Carbonyl Chemistry1
(Read pages 197-201 and review 127-140 in the LSM)
Consider the pKa values for the three following generic molecules:
R
-H
CH3
R
pKa = ~48
CH2
a carbanion
O
O
-H
R
CH 3
R
pKa = ~20
CH 2
an enolate ion
O
O
-H
R
OH
R
pKa = ~5
O
a carboxylate anion
Obviously the protons on the alkane are not very acidic, hence the pKa of 48. But why is
the pKa of an alkane so high? Well, consider its conjugate base. Deprotonation of an
alkane leads to a highly unstable carbanion. Now consider the conjugate base of a
carboxylic acid; a carboxylate anion. This anion is much happier than a carbanion
because not only is the charge located on an electronegative oxygen atom, it is resonance
stabilized as well (onto another oxygen atom!). As a consequence, carboxylic acids have
much lower pKa values. Well obviously they are acidic if they named the molecule an
acid! OK, what about a ketone? Clearly the protons of a ketone are more acidic than
those of an alkane (20 vs 48) and less acidic than those of carboxylic acids (20 vs 5). The
question is, why? Again, consider the conjugate base. Although the conjugate base of a
ketone, called an enolate ion, has the charge located on a carbon atom, it is resonance
stabilized (again onto an oxygen atom). It is crucial that you understand this acid-base
relationship if you are going understand the chemistry of carbonyl compounds. Although
ketones (and aldehydes) are not considered ‘acidic’, they are acidic enough to do a bucket
load of chemistry with.
Note that when we talk about the acidity of aldehydes and ketones, we are talking about
the acidity of the proton attached to the carbon atom that is adjacent to the carbonyl
group. We call this the alpha (α) proton. It is called alpha because each carbon atom
(along with their hydrogen atoms) successively attached to the carbonyl group is labelled
using the Greek alphabet. For example:
O
β
α
δ
γ
23
ε
OK, so what are the implications of this alpha-proton acidity? If you look closely at an
enolate ion, hopefully you can convince yourself that aside from being basic, it is also
nucleophilic. And when you have nucleophiles, you have the potential to do some
chemistry. Essentially, treat enolate ions as you would any other nucleophile (Scheme 1).
Nu
Br
O
R
+
Nu
O
CH 2
R
Br
O
+
Br
CH 2
R
Scheme 1
Another interesting thing about carbonyl compounds is that the carbon atom is
electrophilic (why?). So, if enolates are nucleophilic, and the carbonyl carbon is
electrophilic, it would be reasonable to conclude that they can react with each other
(Scheme 2).
O
R
O
O
CH 2
O
R
Scheme 2
This particular reaction is very important in organic chemistry. How important? It is
important enough to have its own name; the aldol reaction. An aldol reaction is an
addition of an enolate to an aldehyde or ketone.
In this experiment you will perform a crossed aldol condensation. An unknown cyclic
ketone 1 will be reacted with an aromatic aldehyde 2 in the presence of a base catalyst to
give an unknown product. The structure of the unknown product will be determined
using a combination of melting point data, IR and 1H NMR spectroscopy. The structure
of the starting cyclic ketone and aromatic aldehyde can, in turn, be inferred from the
structure of the aldol condensation product.
O
O
C
CH 2
+
NaOH
Ar
C
H2O/EtOH
H
1
2
24
Aldol
Condensation
Product
Br
Experimental – Week 1
Unlike most other labs in Chem2600, this experiment will be done in pairs.
1. Synthesis and Isolation.
• Prepare a water bath and stabilize the temperature to 75-80 °C.
• To a 25 mL Erlenmeyer flask, add 0.25g of your unknown ketone, 1.00g of
your unknown aldehyde, and 5 mL ethanol.
• Once everything is mostly in solution, add 3 mL of 3M NaOH. Swirl the
flask to mix the contents and then let stand for 15-30 min at room temperature
with occasional stirring.
A Note on Your Synthesis: Depending on your unknown ketone and aldehyde, there can
be a wide range of reactions rates. As such, I can’t give one specific protocol. In some
reactions, a thick precipitate will form almost immediately after the addition of base.
However, if little or no precipitates forms after 15 minutes at room temperature, then heat
the flask in your 75-80 °C hot water bath (be sure to add a few boiling stones!) for 15
minutes with occasional stirring. Allow the flask to cool to room temperature. Your
product should now precipitate. Occasionally, the product will ‘oil out’ rather than
precipitate. If this happens, first try cooling the flask in an ice bath with occasional
swirling and scratching. If this doesn’t induce crystallization, warm the solution in a 7580 °C water bath for several minutes then allow it to cool to room temperature.
•
•
•
•
After the appropriate reaction time (and after your product has precipitated),
chill the reaction mixture in an ice bath for 5-10 minutes before collecting the
crude product by suction filtration using a Buchner funnel.
Use 5 mL ice cold ethanol to assist in the transfer of the solid. Wash the solid
with 5 mL ice cold water followed by 5 mL ice cold ethanol.
After air drying, record the weight of your crude product.
Since some of the unknown aldehydes contain chlorine, the filtrate from this
reaction should be disposed in the halogenated waste container.
2. Recrystallizing your Product.
• Place your crude product in a 50 ml Erlenmeyer flask along with 2-3 boiling
stones.
• Add ethanol in 1 mL portions with heating in your 75-80 °C hot water bath. If
the solid hasn’t completely dissolved after adding a total of 10 mL of ethanol,
start adding toluene in 1 mL portion with heating (while some products may
dissolve in 5 mL ethanol, others may take as much as 25 mL of toluene). If
you need to add toluene, add only what is required to actually dissolve
your solid.
• Allow your solution to cool to room temperature, undisturbed.
• After the solution has cooled to room temperature and crystallization appears
to be complete, chill the reaction mixture in an ice bath for 5-10 minutes
before collecting the crude product by suction filtration using a Buchner
funnel.
25
•
•
•
Use a few milliliters of ice cold ethanol to aid in the transfer and to rinse your
product.
Place your crystals in a preweighed, clean and dry 50 mL beaker and store in
your locker until your next lab period.
Since some of the unknown aldehydes contain chlorine, the mother liquor
from this recrystallization should be disposed in the halogenated waste
container.
Experimental – Week 2
1. Characterization.
• Record the weight of your recrystallized product.
• Record the melting point and IR spectrum of your recrystallized product.
• The NMR spectrum of your product will be run by one of the Instrument
Room Technicians. To prepare your sample, first obtain a NMR tube and cap
from your instructor. Add ~ 20 mg of your sample and ~ 1mL (estimate using
a Pasteur pipette) of CDCl3 (available from your TA) to a small (and clean!)
test tube. Transfer the solution to the NMR tube using a Pasteur pipette. If
there is any undissolved solid, run the solution through a pipette filter directly
into the NMR tube. Cap the tube and add a label.
• Bring your sample to the NMR room when it is your turn.
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ALDOL CONDENSATION PRODUCT MELTING POINTS
Ketone
Aldehyde
Product mp (°C)
4-methylcyclohexanone
4-methylcyclohexanone
cycloheptanone
4-methylcyclohexanone
cycloheptanone
cycloheptanone
cyclohexanone
cycloheptanone
cycloheptanone
cycloheptanone
4-methylcyclohexanone
4-tert-butylcyclohexanone
4-methylcyclohexanone
4-tert-butylcyclohexanone
cyclopentanone
cyclohexanone
cyclohexanone
4-tert-butylcyclohexanone
cyclohexanone
cyclohexanone
4-methylcyclohexanone
cyclopentanone
4-tert-butylcyclohexanone
4-methylcyclohexanone
cyclohexanone
4-tert-butylcyclohexanone
4-tert-butylcyclohexanone
cyclohexanone
cyclopentanone
4-tert-butylcyclohexanone
cycloheptanone
cyclopentanone
cyclopentanone
cyclopentanone
cyclopentanone
2-furaldehyde
benzaldehyde
benzaldehyde
4-isopropylbenzaldehyde
2-furaldehyde
4-isopropylbenzaldehyde
benzaldehyde
4-chlorobenzaldehyde
4-methoxybenzaldehyde
4-methylbenzaldehyde
4-methylbenzaldehyde
2-furaldehyde
4-methoxybenzaldehyde
benzaldehyde
4-isopropylbenzaldehyde
2-furaldehyde
4-chlorobenzaldehyde
4-isopropylbenzaldehyde
4-isopropylbenzaldehyde
4-methoxybenzaldehyde
4-chlorobenzaldehyde
2-furaldehyde
4-methylbenzaldehyde
trans-cinnamaldehyde
4-methylbenzaldehyde
4-methoxybenzaldehyde
4-chlorobenzaldehyde
trans-cinnamaldehyde
benzaldehyde
trans-cinnamaldehyde
trans-cinnamaldehyde
4-methoxybenzaldehyde
trans-cinnamaldehyde
4-chlorobenzaldehyde
4-methylbenzaldehyde
96-97
98-99
108
112.5
114
116-117
118
125.5-127.5
128-129
131
133-135
137.5-138
141-142 (148)
142-143
143 (145.5)
145
146.5
150.5-151.5
151
159
161
162 (169)
162-164 (155.5-156)
163-164
169-170
174-175
177-178
181-182
189
197-198
198
212
225
226.5
235-236 (237.5-239)
1
The following lab is a modified version of ‘Aldol Condensation’ by Henry L. Gingrich and Miles
Pickering from ‘The Organic Puzzle Book (2006), and is reproduced with their kind permission.
27