Bürgi-Dunitz Angle & Nucleophillic Addition What is it & why is it important in this experiment? Trajectory of approach between nucleophile & carbonyl of aldehydes & ketones. Controls product diastereoselectivity in nucleophillic addition to RCH=O & RR’C=O. Future connections to Felkin-Anh model for nucleophillic addition to α-chiral RCH=O & RR’C=O. Experimental observations by Bürgi & Dunitz (1974) Analyzed X-ray crystal structures of compounds containing amine nucleophiles & carbonyl electrophiles within the same molecule. Where are the amine groups located? => always adjacent to the carbonyl.

Combined effect (according to molecular mechanics calculations) (Experimental observations, cont’d) Draw a straight line between the amino group (nucleophile) & the carbonyl carbon: the angle from the line to the plane of the carbonyl was found to be 105 ± 5°. The carbonyl bond length increases w/ the approach of N. Interpretation: Nucleophile attacks through electrons in σ HOMO orbital. Electrons flow to empty π* orbital. π* orbital ideally @ 90° to plane of carbonyl…… But, electrons in σ MO are repulsed by electrons in (filled) carbonyl π orbital Overall situation: Currently accepted value: 107° + = Combined effect (according to molecular mechanics calculations)

Take-home message: Any portions of the molecule that interfere w/ the Bürgi-Dunitz trajectory will slow the rate of nucleophillic addition (i.e. steric hinderance). Consider rate of complex hydride (e.g., NaBH4 or LiAlH4) addition to cyclic & especially bicyclic ketones.

Complex Hydrides Simple hydrides: NaH, CaH2 Complex hydrides: [Na][BH4], [Li][AlH4] What is the difference? Simple hydrides act as bases; complex hydrides act as nucleophiles in the reduction of carbonyl compounds Why do simple hydrides act as bases & not nuclueophiles? Simple hydrides have small, filled 1s orbital This is ideal size to interact with the σ* orbital in an H-O, H-N etc. bond Too small to interact π* in carbonyl bond. Why do complex hydrides reduce the C=O bond? Example: BH4- has four B-H σ bonds as HOMO orbitals. These σ bonds have p-character from B atom, and hence are larger. Better overlap with π* in carbonyl bond as LUMO orbital.

Selectivity-reactivity of complex hydrides NaBH4 is weak hydride donor: Stable in aqueous or alcoholic solution. Reduces aldehydes & ketones, but neither esters nor carboxylic acids nor nitro groups. LiAlH4 is strong hydride donor: Reacts violently with all proton donors & produces H2 gas (flamability!). Reduces all carbonyl compounds to alcohols. Aluminum is more electropositive than boron, and so more readily gives up H-.

Volatile Solvents The fire hazard associated with a flammable liquid is usually based on its flash point: Flash point (from Wikipedia): the lowest temperature at which volatile material can vaporize to form an ignitable mixture in air. A certain concentration of vapor in the air is necessary to sustain combustion, & that concentration is different for each flammable liquid. The flash point of a flammable liquid is the lowest temperature at which there will be enough flammable vapor to ignite when an ignition source is applied. Many laboratory solvents have flash points below room temperature. Solvent BP (C) Flash Point (C) Diethyl ether 37 -49 Hexane 68 -7 Acetone 58 Toluene 111 40 Ethanol 78 55

The Reflux Process Reflux is the process by which a substance cycles from the liquid to the gas phase and back again. Occurs at a constant temperature determined by the substance’s boiling point. Practical means of controlling the temperature of a reaction. Use reflux condenser if necessary, cooled with running water (especially for highly volatile liquids). Check for condensation above surface of liquid, especially in lower neck of condenser. Most basic model is Liebigs condenser: ***For running reactions under reflux overnight, it’s necessary to wire the water hose to the condenser (water pressure will fluxuate)***

Extraction Extraction is frequent part of work-up Work-up: process by which product is initially isolated from reaction mixture. Extraction serves to remove product from one solution phase & concentrate it into another. E.g., extract from aqueous phase into organic phase. Frequently necessary to extract the aqueous phase x2 – x3 with organic solvent, especially if the reaction product is partially soluble in water. More efficient to extract several times w/ small volume of solvent than it is a single time with a large volume. Relative densities of different solvents (which layer is which?): Solvent Density (g/mL) Diethyl ether, hexane, toluene, ethyl acetate < 1 Water 1 Dichloromethane, chloroform > 1

Proper procedure for use of separatory funnel – how to avoid an “explosion”: Check to be certain that the “tap” on the funnel correctly holds liquid. Be certain that the liquids that you wish to extract are at room temperature. Add reaction mixture + solvent (or water) Gently swirl the separatory funnel to discharge gases (degas) Place stopper, quickly invert the funnel & open the tap (listen for gases escaping the funnel through the stem) DANGER! Point the stem of the funnel AWAY from people! Gently swirl or shake once (with stopper) & listen again for gases through stem. Rigorously shake for 5-10 seconds (upside down), degas & remove stopper Leave funnel in ring stand until the phases have completely separated degas shake settle