Reactions of Aromatic Molecules
Last updated: March 9th, 2023 |
Birch Reduction of Electron-Rich and Electron-Poor Aromatic Molecules – Examples and Mechanisms
The Birch Reduction is a process for converting benzene (and its aromatic relatives) to 1,4-cyclohexadiene using sodium (or lithium) as a reducing agent in liquid ammonia as solvent (boiling point: –33°C) in the presence of an alcohol such as ethanol, methanol or t-butanol.
Table of Contents
- The Birch Reduction
- Mechanism Of The Birch Reduction
- Don’t Confuse Na/NH3 With NaNH2/NH3
- Substituent Effects In The Birch Reduction
- Aromatic Rings With Electron Withdrawing Groups (EWGs) Are Protonated Adjacent To The EWG
- Aromatic Rings With Electron Donating Groups (EDG’s) Are Protonated On The Carbon “Ortho” To The EDG
- (Advanced) References and Further Reading
1. The Birch Reduction
When benzene is treated with metallic sodium (or lithium) in liquid ammonia as a solvent, in the presence of a proton source (e.g. ethanol, methanol, or t-butanol) the result is the net reduction of one of the double bonds of the benzene ring to give 1,4-cyclohexadiene. This reaction is known as the Birch reduction. [Note 1]
(I say “net” because two C-C pi bonds are broken and one C-C pi bond is formed)
Ordinary alkenes are unaffected by Birch reduction conditions. Conjugated alkenes can be reduced, however. Alkynes are partially reduced to give trans-alkenes under these conditions (see Na/NH3 reduction of alkynes)
2. Mechanism Of The Birch Reduction
Ammonia (NH3) is a gas at room temperature, boiling at a balmy –33 °C. Gaseous ammonia can be condensed to a liquid using a dry ice/acetone (–78°C) cold-finger, where it can serve as a solvent for alkali metals (e.g. Li, Na, and K). Although these metals are only sparingly soluble in liquid ammonia (about 1-5 g of Na per liter of NH3) the result is a spectacular blue color: once made, never forgotten.
The intense blue color is due to the presence of solvated electrons (e –) , swimming in the ammonia solution. [Note 2]
Upon meeting benzene, an electron adds to the aromatic pi system, resulting in a radical anion with seven pi electrons. [Note 3]
[Note that in the arrow-pushing mechanism, two C-C pi bonds are broken and one C-C pi bond is formed, which is why we said that the reaction results in the net breakage of a C-C pi bond].
Being strongly basic, the radical anion is immediately protonated at carbon by the alcohol. [Note 4]
The resulting pentadienyl radical can then accept a second electron from the “electron soup”, resulting in a new anion (a “pentadienyl anion”). (why pentadienyl and not hexadienyl? see Note 5)
It is at this stage where the presence of an alcohol (e.g. ethanol or t-butanol) becomes necessary, since NH3 is not a strong enough acid to protonate this anion.
Protonation of this species, at the central carbon results in the 1,4-cyclohexadiene. Studies by 13-C NMR indicate that the central carbon has the highest electron density.
So although we said that the reaction involves the net breakage of a single pi bond, actually we break two pi bonds and form one.
3. Don’t Confuse Na/NH3 With NaNH2/NH3
Birch reduction conditions can easily be confused for conditions that form sodium amide (NaNH2).
The key is to know the difference between sodium metal (neutral, easily gives up its single electron) in NH3 (solvent) and NaNH2 (sodium amide, strong base) in NH3 (solvent, also conjugate base)
For example this is not a Birch reduction – this is elimination of a chloride to form benzyne followed by attack!
Another common mistake is to imagine that the role of Na / NH3 is to put an NH2 on the ring. This is also incorrect.
4. Substituent Effects In The Birch Reduction
The next question to ask is, what happens when substituents are present on the ring? What kinds of products are obtained?
Since the “nucleophile” here is essentially free electrons (e – ) , the reaction is faster on aromatic rings with electron-withdrawing substituents (e.g. CO2H) and slower on aromatic rings with electron-donating substituents (OCH3).
Electron-withdrawing substituents and electron-donating substituents also give different products.
With electron withdrawing groups you get protonation adjacent to the electron-withdrawing group.
With electron donating groups like OCH3 you get protonation on the carbon adjacent to the carbon bearing the OCH3 (“ortho” to the -OCH3). Like this:
Why the difference?
When a substituent is present, the formation of the first C–H bond determines which product will form. This, in turn, depends on the site where the most stable anion will form.
5. Aromatic Rings With Electron Withdrawing Groups (EWGs) Are Protonated Adjacent To The EWG
When an electron-withdrawing group like CO2CH3 is present, the anion can be delocalized through resonance from carbon to oxygen (which being more electronegative, is much better at stabilizing negative charge). Recall that this is an example of the CO2CH3 being a pi acceptor.
The protonation thus occurs on the carbon bearing the electron-withdrawing (i.e. pi-accepting) substituent. [Note 6]
6. Aromatic Rings With Electron Donating Groups (EDG’s) Are Protonated On The Carbon “Ortho” To The EDG
When there’s a group that’s a strong pi donor (OCH3) then formation of an anion adjacent to that group is actually disfavored. Electrons repel, after all!
In this case the product is determined by placing the negative charge as far away from the pi-donating group as possible.
The resulting vinyl ethers can be hydrolyzed to ketones with aqueous acid. This process became particularly important in the development of steroid hormones, which led to the development of the birth control pill. For instance the synthesis of norethisterone from estradiol relied on a Birch reduction, which we explored a little bit in this post.
As Carl Djerassi once said, “Que viva Don Arturo Birch! ”
7. Birch Reduction of Anthracene
Another interesting dissolving metal reduction is that of the polyaromatic hydrocarbon anthracene.
Anthracene contains three aromatic rings and has a total resonance energy (i.e. the stabilization due to aromaticity) of 83 kcal/mol, or about 27.7 kcal/mol per ring (compare to 36 kcal/mol for benzene). [Ref]
Anthracene undergoes Birch reduction such that the central aromatic ring is reduced and a total of two hydrogens are added to the molecule. [Note 8]. The resulting hydrocarbon has two aromatic rings for a total resonance energy of about 72 kcal/mol. [Procedure here]
(Yes, the numbering system on anthracene is weird)
This is considerably more stable than, for example, reduction of the far aromatic ring to give a substituted naphthalene; naphthalene has a resonance stabilization energy of only 61 kcal/mol (approx 30.5 kcal/mol per ring).
Note 1. Although the reduction of toluene and methoxybenzene was first reported by Wooster and Godfrey in 1937, the reaction came to be known as the Birch reduction after Prof. Arthur J. Birch, an Australian chemist working as a postdoc under Nobel Laureate Robert Robinson, nailed down the structure of the product in 1944 as a 1,4-cyclohexadiene derivative . As noted by John Cornforth in Birch’s biography, Robinson (who was largely away from the lab at this time, assisting with the war effort) disapproved of the time Birch spent developing this reaction.
Birch’s second key contribution in the reduction of methoxybenzene was demonstrating that the enol ether could be hydrolyzed to a ketone. This reaction eventually became very important in the synthesis of steroid derivatives. The first chemist to call this reaction the “Birch reduction” was Carl Djerassi, the “father of The Pill”. [See: The Organic Chemistry Behind, “The Pill”]
Note 2. The nucleophile here is therefore not sodium but “electron”. A reaction that occurs without two molecules having to collide into each other might seem weird – like procreation without sex. The analogy to artificial insemination is apt, as the reaction can be conducted using a battery as a source of electrons without the need for any sodium whatsoever.
Note 3. Drawing out the molecular orbitals of the benzene “radical anion” is a good exam question.
Note 4. The second protonation event is responsible for the formation of the 1,4 diene. Why does the (non-conjugated) 1,4-diene form and not the (conjugated, therefore more stable) 1,3- diene? According to 13C NMR studies, the central carbon is more electron-rich and the rationale is that the reaction happens fastest (and irreversibly) at this position. This is therefore an example of kinetic control.
In the absence of a proton source like CH3CH2OH the first protonation happens (via the solvent NH3), but NH3 is not acidic enough to do the second protonation. If the alcohol (like CH3CH2OH or t-BuOH) is absent, the result is C-C bond formation between the reduced benzene rings.
Note 5. Why pentadienyl and not hexadienyl? Because there are 5 p-orbitals in the conjugated system (since the other carbon in the ring is now a CH2 and can’t participate in resonance).
Note 6. Since the reaction medium is quite basic, if protonation happened on oxygen the resulting product would quickly be deprotonated again. Protonation on carbon, on the other hand, is irreversible.
Note 7. This application of the Birch reduction as a “masking group” for a beta-keto ester is pretty clever. (Reference 7).
Note 8. Note that this is technically a “dissolving metal reduction”, not a “Birch reduction” since NH3 is not being used as the solvent.
(Advanced) References and Further Reading
This article from the In The Pipeline blog by Derek Lowe provides an accessible (no formulae), colorful, and interesting background on the Birch reduction, along with a discussion of a recent (2019) advance in the electrochemical Birch reduction (see reference 8).
Running A Birch Reduction. From ChemTips
These handouts on the Birch Reduction from the groups of Prof. Andrew G. Myers (Harvard) and Prof. Phil S. Baran (Scripps) are particularly useful for advanced undergraduate / graduate-level students
Nobel Laureate Sir John Cornforth wrote a biographical sketch of Birch in Biographical Memoirs of Fellows of The Royal Society. This paper also notes the first chemist to use the term “Birch Reduction” was Carl Djerassi.
- Umsetzungen von ungesättigten und mehrkernigen aromatischen Kohlenwasserstoffen mit Natrium und Calcium in flüssigem Ammoniak
Walter Hückel and Horst Bretschneider
Lieb. Ann. Chem. 1939, 540 (1), 157-189
- Mechanism of the Reduction of Unsaturated Compounds with Alkali Metals and Water
Charles Bushnell Wooster and Kenneth L. Godfrey
Journal of the American Chemical Society 1937, 59 (3), 596-597
These two papers were precursors for Arthur Birch’s work – these describe the reduction of aromatic compounds using Na/NH3.
- Reduction by dissolving metals. Part I
Arthur J. Birch
J. Chem. Soc., 1944, 430-436
Birch’s first paper (of many) on the reduction of aromatics by Na+NH3, which has since come to bear his name.
- The Birch Reduction of Aromatic Compounds
Rabideau, Peter W.; Marcinow, Zbigniew
Org. React. 1992, 42, 1-334
The significance of the Birch reduction should be evident here – this is the subject of a 300+ page review in Organic Reactions! This has everything you need to know on the reaction – history, development, mechanisms, reaction scope, and experimental procedures.
- A Mechanistic Analysis of the Birch Reduction
Howard E. Zimmerman
Accounts of Chemical Research 2012, 45 (2), 164-170
This account by Prof. Zimmerman (a very influential figure in modern physical organic chemistry) summarizes work that has been carried out to establish the mechanism of the Birch reduction.
- Reduction of Organic Compounds by Lithium in Low Molecular Weight Amines. I. Selective Reduction of Aromatic Hydrocarbons to Monoölefins
Robert A. Benkeser, Robert E. Robinson, Dale M. Sauve, and Owen H. Thomas
Journal of the American Chemical Society 1955, 77 (12), 3230-3233
Similar to other dissolving metal reductions, the conditions of the traditional Birch reduction can be extended – Li can be used in the place of Na, and NH3 can be substituted with low-MW amines (e.g. methylamine).
- Synthesis of 1,3-diol synthons from epoxy aromatic precursors: an approach to the construction of polyacetate-derived natural products
David A. Evans, Joelle A. Gauchet-Prunet, Erick M. Carreira, and Andre B. Charette
The Journal of Organic Chemistry 1991 56 (2), 741-750
The source of the reaction scheme in the footnote. From the lab of Prof. David Evans (Harvard), a towering figure in modern natural product synthesis.
- 1,4-DIHYDROBENZOIC ACID
M.E. Kuehne and B. F. Lambert
Org. Synth. 1963, 43, 22
A reliable and reproducible Birch reduction procedure in Organic Syntheses, a source of independently tested synthetic organic laboratory procedures. This also shows the regioselectivity of reduction for arenes with EWG’s.
- Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry
Peters, B. K. et. al.
Science, 22 Feb 2019: Vol. 363, Issue 6429, pp. 838-845
A tour de force study on conducting electrochemical Birch reductions without sodium or ammonia on a wide range of substrates.
- Resonance in Organic Chemistry
G. W. Wheland
Wiley, NY 1955.
Contains resonance energies for a large number of aromatic compounds based on thermodynamic data.
ISBN: QD471 .W57 1955
14 thoughts on “Birch Reduction”
“In the absence of a proton source like CH3CH2OH the first protonation happens, but not the second. The result is C-C bond formation between the reduced benzene rings.”
If no proton source is provided, how come will even the first protonation happen?
Good question. The first protonation is done by NH3 (solvent). I’ll update this paragraph. Thanks Spider
Thanks for solving the doubt.
1. You have claimed that olefins are are not reduced, but i think terminal olefins can be reduced. Correct me if I am wrong.
2. Could you please explain why it reduces selectively conjugative systems only?
3. Further reduction of 1,4-diene system happens if the reagent is added with alkyl amines, am i right? if yes, will it be stopped with olefin or produces cycloalkane?
Generally isolated alkenes are not affected by Birch conditions. In a Birch reduction the “nucleophile” is a solvated electron, and the electrophile is the lowest-unoccupied molecular orbital (LUMO) of the alkene. In a conjugated system the LUMO is considerably lower in energy than for an isolated alkene due to the larger pi-system.
It’s possible to increase the reducing power of the Birch by adding alkylamines (e.g. methylamine for the reduction of dienes like isoprene) but I have not seen examples for the reduction of isolated alkenes.
Why reduction stop at alkene in birch reduction?
Will the Birch reduction be added to the mechanism flashcards?
In the queue. Thanks for asking.
What is relative tendency of reduction of
1 tripple bond
2 conjugated double bond
3 Aromatic ring
My lecturer still called it a cyclohexadienyl radical/anion instead of pentadienyl. Is this something that varies depending on the person?
Depends on what stage of the reduction you’re talking about! The first addition of an electron products a cyclohexadienyl radical anion. After the first protonation happens, you get a pentadienyl radical, which is reduced to a pentadienyl anion by the second electron.
He called all of them cyclohexadienyl!
Hmmm. Once the protonation happens and the pi-system only involves 5 p-orbitals, it’s now become pentadienyl.
I’ll email him to see what he says!