Show how each amine can be prepared from a carbonyl and an amine via reductive amination.
Reductive amination is a two step process. First, an imine or enamine is formed from a carbonyl and an imine.
Then, a the imine (or enamine) is reduced to an amine (using reducing agents such as H2, NaBH4, NaBH3(CN), NaBH(OAc)3, etc.). For practice on forming imine and enamines, see problem 712).
MendelSet practice problem # 754 submitted by Matt on July 27, 2011.
For each amine below, show all Hofmann elmination products.
If more than one product is formed, predict which one will be the major product.
The Hoffman elimination first turns an amine into a better leaving group by methylating it with excess methly iodide, and then eliminates the methylated amine using base (such as -OH fomed from Ag2O in H2O). The products are alkenes.
This reaction is similar to an E2 elimination in that a beta proton is ripped off, and the alkene forms between alpha and beta. One notable difference from the E2 is that the less substituted product is favored, so Hoffman products are usually anti-Zaitsev.
a) There are three different types of beta protons, so three possible products can form. Product A is the least substituted alkene, so it's the major product.
b) There is only one possible product. The Hoffman elimination can't be done on aryl hydrogens (benzene rings).
MendelSet practice problem # 756 submitted by Matt on July 27, 2011.
Imidazole (shown below) has two nitrogen atoms, N-1 and N-3. Which nitrogen is more basic?
To answer this problem, draw the product after each nitrogen protonates, and compare their stabilities. Explain your reasoning.
Imidazole is aromatic. When N-3 protonates, the product is still aromatic.
But when N-1 protonates, the product is no longer aromatic (and therefore significantly less stable).
Because of this, N-3 is much more basic than N-1. Another way of thinking of this is that the lone pair on N-1 is involved in the aromatic circuit, and so is not available to pick up a proton.
MendelSet practice problem # 584 submitted by Matt on July 9, 2011.
Rank the amines A through D below in order of decreasing basicity (1 = most basic). Explain your reasoning.
sp2 carbons are more electronegative (electron withdrawing) than sp3 carbons due to increased s-character. Electron withdrawing groups (EWG) make acids more acidic and bases less basic.
For this reason, piperidine (compound A) is the more basic than pyridine (compound B):
(more basic) A > B (less basic)
Nitro (-NO2) is an EWG, so 4-nitropyridine (compound C) will be less basic than compound A.
Dimethylamine is an electron donating group (EDG), so it adds electron density to pyridine and increases basicity. So dimethylamino pyridine (DMAP, compound D) will be more basic than compound A:
(more basic) D > B > C (less basic)
So how does compound A compare with compound D? There is no way of predicting this based on EWG/EDG rules alone. After all, what should be more basic: piperidine, which has sp3 carbons (increases base strength), or DMAP, which has sp2 carbons (decreases base strength) but also an EDG (increases base strength) ?
There's no way to tell. But it turns out that Piperidine is a little more basic than DMAP. So the overal order is:
(more basic) A > D > B > C (least basic)
MendelSet practice problem # 752 submitted by Matt on July 27, 2011.
Propose a synthesis to accomplish each transformation. The only carbon sources allowed are alkenes and NaCN.
a) The starting alkene has 4 carbons, and the product has 5 carbons and a nitrogen. So you have to add 1C and 1N. This screams "add cyanide!"
Based on the location of the alcohol on the product, it looks like the way to go is to add NaCN to an epoxide. This puts the -CN and the -OH in the right positions.
b) The best way to prepare 2º and 3º amines is via reductive amination. Working backwards, the product can be prepared from a 4-carbon aldehyde (butyraldehyde) and a 3-carbon amine (propyl amine).
Performing hydroboration on the butene results in the anti-Markovnikov alcohol, which can be oxidized to the aldehyde using PCC.
To prepare propyl amine from an alkene, add HBr/peroxides to make the bromide (anti-Markovnikov), and then add NaN3 follow by H2/Pd.
MendelSet practice problem # 757 submitted by Matt on July 27, 2011.