β€” The Core Distinctions
The Central Question:
When a reaction can give more than one product, what controls which product forms β€” and how much of it?

STEREO = about the 3-D arrangement of atoms (which face, which configuration, cis or trans)
REGIO = about which atom of the substrate is attacked (which position, C-1 vs C-2, etc.)
CHEMO = about which functional group reacts when more than one is present in the molecule

πŸ”΄ STEREOSPECIFIC

One reactant (stereoisomer) --> One Product (Stereoisomer)
Different stereoisomers of the starting material give different stereoisomeric products.

Example landmark: SNβ‚‚ always inverts. No matter what you do, (R) β†’ (S). That is stereospecific.

🟠 STEREOSELECTIVE

One reactant (stereoisomer) --> One Major Product (Stereoisomer) (Out of Two.)
A reaction where one stereoisomeric product forms preferentially over another, but both are possible.

Here kinetics or thermodynamics favours one face or configuration.

A yield of 90% one diastereomer is still stereoselective even if 10% of the other forms.

Example: NaBHβ‚„ reduction of a cyclic ketone gives mainly equatorial alcohol (less hindered face, ~85:15).

πŸ”΅ REGIOSPECIFIC

A reaction where the regiochemical outcome is completely determined by the mechanism β€” only one constitutional isomer is possible from a given mechanism.

Both substrates (or conditions) give different, but each completely one, constitutional isomers.

Example: HBr addition to propene via free radical gives 100% 1-bromopropane (anti-Markovnikov). No Markovnikov product is formed under those conditions.

🟣 REGIOSELECTIVE

A reaction that can give two or more constitutional isomers, but one regioisomer forms predominantly.

The major product is governed by electronic or steric preference, not mechanistic necessity.

Example: Electrophilic addition of HBr to 2-methylpropene gives mainly (CH₃)β‚‚CHBr (tertiary). Both positions can react but tertiary is strongly preferred.

🟒 CHEMOSELECTIVE

A reaction that is selective for one functional group over another within the same molecule (or reaction mixture).

The reagent preferentially reacts with one type of functional group while leaving other reactive sites untouched.

Chemoselectivity is a property of the reagent as much as the substrate β€” a mild reagent is chemoselective; a harsh one is not.

Example: NaBHβ‚„ reduces an aldehyde in the presence of a ketone (both are C=O, but aldehyde is more electrophilic).
SPECIFIC vs SELECTIVE β€” The Iron Rule:
-SPECIFIC = mechanistically enforced; starting material controls outcome; different SM β†’ different product. Only ONE constitutional isomer or stereoisomer is possible.
-SELECTIVE = preference; one outcome is favoured over others but not mandatory. The other isomer CAN form (just less of it). Quantified by ratio, ee, dr.
Β§B Β· Stereospecific Reactions β€” Mechanism Enforces Outcome
In a stereospecific reaction: (R)-SM β†’ Product X; (S)-SM β†’ Product Y (the enantiomer of X) OR diastereomer. The SM determines the product absolutely.

B1 Β· SNβ‚‚ Reaction β€” THE textbook stereospecific example

Mechanism forces COMPLETE INVERSION (Walden Inversion) at the reacting centre.
Nucleophile attacks the BACK face (180Β° to leaving group) β†’ trigonal bipyramidal TS β†’ configuration inverted.
(R)-2-bromobutane + NaOH β†’ ONLY (S)-butan-2-ol. No retention. No racemisation. Inversion is 100%.
(S)-2-bromobutane + NaOH β†’ ONLY (R)-butan-2-ol.
The TWO enantiomeric starting materials give TWO DIFFERENT enantiomeric products β€” that is the hallmark of stereospecificity.
(R)-CH₃CHBrCHβ‚‚CH₃ + NaOH(aq) β†’ (S)-CH₃CHOHCHβ‚‚CH₃ + NaBr (S)-CH₃CHBrCHβ‚‚CH₃ + NaOH(aq) β†’ (R)-CH₃CHOHCHβ‚‚CH₃ + NaBr Both give 100% inverted product. STEREOSPECIFIC β€” no choice.

B2 Β· E2 Elimination β€” Anti-Periplanar Requirement

E2 requires H and X to be ANTI (dihedral 180Β°). This is mechanistically enforced.
meso-2,3-dibromobutane: anti elimination of HBr β†’ gives only (E)-2-butene (trans).
(R,R)- or (S,S)-2,3-dibromobutane: anti elimination β†’ gives only (Z)-2-butene (cis).
Different diastereomers of starting material β†’ DIFFERENT geometric isomers of product. Mechanistically locked. STEREOSPECIFIC.
meso-2,3-dibromobutane + KOH/EtOH β†’ (E)-but-2-ene ONLY [anti elimination; H and Br anti-periplanar] (R,R)-2,3-dibromobutane + KOH/EtOH β†’ (Z)-but-2-ene ONLY [H and Br anti in the other conformation] These two diastereomeric SM give two DIFFERENT geometric-isomeric products. STEREOSPECIFIC.

B3 Β· Epoxide Ring Opening (SNβ‚‚) β€” Inversion at Attacked Carbon

SNβ‚‚ opening of an epoxide by a nucleophile: backside attack β†’ INVERSION at the attacked carbon.
Trans-epoxide (cyclohexene oxide, trans) + NaN₃ β†’ trans-diaxial product (both groups anti).
Cis-epoxide + NaN₃ β†’ different relative configuration at the two carbons.
Different epoxide stereoisomers β†’ different product diastereomers. STEREOSPECIFIC.
trans-2,3-epoxybutane + CH₃OH (acid cat.) β†’ (2R,3R)-3-methoxy-2-butanol [Markovnikov opening + inversion] cis-2,3-epoxybutane + CH₃OH (acid cat.) β†’ (2R,3S)-3-methoxy-2-butanol [meso product] Different SM diastereomers β†’ DIFFERENT product diastereomers. STEREOSPECIFIC.

B4 Β· Hydroboration-Oxidation β€” Syn Addition

BH₃ adds B and H to the SAME FACE of the double bond (concerted 4-membered TS). SYN addition is mechanistically enforced.
Hβ‚‚Oβ‚‚/NaOH replaces B with OH with RETENTION of configuration at that carbon.
cis-2-butene β†’ syn addition β†’ meso-2-butanol ONLY.
trans-2-butene β†’ syn addition β†’ (R,R)+(S,S) 2-butanol (racemic, but each molecule is one diastereomer).
Different alkene geometries β†’ DIFFERENT diastereomeric product ratios. STEREOSPECIFIC.
cis-2-butene + BH₃·THF β†’ [syn addition] β†’ Hβ‚‚Oβ‚‚/NaOH β†’ meso-2,3-butanediol ONLY trans-2-butene + BH₃·THF β†’ [syn addition] β†’ Hβ‚‚Oβ‚‚/NaOH β†’ (Β±)-2,3-butanediol (racemic) ONLY Geometry of SM forces diastereomeric outcome. STEREOSPECIFIC.

B5 Β· Dihydroxylation with OsOβ‚„ β€” Syn Diol Formation

OsOβ‚„ delivers BOTH oxygens from the SAME face (concerted [3+2] mechanism). SYN addition enforced.
cis-2-butene + OsOβ‚„ β†’ meso-2,3-butanediol ONLY (syn diol, same face).
trans-2-butene + OsOβ‚„ β†’ (R,R)+(S,S)-2,3-butanediol (racemic; syn diol).
Contrast with mCPBA epoxidation then acid ring-opening β†’ ANTI diol.
STEREOSPECIFIC β€” geometry of alkene controls diastereomeric outcome.
cis-but-2-ene + OsOβ‚„/NMO β†’ meso-2,3-butanediol [syn, same face delivery] trans-but-2-ene + OsOβ‚„/NMO β†’ (Β±)-(2R,3R)+(2S,3S)-2,3-butanediol [syn, racemic mixture] Contrast (anti diol from epoxide pathway): trans-but-2-ene + mCPBA β†’ trans-epoxide + H₃O⁺ β†’ (2R,3S)-2,3-butanediol [anti-STEREOSPECIFIC]

B6 Β· Bromine Addition to Alkenes β€” Anti Addition via Bromonium Ion

Brβ‚‚ forms a BRIDGED BROMONIUM ION intermediate. Br⁻ then attacks the BACK face (SNβ‚‚). ANTI addition is enforced.
cis-2-butene + Brβ‚‚ β†’ (R,S)-2,3-dibromobutane (MESO compound) ONLY.
trans-2-butene + Brβ‚‚ β†’ (R,R)+(S,S)-2,3-dibromobutane (RACEMIC) ONLY.
STEREOSPECIFIC β€” the geometry of the starting alkene determines which diastereomer of product forms.
cis-but-2-ene + Brβ‚‚/CClβ‚„ β†’ meso-2,3-dibromobutane ONLY [anti addition, bromonium TS] trans-but-2-ene + Brβ‚‚/CClβ‚„ β†’ (Β±)-(2R,3R)+(2S,3S)-2,3-dibromobutane ONLY [anti addition, racemic] STEREOSPECIFIC β€” two diastereomeric SM β†’ two different diastereomeric products.
Other stereospecific reactions: Diels-Alder (suprafacial on both components, endo preference mechanistically controlled) Β· Claisen rearrangement (chair-like TS, syn-periplanar; substituents control E/Z of product) Β· Cope rearrangement Β· [2,3]-sigmatropic Β· Mitsunobu (double inversion β†’ retention overall) Β· SOClβ‚‚ without pyridine (SNi = retention) Β· Enzymatic reactions (single face of substrate accessible to enzyme active site)
Β§C Β· Stereoselective Reactions β€” One Stereoisomer Preferred
In a stereoselective reaction, BOTH stereoisomeric products are mechanistically possible β€” but ONE is formed in EXCESS due to steric, electronic, or chelation control. Quantified by enantiomeric excess (ee) or diastereomeric ratio (dr).

C1 Β· NaBHβ‚„ Reduction of Cyclic Ketone β€” Equatorial Attack Preference

NaBHβ‚„ reduces 4-t-butylcyclohexanone. Both axial and equatorial attack possible (H⁻ can approach either face).
Equatorial attack (on axial C=O face; less torsional strain) β†’ axial –OH product (trans-4-t-butylcyclohexanol).
Axial attack (on equatorial face; hindered) β†’ equatorial –OH product (cis-4-t-butylcyclohexanol).
Ratio: trans : cis = ~92 : 8. Not 100:0. STEREOSELECTIVE, not stereospecific.
Bulky LiAlH(OtBu)₃ reverses selectivity β†’ more axial attack β†’ equatorial –OH dominant.
4-t-butylcyclohexanone + NaBHβ‚„/EtOH β†’ trans-4-t-butylcyclohexanol (92%) + cis (8%) [equatorial attack kinetically preferred; less steric clash in TS] With LiAlH(OBu-t)₃ (bulky): β†’ cis-4-t-butylcyclohexanol (92%) + trans (8%) [bulky reagent forced to axial attack, gives equatorial OH product] STEREOSELECTIVE (not 100:0). Both products possible; one preferred.
Β§D Β· Regiospecific Reactions β€” Mechanism Enforces Which Position
REGIOSPECIFIC: The mechanism ONLY allows reaction at ONE specific position. No mixture of constitutional isomers is possible. Different conditions (or different substrates) give different, but each uniquely determined, constitutional isomers.

D1 Β· HBr Addition to Propene β€” Ionic vs Free Radical (THE Regiospecific Pair)

Ionic conditions (no peroxide): Markovnikov addition. Proton goes to C-1 (less substituted) β†’ 2Β°carbocation at C-2 β†’ Br goes to C-2. Gives ONLY 2-bromopropane (CH₃CHBrCH₃). Product from C-1 would give 1Β°carbocation β†’ impossible under ionic. REGIOSPECIFIC for ionic mechanism.

Free radical (ROOR peroxide): Brβ€’ adds to C-1 (less substituted, gives more stable 2Β°radical at C-2) β†’ H adds to C-2. Gives ONLY 1-bromopropane (CH₃CHβ‚‚CHβ‚‚Br). REGIOSPECIFIC for radical mechanism.

Two conditions β†’ two COMPLETELY DIFFERENT constitutional isomers. Neither gives a mixture.
Ionic: CH₃CH=CHβ‚‚ + HBr ──no peroxide──→ CH₃CHBrCH₃ ONLY (2-bromopropane) [Br goes to C-2 via 2Β° carbocation β€” REGIOSPECIFIC] Free Radical: CH₃CH=CHβ‚‚ + HBr ──ROOR, hν──→ CH₃CHβ‚‚CHβ‚‚Br ONLY (1-bromopropane) [Brβ€’ adds to C-1 via 2Β° radical β€” REGIOSPECIFIC] Each mechanism gives ONE constitutional isomer. No mixture.

D2 Β· Hydroboration-Oxidation β€” Regiospecific Anti-Markovnikov

The 4-membered cyclic TS of hydroboration forces B to bond to the LESS substituted carbon (BH₃ is bulky; approaches less hindered end of alkene).
This is NOT a preference β€” it is mechanistically enforced. B CANNOT go to the more substituted carbon in a simple terminal alkene.
CHβ‚‚=CHCH₃ + BH₃ β†’ B at C-1, H at C-2 β†’ Hβ‚‚Oβ‚‚/NaOH β†’ CH₃CHβ‚‚CHβ‚‚OH (1-propanol) ONLY.
REGIOSPECIFIC for anti-Markovnikov position. No 2-propanol formed.
CHβ‚‚=CHCH₃ + BH₃·THF β†’ CH₃CHβ‚‚CH₂–B (B at C-1, less hindered) ──Hβ‚‚Oβ‚‚/NaOH──→ CH₃CHβ‚‚CHβ‚‚OH (propan-1-ol, anti-Markovnikov) REGIOSPECIFIC: no Markovnikov (2-propanol) formed. Mechanism forces B to C-1.

D3 Β· Epoxide Ring Opening β€” Acid vs Base (Regiospecific Pair)

Acid-catalysed (SN₁-like): protonation of epoxide oxygen makes the more substituted C more electrophilic (more cationic character) β†’ Nu attacks MORE substituted C. REGIOSPECIFIC for Markovnikov position.

Base-catalysed (SNβ‚‚): Nu⁻ attacks LESS hindered (less substituted) C. REGIOSPECIFIC for anti-Markovnikov position.

2-methyloxirane + MeOH: acid β†’ 1-methoxy-2-propanol; base β†’ 2-methoxy-1-propanol. Different constitutional isomers from different conditions.
2-methyloxirane (propylene oxide): Acid (H₃O⁺): CH₃–CH(O)–CHβ‚‚ + MeOH/H⁺ β†’ CH₃CH(OMe)CHβ‚‚OH [Nu at C-2, more hindered β€” Markovnikov opening] Base (NaOMe): CH₃–CH(O)–CHβ‚‚ + NaOMe β†’ CH₃CH(OH)CHβ‚‚OMe [Nu at C-1, less hindered β€” anti-Markovnikov] REGIOSPECIFIC for each set of conditions.

D4 Β· Wacker Oxidation β€” Regiospecific Markovnikov Ketone

Terminal alkene + Oβ‚‚/Hβ‚‚O + PdClβ‚‚/CuClβ‚‚ β†’ methyl ketone ONLY. OH always goes to internal (more substituted) carbon.
R–CH=CHβ‚‚ β†’ R–CO–CH₃. No aldehyde R–CHO from terminal alkene under Wacker. The regioselectivity is enforced by the mechanism (Pd coordinates, nucleopalladation, Ξ²-hydride elimination).
REGIOSPECIFIC β€” constitutional isomer with carbonyl at C-1 is NOT formed.
CH₃CHβ‚‚CH=CHβ‚‚ + Oβ‚‚ ──PdClβ‚‚/CuClβ‚‚, Hβ‚‚O──→ CH₃CHβ‚‚COCH₃ (butanone, methyl ketone) NOT CH₃CHβ‚‚CHβ‚‚CHO (aldehyde at terminal C). REGIOSPECIFIC β€” carbonyl always at internal C in Wacker of terminal alkene.
Other regiospecific reactions: Ozonolysis (C=C cleavage gives only the two fragments of the double bond, no other position) Β· Permanganate glycol cleavage (only the diol C–C breaks) Β· Baeyer-Villiger (oxygen always inserts between C=O and the more migratory group, predictable) Β· Hunsdiecker reaction (specific chain shortening by 1C) Β· Clemmensen/Wolff-Kishner (specifically reduces C=O to CHβ‚‚, no other reduction) Β· HVZ Ξ±-halogenation (specifically Ξ± to C=O only, not Ξ² or further)
Β§E Β· Regioselective Reactions β€” One Regioisomer Preferred
REGIOSELECTIVE: Two or more constitutional isomers CAN form, but ONE predominates due to electronic or steric preference. The major product is not the only product.

E1 Β· Electrophilic Aromatic Substitution (EAS) on Substituted Benzenes

Substituents on the ring direct incoming electrophile to specific positions. Both ortho/para and meta products CAN form β€” but the ratio is determined by the directing power.

Activating groups (–OH, –NHβ‚‚, –OR, –NRβ‚‚): ortho/para directors β†’ predominantly o/p (but small % meta still forms).
Deactivating groups (–COOH, –CN, –NOβ‚‚, –CHO): meta directors β†’ predominantly meta (but some o/p forms).
Halogens (–Cl, –Br): ortho/para directors (lone pair donation) despite deactivating (–I effect).
REGIOSELECTIVE β€” ratio varies widely but never 100:0 at any position.
Nitration of toluene: CH₃ CH₃ CH₃ | | | C₆Hβ‚…CH₃ ──HNO₃/Hβ‚‚SO₄──→ o-nitrotoluene (58%) + p-nitrotoluene (38%) + m-nitrotoluene (4%) [Me is o/p director β€” REGIOSELECTIVE for ortho and para; not zero at meta] Nitration of nitrobenzene: C₆Hβ‚…NOβ‚‚ ──HNO₃/Hβ‚‚SO₄──→ m-dinitrobenzene (93%) + o/p- (7%) [–NOβ‚‚ is meta director β€” REGIOSELECTIVE for meta; not zero at o/p]

E2 Β· Elimination β€” Zaitsev vs Hofmann Regioselectivity

E2 elimination of 2-bromobutane: two different Ξ²-carbons available (C-1 and C-3). BOTH can lose H.
Small base (KOH/EtOH): Zaitsev product β€” more substituted alkene (but-2-ene) predominates.
Bulky base (t-BuOK/t-BuOH): Hofmann product β€” less substituted alkene (but-1-ene) predominates.
Neither gives 100% of one alkene β€” REGIOSELECTIVE in all cases. The ratio changes with base size.
CH₃CHBrCHβ‚‚CH₃ + KOH/EtOH β†’ CH₃CH=CHCH₃ (but-2-ene, Zaitsev, ~80%) + CHβ‚‚=CHCHβ‚‚CH₃ (but-1-ene, Hofmann, ~20%) REGIOSELECTIVE for Zaitsev under small base. CH₃CHBrCHβ‚‚CH₃ + (CH₃)₃COK/t-BuOH β†’ CHβ‚‚=CHCHβ‚‚CH₃ (but-1-ene, Hofmann, ~75%) + CH₃CH=CHCH₃ (but-2-ene, ~25%) REGIOSELECTIVE for Hofmann under bulky base.

E3 Β· Markovnikov HX Addition β€” Regioselective (not regiospecific)

Ionic addition of HBr to 2-methylpropene. BOTH C-1 and C-2 can receive Br in principle (H can go to either).
C-2 gives 3Β° carbocation (stable) β†’ Br at C-2 = 2-bromo-2-methylpropane (major).
C-1 would give 1Β° carbocation (highly unstable) β†’ Br at C-1 = 1-bromo-2-methylpropane (minor, formed via hydride shift or rearrangement).
Major product >> minor but not 100%. REGIOSELECTIVE.
(CH₃)β‚‚C=CHβ‚‚ + HBr β†’ (CH₃)β‚‚CBrCH₃ (2-bromo-2-methylpropane, ~97%) + (CH₃)β‚‚CHCHβ‚‚Br (1-bromo-2-methylpropane, ~3%, via rearrangement) REGIOSELECTIVE (major >> minor; not 0% minor). NOT regiospecific.

E4 Β· Electrophilic Substitution on Naphthalene β€” C-1 vs C-2

Naphthalene: both C-1 (Ξ±) and C-2 (Ξ²) positions available. Attack at C-1 gives Wheland intermediate that preserves more aromaticity in the second ring (arenium ion at C-1 is more stable). REGIOSELECTIVE for C-1.
Mononitration: mainly 1-nitronaphthalene (~95%) + 2-nitronaphthalene (~5%). REGIOSELECTIVE.
Sulfonation at 80Β°C: kinetic β†’ 1-naphthalenesulfonic acid; at 160Β°C: thermodynamic β†’ 2-naphthalenesulfonic acid.
Naphthalene + HNO₃/Hβ‚‚SOβ‚„ β†’ 1-nitronaphthalene (95%) + 2-nitronaphthalene (5%) REGIOSELECTIVE for Ξ±-position (C-1) under kinetic control. Naphthalene + conc. Hβ‚‚SOβ‚„, 80Β°C β†’ 1-naphthalenesulfonic acid (major, kinetic) Naphthalene + conc. Hβ‚‚SOβ‚„, 160Β°C β†’ 2-naphthalenesulfonic acid (major, thermodynamic)
Other regioselective reactions: Aldol condensation (which C=O acts as electrophile vs enolate when two different ketones present) Β· Claisen condensation (mixed) Β· Formylation (Reimer-Tiemann favours o/p) Β· Selective alkylation of enolates (LDA at –78Β°C β†’ kinetic enolate, C-2; thermodynamic conditions β†’ C-3 for 2-methylcyclohexanone) Β· Directed ortho-metalation (DoM; directed by –OMe, –NRβ‚‚, –CONRβ‚‚)
Β§F Β· Chemoselectivity β€” Which Functional Group Reacts?
CHEMOSELECTIVE: The reagent reacts preferentially with ONE type of functional group in the presence of ANOTHER reactive group in the same molecule. The unreacted group is left intact.

F1 Β· NaBHβ‚„ vs LiAlHβ‚„ β€” Carbonyl Selectivity

A molecule containing both an aldehyde and an ester (or carboxylic acid) can be selectively reduced.
NaBHβ‚„: reduces aldehyde and ketone ONLY. Does NOT reduce ester, carboxylic acid, amide, nitrile, isolated C=C. CHEMOSELECTIVE for aldehyde/ketone.
LiAlHβ‚„: reduces everything β€” aldehyde, ketone, ester, carboxylic acid, amide, nitrile, epoxide. NOT chemoselective for C=O alone.
DIBAL-H at –78Β°C: reduces ester to aldehyde (stops at acylaluminium intermediate) β€” CHEMOSELECTIVE for partial reduction of ester.
EtOOC–(CHβ‚‚)₄–CHO (ethyl 6-oxohexanoate β€” has BOTH ester AND aldehyde): + NaBHβ‚„ / EtOH β†’ EtOOC–(CHβ‚‚)₄–CHβ‚‚OH [aldehyde reduced; ester INTACT β€” CHEMOSELECTIVE] + LiAlHβ‚„ / Etβ‚‚O β†’ HO–(CHβ‚‚)₆–OH [BOTH groups reduced β€” NOT chemoselective] + DIBAL-H / –78Β°C β†’ EtOOC–(CHβ‚‚)₄–CHO (ester only partially reduced to aldehyde)

F2 Β· Aldehyde vs Ketone β€” Meerwein-Ponndorf-Verley Chemoselectivity

Molecule contains both aldehyde and ketone. MPV reagent [Al(OiPr)₃] reduces carbonyl to alcohol.
Aldehyde is more electrophilic (less electron donation from R, less steric shielding) β†’ reacts FASTER with most reagents.
NaBHβ‚„ reduces aldehyde preferentially in a 1:1 mix of aldehyde + ketone when used in exactly 1 equiv. (kinetic preference for aldehyde). CHEMOSELECTIVE.
Luche reduction (NaBHβ‚„/CeCl₃): reduces ketone C=O in an Ξ±,Ξ²-unsaturated system chemoselectively (1,2-addition) over 1,4-conjugate addition.
CH₃CHO + (CH₃)β‚‚CO + NaBHβ‚„ (0.5 equiv) β†’ CH₃CHβ‚‚OH (mainly) + acetone (unreacted) [aldehyde more reactive; NaBHβ‚„ reduces aldehyde first β€” CHEMOSELECTIVE] Luche reduction: CHβ‚‚=CH–CO–CH₃ + NaBHβ‚„/CeCl₃ β†’ CHβ‚‚=CH–CHOH–CH₃ [1,2-reduction; C=C untouched β€” CHEMOSELECTIVE] Without CeCl₃: NaBHβ‚„ gives mainly 1,4-reduction (saturated ketone). CeCl₃ switches chemoselectivity.

F3 Β· C=C vs C=O Chemoselectivity β€” Hydrogenation Conditions

A molecule with both C=C (alkene) and C=O (aldehyde/ketone). Which gets hydrogenated?
Hβ‚‚ / Pd-C (normal): reduces C=C preferentially (alkene hydrogenation is faster than C=O; carbonyl needs higher T or Pt).
Lindlar's catalyst (Pd/BaSOβ‚„/quinoline): semi-hydrogenation of alkyne to cis-alkene, C=O left INTACT.
Hβ‚‚ / Pt: both C=C and C=O reduced. Not chemoselective.
LiAlHβ‚„: reduces C=O; does NOT reduce isolated C=C (no B–H bond, cannot hydrogenate).
NaBHβ‚„: same β€” C=O only, C=C intact (unless conjugated with C=O and Luche used).
CHβ‚‚=CH–CH₂–CHO (but-3-enal, has C=C and C=O): + Hβ‚‚/Pd-C (1 bar) β†’ CH₃CHβ‚‚CHβ‚‚CHO [C=C reduced; C=O INTACT β€” CHEMOSELECTIVE] + LiAlHβ‚„ β†’ CHβ‚‚=CH–CH₂–CHβ‚‚OH [C=O reduced; C=C INTACT β€” CHEMOSELECTIVE] + Hβ‚‚/PtOβ‚‚ (Adams cat) β†’ CH₃CHβ‚‚CHβ‚‚CHβ‚‚OH [both reduced β€” NOT chemoselective]

F4 Β· Selective Acylation β€” Amine vs Alcohol in Same Molecule

Molecule contains both –NHβ‚‚ and –OH (e.g., amino alcohol). Both can react with acyl chloride.
–NHβ‚‚ (pKa ~10 for ammonium) is far more nucleophilic than –OH (pKa ~16). At low temperature in non-polar solvent with 1 equiv. RCOCl β†’ acylation occurs at N, not O.
CHEMOSELECTIVE for amine over alcohol.
If both groups must be acylated, 2 equiv. RCOCl or anhydride used. If only O-acylation needed, first protect –NHβ‚‚ as Boc or Cbz, then acylate –OH.
Hβ‚‚N–CH₂–CH₂–OH (ethanolamine): + CH₃COCl (1 equiv., –10Β°C, CHβ‚‚Clβ‚‚) β†’ CH₃CONH–CH₂–CH₂–OH [N-acylation; –OH INTACT β€” CHEMOSELECTIVE] + CH₃COCl (2 equiv.) β†’ CH₃CONH–CH₂–CH₂–OCOCH₃ [both acylated] p-aminophenol + acetic anhydride (1 equiv.) β†’ paracetamol (4-acetamidophenol) [–NHβ‚‚ acylated preferentially over phenolic –OH β€” CHEMOSELECTIVE: this is the industrial synthesis of paracetamol]

F5 Β· Selective Oxidation β€” MnOβ‚‚ for Allylic/Benzylic Alcohols

Molecule contains both an allylic alcohol and a non-allylic (saturated) alcohol. Need to oxidise only one.
MnOβ‚‚ (activated): oxidises ONLY allylic and benzylic alcohols to the corresponding carbonyl. Saturated alcohols are NOT oxidised under mild MnOβ‚‚ conditions. CHEMOSELECTIVE.
PCC/PDC: oxidises both types of alcohol (primary β†’ aldehyde; secondary β†’ ketone). NOT chemoselective between allylic and saturated.
Swern oxidation: oxidises primary and secondary alcohols; not selective between allylic and non-allylic.
Geraniol (allylic alcohol): (CH₃)β‚‚C=CHCHβ‚‚CHβ‚‚C(CH₃)=CHCHβ‚‚OH + MnOβ‚‚ β†’ geranial (citral) [allylic C=O formed β€” CHEMOSELECTIVE] A saturated –CHβ‚‚OH elsewhere in the same molecule: NOT oxidised by MnOβ‚‚. Contrast with PCC: Any primary alcohol (allylic or not) + PCC β†’ aldehyde [not allylic-specific β€” NOT chemoselective]

F6 Β· Protection Strategy as Chemoselectivity Tool

When no reagent is intrinsically chemoselective, PROTECTION makes a reaction chemoselective overall.

Protecting groups are a STRATEGY to achieve chemoselectivity:
β€’ TBS (t-butyldimethylsilyl) ether: selectively protects primary –OH over secondary –OH in some cases
β€’ PMB (p-methoxybenzyl): easily removed by DDQ (oxidative) without touching other groups
β€’ Boc: selectively protects –NHβ‚‚ over –OH; removed by TFA
β€’ Cbz (Cbz-Cl): protects –NHβ‚‚; removed by Hβ‚‚/Pd-C
β€’ Acetal: protects C=O against nucleophiles; unmasked by aqueous acid (C=C or –OH untouched)
Problem: reduce ester without reducing aldehyde in same molecule (opposite of NaBHβ‚„ selectivity). Strategy: protect aldehyde as acetal (1,3-dioxolane) + H⁺ β†’ acetal, then LiAlHβ‚„ reduces only ester β†’ H₃O⁺ unmasks acetal β†’ product with reduced ester, aldehyde intact. CHEMOSELECTIVITY ACHIEVED THROUGH PROTECTION.

F7 Β· mCPBA β€” Chemoselective Epoxidation of More Electron-Rich Alkene

Molecule with TWO alkene double bonds of DIFFERENT electron density. mCPBA is ELECTROPHILIC (electron-deficient peracid).
Reacts faster with the MORE electron-rich (more substituted or more nucleophilic) alkene. CHEMOSELECTIVE for the electron-rich C=C.
Ξ±,Ξ²-unsaturated C=C (conjugated, electron-poor) is NOT epoxidised by mCPBA. Use nucleophilic epoxidation (Hβ‚‚Oβ‚‚/NaOH, Weiss-Cook) for that.
Molecule with C=C and C=O: mCPBA epoxidises C=C (not C=O) β†’ CHEMOSELECTIVE.
Limonene (has trisubstituted C=C AND disubstituted C=C): + 1 equiv. mCPBA β†’ epoxidation at TRISUBSTITUTED alkene (more e-rich) preferentially β€” CHEMOSELECTIVE Chalcone (C₆H₅–CH=CH–CO–C₆Hβ‚…, Ξ±,Ξ²-unsaturated ketone): + mCPBA β†’ NO reaction at conjugated C=C (too electron-poor) + Hβ‚‚Oβ‚‚/NaOH β†’ chalcone epoxide [nucleophilic Weiss-Cook = CHEMOSELECTIVE for conjugated alkene]
Other chemoselective examples: Birch reduction (reduces electron-poor ring positions; keeps electron-rich substituents intact) Β· Ozonolysis (only cleaves C=C; C=O, C–C not affected) Β· Osmium tetroxide (only dihydroxylates C=C; leaves C=O) Β· Mitsunobu (–OH β†’ inverted product; other groups untouched) Β· DDQ (oxidatively removes PMB protecting group without touching benzyl or TBS) Β· CAN (removes PMB over other protecting groups) Β· TFA (removes Boc; leaves Cbz intact) Β· Pd-C/Hβ‚‚ (removes Cbz; leaves Boc intact)
Β§G Β· The Master Contrast β€” Side-by-Side Comparisons

πŸ”΄ STEREOSPECIFIC

Starting material CONTROLS product stereochemistry
(R)-SM β†’ one specific product; (S)-SM β†’ different specific product
Mechanism allows ONLY one stereochemical outcome
Different SM stereoisomers β†’ different product stereoisomers
Not quantified by ee/dr β€” it is either 100% or it's not stereospecific
Examples: SNβ‚‚ (inversion), E2 (anti), Brβ‚‚ addition (anti), BH₃ (syn), OsOβ‚„ (syn)

🟠 STEREOSELECTIVE

One stereoisomeric product PREFERRED over another
Both products mechanistically possible
Ratio depends on conditions, reagent, temperature
Quantified by ee (%) for enantioselectivity or dr for diastereoselectivity
ANY excess of one isomer = stereoselective; 99% ee = highly stereoselective
Examples: NaBHβ‚„ on cyclohexanone, Sharpless epoxidation, Felkin-Anh addition, CBS reduction

πŸ”΅ REGIOSPECIFIC

Mechanism ONLY allows reaction at ONE position
No mixture of constitutional isomers possible from one set of conditions
Different conditions/mechanisms β†’ different constitutional isomers (each 100%)
Not about ratio β€” it's mechanistic necessity
Examples: HBr (ionic) β†’ 2-bromopropane ONLY; HBr (radical) β†’ 1-bromopropane ONLY; Hydroboration β†’ anti-Markovnikov ONLY; Wacker β†’ methyl ketone ONLY

🟣 REGIOSELECTIVE

Two or more constitutional isomers CAN form
One predominates due to electronic/steric preference
Minor regioisomer is always detectable
Quantified by ratio of regioisomers (e.g., o:p:m ratio in EAS)
Examples: Markovnikov HX addition (major: more subst. C; minor: less subst.), EAS on toluene (58% ortho, 38% para, 4% meta), Zaitsev/Hofmann alkene ratio

πŸ”‘ Tricky Questions β€” Answered

Is SN₁ stereospecific? NO. SN₁ goes via a flat carbocation attacked from both faces β†’ racemisation. Not stereospecific (no particular outcome enforced by SM configuration) and not stereoselective (no preference for one face; ~50:50).

Is Markovnikov addition regiospecific or regioselective? REGIOSELECTIVE. Minor amounts of the anti-Markovnikov product can form (via rearrangement or if the two carbons are similar in stability). But free-radical HBr giving ONLY anti-Markovnikov = REGIOSPECIFIC.

Can a reaction be BOTH stereospecific AND regioselective? YES. Hydroboration is both: regiospecific for anti-Markovnikov position (B always at less substituted C; no mixture of regioisomers) AND stereospecific for syn addition (H and B always same face).

Is Diels-Alder stereospecific or stereoselective? BOTH. The suprafacial addition (cis groups in diene remain cis in product) is STEREOSPECIFIC. The endo/exo ratio (preference) is STEREOSELECTIVE.

Is enzyme catalysis stereospecific or stereoselective? STEREOSPECIFIC (in most textbook contexts) β€” the enzyme active site only accepts one face of the substrate; the other diastereomeric/enantiomeric product simply cannot form under those conditions.
Β§H Β· Master Quick Reference Table
ReactionStereospecificStereoselectiveRegiospecificRegioselectiveChemoselective
SNβ‚‚YES β€” inversionβ€”β€”β€”β€”
SN₁NO β€” racemisationNO β€” ~50:50β€”β€”β€”
E2 (anti-periplanar)YES β€” antiβ€”β€”β€”β€”
E2 Zaitsev/Hofmannβ€”β€”β€”YES β€” alkene ratioβ€”
Brβ‚‚ addition to alkeneYES β€” anti (bromonium)β€”β€”β€”β€”
HBr ionic (Markovnikov)β€”β€”YESβ€”β€”
HBr radical (anti-Mkov.)β€”β€”YESβ€”β€”
Hydroboration-oxidationYES β€” synβ€”YES β€” anti-Mkov.β€”β€”
Oxymercuration-demercurationYES β€” antiβ€”YES β€” Markovnikovβ€”β€”
OsOβ‚„ dihydroxylationYES β€” syn diolβ€”β€”β€”YES β€” C=C over C=O
Epoxide opening (acid)YES β€” anti, inversionβ€”YES β€” more subst. Cβ€”β€”
Epoxide opening (base)YES β€” anti, inversionβ€”YES β€” less subst. Cβ€”β€”
EAS on tolueneβ€”β€”β€”YES β€” o/pβ€”
NaBHβ‚„ reductionβ€”YES β€” equatorial attackβ€”β€”YES β€” C=O not ester/acid
LiAlHβ‚„ reductionβ€”β€”β€”β€”NO β€” reduces most FGs
DIBAL-H (–78Β°C)β€”β€”β€”β€”YES β€” ester β†’ aldehyde
Luche (NaBHβ‚„/CeCl₃)β€”β€”β€”β€”YES β€” 1,2 over 1,4
MnOβ‚‚ oxidationβ€”β€”β€”β€”YES β€” allylic/benzylic OH only
mCPBA epoxidationβ€”β€”β€”β€”YES β€” electron-rich alkene
Wacker oxidationβ€”β€”YES β€” methyl ketone onlyβ€”β€”
Free radical chlorinationβ€”β€”β€”POOR β€” low selectivityβ€”
Free radical brominationβ€”β€”β€”GOOD β€” 3°≫2°≫1Β°β€”
Acylation (RCOCl)β€”β€”β€”β€”YES β€” NHβ‚‚ over OH
Hβ‚‚/Pd-C hydrogenationβ€”β€”β€”β€”YES β€” C=C over C=O
Birch reductionβ€”β€”β€”YES β€” e-poor positionsYES β€” reduces ring not chain
Final Memory Anchor:
STEREO = about 3-D spatial outcome  |  REGIO = about which atom/position  |  CHEMO = about which functional group
-SPECIFIC = mechanistically enforced (100%, no choice, SM controls)  |  -SELECTIVE = preferred (quantified by ratio/ee/dr, but other product can form)