### Reactivity Profiles - Alkenes - Strong, non-polar C-C and C-H σ bonds - Negligible electrophilic character (unless special substituents) - Relatively low acidity (pKa 40-45) - Relatively weak π bond (ca. 65 kcal/mol vs. 89 kcal/mol for σ bond) - Polarizable π electrons - moderate nucleophilic character - Eagerly reacts with strong electrophiles - H-Br - Strong Brønsted acid with pKa = -9 - Strong electrophilic character - Very weak nucleophilic character - Carbocations - Planar geometry, sp$^{2}$ hybridization at carbon - Positive charge on carbon (Pauling EN = 2.5) - high energy species! - Irresistibly attracted to nucleophiles, δ- species - Incomplete octet - Powerful electrophile: covets electron pairs! - Should react with even weak nucleophiles - Alkyl substitution on positively charged carbon reduces electrophilicity - Water - Moderately good nucleophile (not as good as hydroxide) - Weak electrophilic character - Brønsted acid with pKa = 15.7 - H$_{3}$O$^{+}$ - Strong Brønsted acid with pKa = -1.7 - Strong electrophilic character - No nucleophilic character - Bromine and Chlorine - X-X bonds are very weak (F-F 38 kcal/mol, Cl-Cl 58, Br-Br 46, I-I 36) - X-X bonds are highly polarizable - X-X bonds have a low energy vacant σ* orbital - Br$_{2}$, Cl$_{2}$, and I$_{2}$ are relatively strong electrophiles; F$_{2}$ is untameably strong - Relatively low nucleophilicity due to high electronegativity of halogens - Bromonium Ions - Positively charged species - highly electron deficient - Carbon atoms have significant δ+ character - High degree of angle strain in three-membered ring - Powerful electrophile - will react with even weak nucleophiles - Nucleophilic attack favored at carbon thus neutralizing + charge on bromine - Carbon-bromine bond has low energy vacant σ* orbital - Nucleophilic attack at carbon occurs anti to C-Br bond ("backside attack") - Borane - Incomplete octet - only six electrons in valence shell - Vacant p orbital - Very strong electrophilic character and Lewis acidity - Behavior: ravenous desire for electron pairs! - Forms complexes with Lewis bases that then have anionic character on the hydrogens attached to boron - Hydrogen - Very strong, non-polar bond (H-H BDE = 104 kcal/mol) - Very weak Brønsted acid (pKa = 35-40) - Behavior: expected to be neither a nucleophile or electrophile - Reacts with certain transition metals in "insertion" reactions (e.g., Pd + H-H → H-Pd-H) - Peroxyacids - Brønsted acids with pKa = 7-8 (less acidic than carboxylic acids) - Extremely weak O-O bond (BDE = ca. 35 kcal/mol) - O-O bond has low energy σ* orbital - Expected behavior: significant electrophilic character at the oxygen of the hydroxyl group - Free Radicals - Incomplete octet and unpaired electron: not a happy state! - High energy species, usually only transient intermediates - Stabilized by hyperconjugation (3° > 2° > 1°), π delocalization (allylic, α-heteroatom) - Behavior: combination of two radicals to form a σ bond is very exothermic! - Addition of a radical (X•) to a carbon-carbon π bond (relatively weak, ca. 66 kcal/mol) can be favorable, especially if a more stable radical and a strong C-X bond results - Hydrogen atom transfer to a radical (X•) can be a facile process, especially if a stronger bond to hydrogen and a more stable radical results - Halogen atom transfer to a radical (Z•) can be a facile process, especially if a strong bond to halogen results - Reactions with "lone pair" nucleophiles are generally not observed - Alkynes - Strong C-C and C-H σ bonds - Negligible electrophilic character (unless special substituents) - Relatively weak π bond with polarizable π electrons - Moderate nucleophilic character - Eagerly reacts with strong electrophiles - Depending on mechanism, rate of addition may be faster (e.g., hydrogenation) or slower (e.g., HBr ionic addition, Br$_{2}$ addition) compared to alkenes - Relatively acidic proton (pKa = ca. 25) due to sp "orbital electronegativity" - Sodium Amide (Na$^{+}$NH$_{2}^{-}$) - Powerful Brønsted base (pKa of conjugate acid NH$_{3}$ = 33) - Strong nucleophilic character - Metal Acetylides - Carbon (EN = 2.5) is not very electronegative and does not tolerate a full negative charge well - Alkynes are relatively acidic (pKa = ca. 25), however, due to sp "orbital electronegativity" - Metal acetylides (e.g., Met = Li, Na, MgX) exhibit strong nucleophilic character - Sodium acetylides are more reactive than lithium acetylides due to greater electropositive character of sodium compared to lithium - Primary Alkyl Halides - Highly polarized C-X bond with δ+ character at carbon - C-X bond has low-energy vacant σ* orbital - Moderate electrophilic character at carbon of C-X bond - Very weak nucleophiles due to electronegativity of halogens and lack of negative charge - Good Leaving Groups - Groups that readily accept an electron pair - Weak Brønsted bases (i.e., have strong conjugate acids) are good leaving groups - Leaving groups that are Brønsted bases with conjugate acids pKa < 0 are best - Weak bonds to carbon lead to better leaving groups - Commonly used leaving groups include iodide, bromide, and chloride anions, sulfonate anions (RSO$_{3}^{-}$), and water (from protonated hydroxyl groups) - Potent Nucleophiles - Nucleophilic sites in a molecule are sites of excess electron density and include - Lone pair electrons - Polarizable π bond electrons - Highly polarized σ bond electrons - Nucleophilicity increases with increased negative charge character. Good nucleophiles have less tightly held electrons. - Nucleophilicity parallels Brønsted basicity in some respects. For example, - For nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. - Negatively charged nucleophiles are stronger nucleophiles than their conjugate acids. - Nucleophilicity differs from Brønsted basicity in other respects. For example, - Nucleophilicity is reduced by steric hindrance around the nucleophilic atom or bond. Brønsted basicity is less sensitive to steric effects. - Polarizability greatly enhances nucleophilicity (but less so Brønsted basicity). - Nucleophilicity is strongly affected by solvent effects - Potassium tert-Butoxide (KOt-Bu) - Strong Brønsted base (pKa of conjugate acid t-BuOH is only 19) - Weak nucleophilic character due to steric shielding of oxygen - DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) - Planar amidine moiety with amide-like π delocalization - Strong Brønsted base (protonated at C=N nitrogen) (pKa of conjugate acid = 13.5) - Weak nucleophilic character (steric shielding of nitrogen) - Very weak electrophilic character at ring junction carbon - Sodium Hydride (NaH) - Strong Brønsted base (pKa of conjugate acid H$_{2}$ is 35-40) - Weak nucleophilic character - Insoluble in organic solvents; reactions take place on solid surface - Alkenes - Part II - Alkenes are stabilized by delocalization with adjacent π-bonds - Alkenes are stabilized by hyperconjugation (e.g., alkyl substitution) - Alkenes are destabilized by non-bonded interactions of cis-substituents - E alkenes are generally lower in energy than the corresponding Z isomers - Alkenes are destabilized by angle strain - Alkyl Sulfonates (tosylate R-OTs, mesylate R-OMs, triflate R-OTf) - Sulfonates are strong electron-withdrawing groups via inductive effects - Carbon attached to OSO$_{2}$R is highly electrophilic - Sulfonates are excellent leaving groups (Brønsted bases with conjugate acids pKa -3 to -13) - Sulfonate anions are very weak bases and very weak nucleophiles - Ethers - Simple ethers have no protons with significant acidity - Ethers are very weak Brønsted bases (pKa of conjugate acid is ca. -3) - Ethers are moderate Lewis bases (recall complexes with strong Lewis acids) - α carbons have some δ+ character due to inductive electron withdrawal in C-O bond - α carbons are thus weakly electrophilic but ethers do not undergo nucleophilic substitution because alkoxy anions are very poor leaving groups - Metal Alkoxides (e.g., NaOEt) - Moderately strong Brønsted base (pKa of conjugate acid 16-19) - Stronger base than NH$_{3}$ and amines, similar to hydroxide - Strong nucleophilic character (greater than ROH!) - Nucleophilic character suppressed if R is sterically bulky (e.g., KOt-Bu) - Ammonia (NH$_{3}$) - Moderately strong Brønsted base (pKa of conjugate acid NH$_{4}^{+}$ is 9.4) - Stronger base than H$_{2}$O, weaker than OH$^{-}$ (pKa of their conjugate acids: -1.7 and 15.7) - Strong nucleophilic character (greater than H$_{2}$O!) - Weak Brønsted acid (pKa to form amide anion (NH$_{2}^{-}$) is ca. 38) - Sodium Azide (NaN$_{3}$) - Strong nucleophilic character (highly polarizable anion) - Delocalized negative charge shared equally at terminal nitrogen atoms - Weak Brønsted base (pKa of hydrazoic acid HN$_{3}$ is 4.6) - Sodium Cyanide (NaCN) - Strong nucleophilic character (highly polarizable anion) - Moderate Brønsted base (pKa of HCN is 9.1) - Small anion, not as sensitive to steric shielding of electrophilic sites - Dimethyl Sulfoxide (DMSO) - Very high dipole moment (4.0 D) and high dielectric constant (47) - Very weak Brønsted acid (pKa ca. 35) - Dipolar structure with tetrahedral geometry at sulfur which has lone pair - Weak Lewis acid and weak electrophile; δ+ sulfur is shielded by methyl groups - Lewis basic oxygen good at solvating cations and δ+ species - Lithium Aluminum Hydride (LiAlH$_{4}$) - Polarized Al-H bonds from Al (Pauling EN 1.5) to more electronegative H (EN 2.1) - AlH$_{4}^{-}$ has formal negative charge on Al (but Al is actually electron deficient!) - Excess electrons actually distributed at four hydrogen atoms - Behaves as a soluble equivalent of hydride anion (use THF or Et$_{2}$O) - Reacts as nucleophilic equivalent of hydride anion with even weakly electrophilic species - Highly basic and reacts even violently with moderate acids like water and alcohols - Thiols and Thiolates - Thiols (pKa 10-12) are more acidic than alcohols (pKa 16-19) - Thiols can be deprotonated by strong bases (NaOH, NaH) to form thiolate anions - Thiols (and thiolate anions) are very polarizable - Thiols (and thiolate anions) are very strong nucleophiles especially in protic solvents - General Reactivity of Carbonyl Compounds - C-O σ and (especially) π bonds are significantly polarized toward oxygen - Carbonyl carbon thus has significant δ+ character and is very electrophilic - Good nucleophiles attack carbonyl carbon with displacement of π electrons onto oxygen - Oxygen (δ-) is moderately Lewis basic and forms complexes with strong Lewis acids - Oxygen (δ-) is a weak Brønsted base (pKa of protonated carbonyls are -7 to -10) and is protonated by very strong acids and forms hydrogen bonds with water, alcohols, etc. - Protons on α-carbons are moderately acidic (pKa 20-25, similar to alkynes) and can be deprotonated ~completely by LiN(i-Pr)$_{2}$ and partially by NaOEt and KOt-Bu - Reactivity of Carbonyl Compounds as Electrophiles - Carbonyl carbon has significant δ+ character due to inductive effect and delocalization and is very electrophilic - Attack of nucleophiles at carbon shifts electrons of the highly polarized π bond onto the electronegative oxygen - Carbonyl groups are generally more electrophilic than alkyl halides and sulfonates (inductive withdrawal in σ bond only) - Adduct is an alkoxide and typically is "quenched" by addition of water or dilute acid to afford an alcohol product - Steric effects: large substituents slow attack due to steric hindrance and more crowded transition state (substituents pushed closer together as carbon goes from sp$^{2}$ (120°) to sp$^{3}$ (109.5°)) - Electronic effects: alkyl groups on the carbonyl carbon are electron donating (in addition to being sterically shielding) and reduce electrophilic reactivity (HCHO electrophilicity > aldehydes > ketones) - Electronic effects: π bonds (alkenyl and aryl groups) and heteroatoms (O, N, etc.) on the carbonyl carbon reduce electrophilic reactivity by delocalization of δ+ charge - Electronic effects: nearby electron-withdrawing groups increase electrophilicity by inductive effect (Cl$_{3}$CCHO electrophilicity > CH$_{3}$CHO) - Protonation of the carbonyl oxygen (or complexation to a Lewis acid) increases the electrophilicity by generating a carbocation (C$^{+}$ with OH or O-Met substituent) - Sodium Borohydride (NaBH$_{4}$) - Polarized B-H bonds from B (Pauling EN 2.0) to more electronegative H (EN 2.1), but not polarized as much as Al-H bonds in LAH - BH$_{4}^{-}$ has formal negative charge on B (but B is actually electron deficient!) - Excess electrons actually distributed at four hydrogen atoms - Behaves as a soluble equivalent of hydride anion - Reacts as nucleophilic equivalent of hydride anion with moderately electrophilic species (but less nucleophilic than LiAlH$_{4}$) - Less basic than LAH and reacts slowly with water and alcohols, so they can be used as solvents - n-Butyllithium - Very polarized σ bond (carbon EN = 2.5, lithium 1.0) with significant carbanionic (δ-) character at carbon bonded to lithium - "Unactivated" carbons (sp$^{3}$ and sp$^{2}$) do not tolerate negative charge character well - Extremely powerful nucleophile, reacts with wide range of weak to strong electrophiles - Extremely high Brønsted basicity - pKa of butane is ca. 50 - Deprotonates weak acids including wide range of compounds with O-H and N-H bonds - Reacts rapidly and vigorously with H$_{2}$O, CO$_{2}$, and O$_{2}$ in atmosphere - Grignard Reagents (R-Mg-X) - Very polarized σ bond (carbon EN = 2.5, magnesium 1.2) with significant carbanionic (δ-) character at carbon bonded to magnesium - Extremely powerful nucleophile, reacts with wide range of weak to strong electrophiles - Extremely high Brønsted basicity - pKa of butane is ca. 50 - Deprotonates weak acids including wide range of compounds with O-H and N-H bonds - Reacts rapidly and vigorously with H$_{2}$O, CO$_{2}$, and O$_{2}$ in atmosphere - Ethylene Ketals - Very weak Brønsted bases (pKa of conjugate acids is ca. -5), similar to ethers - Very weak nucleophilicity, similar to ethers - Weak electrophilicity (alkoxides are poor leaving groups) - Hydrolyzed in aqueous strong acid (e.g., HCl, H$_{2}$SO$_{4}$) to generate ketone or aldehyde - Stable to most reducing agents (e.g., H$_{2}$, LiAlH$_{4}$, Na) and oxidizing agents (if non-acidic) - Amines (e.g., RNH$_{2}$, R$_{2}$NH) - Moderately strong Brønsted base (pKa of conjugate acid RNH$_{3}^{+}$ is 9-12) - Stronger base than H$_{2}$O, weaker than OH$^{-}$ (pKa of their conjugate acids is -1.7 and 15.7) - Strong nucleophilic character (greater than H$_{2}$O since N is less electronegative) - Very weak Brønsted acid (pKa to form amide anion (RNH$^{-}$) is ca. 38) - Weak electrophile (not much δ+ character on carbon of C-N bond) - Not subject to nucleophilic attack since amide anion (NH$_{2}^{-}$) is a very poor leaving group - Sodium Cyanoborohydride (NaBH$_{3}$CN) - Polarized B-H bonds from B (Pauling EN 2.0) to more electronegative H (EN 2.1) (but not polarized as much as Al-H bonds in LiAlH$_{4}$) - BH$_{3}$CN$^{-}$ has formal negative charge on B (but B is actually electron deficient!) - Excess electrons actually distributed at 3 H atoms, H atoms have significant δ- character - Electron-withdrawing cyano group reduces excess electron density on hydrogens - Behaves as a soluble equivalent of hydride anion - Reacts as nucleophilic equivalent of hydride anion with electrophilic species but is less nucleophilic than NaBH$_{4}$ and LAH (reacts with iminium ions but not carbonyls if pH > 5) - Less basic than NaBH$_{4}$ and reacts slowly with water even under mildly acidic conditions - Amides (RCONH$_{2}$, RCONHR, RCONR$_{2}$) - Moderately electrophilic carbonyl group; less electrophilic than esters due to greater delocalization - Weak Brønsted base pKaH ca. -1, protonated on oxygen (pKaH of amines RNH$_{3}^{+}$ is 9-12) - Weak nucleophile, generally reacts on oxygen (note structure of resonance hybrid) - Weak Brønsted acid pKa ca. 15, comparable to H$_{2}$O, ROH (pKa of amines is ca. 35-38) - Four-membered cyclic amides (β-lactams) are more electrophilic than acyclic amides - Enolates - Highly polarized covalent oxygen-metal bond in organic solvents (e.g., THF) - Strong nucleophiles with negative charge character on both oxygen and carbon - Reactivity as nucleophiles is related to pKa of conjugate acids - Ambident nucleophiles, react at oxygen with very reactive electrophiles (e.g., acyl chlorides, Me$_{3}$SiCl - will not be studied in 5.12) - Ambident nucleophiles, react at carbon with most carbon electrophiles (e.g., alkyl halides, carbonyl compounds) - Lithium Diisopropylamide (LDA, LiN(i-Pr)$_{2}$) - Very strong Brønsted base (pKa of conjugate acid R$_{2}$NH is ca. 35) - Weak nucleophilic character due to steric shielding of nitrogen - Reactions with electrophiles (R-X, carbonyl groups) slow - Soluble in THF even at -78 °C - Benzenoid Aromatic Compounds - Strong, non-polar C-C and C-H σ bonds - Negligible electrophilic character (unless strongly electron-withdrawing substituents) - Relatively weak acidity (pKa 40-45) - Polarizable π electrons - moderate nucleophilic character - Less nucleophilic compared to alkenes and non-aromatic polyenes since electrophilic attack disrupts aromaticity - Requires especially strong electrophiles for addition to π system