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Ambident Nucleophiles. +. By Jane Moore June 2004. What is an Ambident Nucleophile?. Certain nucleophiles may be represented by two or more resonance forms, in which an unshared pair of electrons may reside on different donor atoms. Examples include:- Cyanide Thiocyanate Amide anion
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Ambident Nucleophiles + By Jane Moore June 2004
What is an Ambident Nucleophile? Certain nucleophiles may be represented by two or more resonance forms, in which an unshared pair of electrons may reside on different donor atoms. Examples include:- • Cyanide • Thiocyanate • Amide anion • Enolate • Phenoxide The nucleophile may potentially attack using two or more different modes leading to two or more possible alternative products depending on the reaction conditions. Reagents with the ability to do this are known as Ambident nucleophiles.
The Hard/Soft Acid Base Principle In some cases it is possible to accurately predict the way in which an ambident nucleophile will react. Organic chemists have a number of key concepts which enable them to do this. The first we shall consider is the Hard/Soft Acid Base Principle. Hard Bases Donor atoms have high electronegativity (low HOMO) and low (nucleophiles) polarizability and are hard to oxidize. They hold their valence electrons tightly. Soft Bases Donor atoms have low electronegativity (high HOMO) and (nucleophiles)high polarizability and are easy to oxidize. They hold their valence electrons loosely. Hard Acids Possess small acceptor atoms, have high positive charge and (electrophiles) do not contain unshared electron pairs in their valence shells. They have low polarizability and high electronegativity (high LUMO). Soft Acids Possesslarge acceptor atoms, have low positive charge and (electrophiles) contain unshared pairs of electrons (p or d) in their valence shells. They have high polarizability and low electronegativity (low LUMO) n.b “The HSAB principle is not a theory but a statement of experimental facts.” Pearson, R.G, Songstad, J.Amer.Chem.Soc., 1967, 89, 1827
Hard Bases Soft Bases Borderline Bases Hard Acids H2O OH- F- R2S RSH RS- Soft Acids ArNH2 C5H5N AcO- SO42- Cl- I- R3P (RO)3P N3- Br- H+ Li+ Na+ Cu+ Ag+ Pd2+ Fe2+ Co2+ Cu2+ CO32- NO3 ROH CN- RCN CO NO2- K+ Mg2+ Ca2+ Pt2+ Hg2+ BH3 Zn2+ Sn2+ Sb3+ RO- R2O NH3 C2H4 C6H6 Al3+ Cr2+ Fe3+ GaCl3 I2 Br2 Bi3+ BMe3 SO2 RNH2 H- R- BF3 B(OR)3 AlMe3 CH2 carbenes R3C+ NO+ GaH3 AlCl3 AlH3 SO3 C6H5+ RCO+ CO2 HX (hydrogen-bonding molecules) Pearson Classification of Acids and Bases Table 1 Hard and Soft Acids and Bases Borderline Acids
Hard/Soft Acids and Bases • Rule: Hard acids prefer to bond to hard bases, and soft acids prefer to bond to soft bases (there is an extra stabilisation if both the acid and base are hard or if both the acid or base are soft) • The terms hard and soft do not mean the same as strong and weak! • The HSAB principle predicts that in the above example the equilibrium will lie to the right because the hard acid CH3CO+ has a larger affinity for the hard alkoxide RO- base than for the softer RS- base. • The simplest hard acid is the proton and methyl mercury cation is the simplest soft acid. In the above example, if the equilibrium is to the right then the base (B) is soft, however if it is to the left the base is hard. • Soft lewis acids and soft bases tend to form covalent bonds whereas hard acids and hard bases prefer to form ionic bonds (see next slide).
Hard/Soft Acid Base Principle- Molecular Orbital Theory • Hard acid (high LUMO)/ hard base (low HOMO)interaction is an ionic interaction. • Soft acid (low LUMO) and soft base (high HOMO) interactions have the orbitals closer in energy which gives covalent bonding.
The Symbiotic Effect • SN2 reaction has a TS analogous to acid-base complex. • When several hard ligands (or several soft ligands) cluster around the reaction centre this leads to a stabilisation of the TS giving rise to an increased rate of reaction. This is known as a symbiotic effect i.e for the diagram shown opposite when B and B’ are both hard (or both soft). Table 2 reactivity ratio’s for methyl halides in water at 25 °C. Also, increasing numbers of hard bases on the acceptor makes the acceptor atom hard and increasing numbers of soft atoms makes it soft e.g. BF3 is hard and BH3 is soft.
MO Theory - Illustrative Examples • OH-is a hard nucleophile, the charge is situated on oxygen (which is small and highly electronegative) and therefore reacts quickly with the hard electrophile such as the proton. • Alkenes are very soft uncharged nucleophiles with high HOMO’s, they react most easily with Br2 which is a soft electrophile possessing a low energy LUMO.
Enolate Reactivity Orbital vs. Charge Control • (1) shows a soft-soft molecular orbital controlled reaction, this gives rise to bond formation at carbon (which has the largest HOMO coefficient) orbital control. • (2) shows a hard-hard charge-controlled process. The largest quantity of charge density resides on the oxygen atom and the new bond is formed at oxygen under charge control.
πOrbitals Of The Enolate Anion • HOMO orbital is polarized away from O. However, O is site of most charge (hard) and is attacked by charged electrophiles (hard). • Uncharged electrophiles possessing low lying LUMO’s attack at the site with largest coefficient in the HOMO ie at C. • The ψ1lowest energy orbital is polarisedtowards O. ψ3* LUMO ψ2HOMO ψ1 Hard acids attack oxygen, soft acids attack carbon due to closer HOMO/LUMO overlap
Effect of The Leaving Group • The aceto-acetate anion is soft due to charge delocalisation over several atoms. The predominant product with the soft alkyl halide results in C-alkylation (orbital control). • Variation of leaving group X leads to different product ratio’s i.e increasing the electronegativity of X increases the proportion of charge control. Table 2
Ambident Nucleophiles -The Influence of Reaction Mechanism • SN1 mechanism- the nucleophile attacks a hard carbocation • SN2 mechanism- the nucleophile attacks the carbon atom of a molecule which is a softer acid. • The more electronegative atom of an ambident nucleophile is harder than the less electronegative atom, therefore moving from an “SN1 like” to “SN2 like” mechanism means that the ambident nucleophile is more likely to attack via it’s less electronegative (softer) atom.
Lewis Acids Consider, + • Alkyl halides are soft electrophiles in SN2 reactions and therefore react with the soft carbon anion of cyanide leading to the nitrile product. • Addition of lewis acids (Ag+, Hg2+, Zn2+) assists the leaving halide ion. This gives rise to a development of charge on the carbon atom undergoing substitution (more SN1 like in character). Carbonium ions are hard and this causes cyanide to react via the harder nitrogen atom leading to isocyanides.
Alkylation of 2-Hydroxypyridine K+ counterion does not coordinate to I leaving group closely therefore reaction is via SN2 TS alkylation at soft N atom. Ag+ is able to coordinate effectively to I leaving group therefore reaction is via hard SN1 TS alkylation at hard O atom Me-I alkylation, even in the presence of silver still gives 74% N-Me product. Et-I allows a greater amount of carbonium SN1 character to form than Me-I (due to Et-I better ability to stabilise charge).
Steric Effects The proportion of C-alkylation increases in the order Me < Et < iPr (exclusively C-alkylation) • When one of the nucleophilic centres is sterically more accessible than the other these steric factors have a significant influence on the proportion of alkylation products obtained. • The above example shows how increasing the steric hindrance around oxygen leads to alkylation of the para carbon. • Steric hindrance in the alkyl halide electrophile augments this effect leading to even more C-alkylation.
Aprotic Solvents- Increasing polarity favours alkylation at hard centre. The ambident anion is usually coordinated to some extent with cation (ion pair) so that the atom of highest e- density (hard atom) is screened, thus hindering rxn at hard site. Solvent ability to solvate cations disrupts ion pair formation. Polar aprotic (and dipolar aprotic solvents) are extremely effective at weakening ion pair coordination by cation solvation rxn occurs at atom of high e- density (hard atom). Solvation Effects Table 3 Dipolar aprotic solvents such as DMF, DMAA, DMSO, HMP further hard centre alkylation. THF>dioxane>isopropyl ether>Et2O>benzene, toluene, n-heptane,methylcyclohexane
Protic Solvents act as hydrogen bond donors which solvate anions (especially hard electronegative oxygen). This leaves the soft atom of the nucleophile free to react. Solvation Effects DMF, THF, Et2O and toluene give exclusively O-alkylation. Protic solvents for example simple aliphatic alcohols do not have enough H-bonding capacity to change from O to C-alkylation. However, H2O, phenol and fluorinated alcohols form far stronger hydrogen bonds significant C-alkylation
The - Effect • A principal factor determining the nucleophilicity of a given nucleophile is not only basicity and polarizability but also the -effect. • A phenomenon by which nucleophiles flanked by a heteroatom (possessing a lone pair) such as; HO2-, ClO-, HONH2, N2H4 and R2S2 are much more nucleophilic than one would expet from their pKa values. Increased nucleophilicity with electrophiles possessing any soft character at all. Lowest E LUMO
Summary Although we cannot predict exactly how an ambident nucleophile will react with every single electrophile, we can however adjust the reaction conditions in order to favour one mode of reaction over the other. • Reaction at a hard nucleophilic atom • Hard electrophile • Polar/ dipolar aprotic solvent • Soft lewis acid such as Ag+ • Reaction at a soft nucleophilic atom • Soft electrophile • Non-polar aprotic solvent or protic solvent • Hard lewis acid such as Na+
References & Further Reading • “Advanced Organic Chemistry, Reactions ,Mechanisms and Structure”, (4th Ed), Jerry March, 261-263. • Pearson. R.G, Songstad. J., J.Amer.Chem.Soc., 1967, 89, 1827 • Shevelev. S.A., Russ. Chem. Rev., 1970, 39, 844-858. • Gompper. R., Wagner. H., Angew.Chem. Int. Ed. Engl.,1976, 15, 321-390. • “Frontier Orbitals and Organic Chemical Reactions”, Ian Fleming, Ch 2 & 3. • Kornblum., J.Amer.Chem.Soc,1955, 77, 6269 • Hobbs. C.F., McMillin. C.K., Papadopoulos. E. P., J.Amer.Chem.Soc., 1962, 84, 43.
