Orbitals, VKA

"Orbitals in Organic Chemistry"

Neighbouring group participation in S_N2 reactions: faster with allyl, benzyl and α-carbonyl halides due to stabilisation of the carbon 2p orbital in the transition state
Stereochemistry of E2 eliminations (requirement that acidic hydrogen and leaving group are antiperiplanar) arises due orbital geometry
Order of stability of carbocations (3° > 2° > 1° > methyl) is due to hyperconjugation of C-H σ bonds with empty 2p_z orbital of the cationic trigonal planar carbon
Grob fragmentation
- C-C σ bond donates its electron pair into a C-OMs σ* orbital, breaking the C-C and C-OMs σ bonds
- OH lone pair donates its electrons into C-C σ*, forming C=O π bond and breaking the C-C σ bond
- See also Eschenmoser fragmentation and this 2010 review: Synthetic Applications of the Carbonyl Generating Grob Fragmentation
Orbital effects on conformation
- C-H σ → C-H σ* hyperconjugation as a contributory factor in the preference of ethane for a staggered conformation
- C-H σ → C-F σ* hyperconjugation is much better than C-F σ → C-F σ*, so 1,2-difluoroethane prefers a gauche conformation. This is called the gauche effect.
Anomeric effect — pyrans
- Important in carbohydrate conformation
Esters prefer the conformation that allows the non-carbonyl oxygen to donate a lone pair into the carbonyl C-O σ* orbital
- Lactones normally cannot access this conformation, so they are more reactive

Pericyclic reactions

Diels-Alder reaction (regio- and stereoselectivity)
- Cyclopentadiene > furan (often reacts reversibly because aromaticity is lost) > pyrrole (poor diene for DA)
Acyclic dienes (e.g. 1,3-butadiene) need to adopt the s-cis conformation to react, although the equilibrium lies heavily in favour of s-trans
- Isoprene reacts better as its methyl group sterically clashes with a methylene H in both s-trans and s-cis conformations, pushing the equilibrium further towards s-cis than usual
- 4-methylpenta-1,3-diene reacts very poorly as its s-cis conformation is heavily sterically crowded
- 3-methylenecyclohex-1-ene does not react at all, as it is locked in the s-trans conformation
Dienophiles with electron withdrawing groups work best (lowest LUMO)
- Maleic anhydride and maleate esters are excellent, methyl acrylate very good, 1,3-butadiene OK
Dienes with electron donating groups work best (highest HOMO)
- Danishefsky's diene is exceptionally good
Woodward–Hoffmann rules
- for an allowed thermal cycloaddition process, (4n+2) π electrons are required
- [2+2] cycloadditions are symmetry forbidden, fail thermally, proceed photochemically
Endo rule
Lewis acid catalysis (e.g. SnCl₄) lowers LUMO of dienophile, increasing rate and selectivity
Nitrone, ozone and nitrile oxide [3+2] cycloadditions
- Nitrone + alkene → isoxazolidine
- Ozonolysis: first step is O₃ + alkene → molozonide
- Nitrile oxide + alkene → isoxazoline

Sigma (σ bonds), tropic (movement)
The main class is [3,3] sigmatropic rearrangements
Cope rearrangement (all carbon in the cyclic TS)
Claisen rearrangement (oxygen in the cyclic TS)
- Industrial synthesis of citral (BASF)
oxy-Cope rearrangement (oxygen present, but outside the all-carbon cyclic TS)

5- and 6-endo-tet cyclisations are disfavoured
3-, 4-, and 5-endo-trig cyclisations are disfavoured; 6- and 7-endo-trig are favoured