Carbonyl Chemistry: Learn Six Mechanisms For the Price Of One

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30 thoughts on “Carbonyl Chemistry: Learn Six Mechanisms For the Price Of One”

1. i need a pdf with all carboylic acid derivaitves
   and list of all organic derivatives

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2. Hello, I’d like to know how could we tell which functional group in a molecule is more reactive than the other, in other words : on which functional group the reaction will take place ( like in the case of addition or protonation). I also have the same question but this time for atoms in the same functional group like for example which oxygen in an ester is more basic and thus would undergo protonation by an acid or in the case of the last reaction in this post ”Conversion of carboxylic acids to anhydrides” why was it the oxygen with the H that did the 1,2 addition and not the oxygen with the double bond ? it’s the same atom (O) and it has the same number of lone electron pairs (2). do you have a post or several posts that covers all of these questions ? If yes could you please provide the link(s) to them ?

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3. The RDX step of acyl substitution-elimination reactions like all those above is the formation of tetrahedral intermidiate,so rate of reactions should almost depend on the energy of Transition state of this step and this Transition state only consists of formation of transition bond of nucleophile with carbonyl carbon and breaking of carbonyl oxygen pi bond.There is no role of the bond of the leaving group(LEAVING GROUP:the group which leaves at last) .Then why rate of acyl substitution depend on the tendency of leaving group to leave(eg. acyl chloride are most reactive and amides are least reactive).

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4. Great post as always!

   In Klein’s text, he explains that protonation of the carbonyl O is not likely in the production of imines or enamines. So that threw me a bit off.

   Secondly, in your mechanism for anhydride 1,2-addition, the arrow doesn’t make sense. (At least from my perspective)

   Thanks!

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5. If it helps anybody, the mnemonic PAPER works for this mechanism; it’s not super specific, but IMO mnemonics are meant to help rejog your memory:

   Protonate Carbonyl
   Addition of Nucleophile
   Proton Transfer
   Eliminate H2O
   Restore Carbonyl via Deprotonation

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6. Omg I can’t even express in words how useful this website is for my exam preparation.
   THANK YOU. Really appreciate it:D

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7. Hi James,

   I love this! Isn’t the anagram a bit misleading for the formation of imines? I get that you need to protonate the O at some point but surely as a 1st step it would inhibit the approach of the RNH2 (which would also presumably protonate before C=O)

   Thanks, Tom

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8. Hi,
   I have a huge orgo 2 exam in two weeks. I’m a little confused about the mechanisms. I’m always confused on what will be protonated/ deprotonated in the different mechanisms. I’m still waiting for that lightbulb to go off haha. My professor wants us to memorize the mechanisms, but I’d like to know exactly why all the steps in each mechanism happen the way they do. I really want to understand this better. Help =(

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9. In the conversion of carboxylic acid to anhydride mechanism, the second structure isn’t right, the proton is on the wrong oxygen.

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   1. Shoot. You are correct. Thanks for the spot.

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10. I’d go a bit perverted if it were one of my organic chemisty students, but I like the idea of an acronym. I try to use words that sound like what’s actually happening. So, for example, instead of PAPED I would use PATED (or RAPED) and make it the Penis (Proton) Added himself, Transferred himself, got shit on (Eliminated), and De-Penified (got cut off). So P for Penis (and Proton), Added, Transferred, got shit on (Eliminated), and cut off (Bobbit style). Would likely work well for guys but equally good for girls, so I have found.

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11. On the proton transfer (step 3) why shouldnt it say electrophilic?

    “where a proton is transferred from the *nucleophilic* atom to a different atom (either O or N)”

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    1. If you read it again it says “which previously acted as a nucleophile”.
       Electrophilic substances are either positively charged or have vacant orbitals which attract electrons(or they are attracted to electrons?).In this case proton transfer from oxygen doesn’t make it an electrophile.

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12. This is why James’s is awesome. This helped me alot on my orgo 2 midterm.

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13. James,

    The fischer esterification mechanism (acetic acid with ethanol, sulfuric acid, and heat) in my text book is described as the following:

    1. Protonation of carbonyl oxygen from ethyloxonium ion
    2. nuclephilic addition of ethanol
    3. deprotonation of oxonium ion to form neutral tetrahedral intermediate
    4. protonation of hydroxyl oxygen
    5. 1,2 elimination
    6. deprotonation.

    Why may step three and four be as shown above rather than your described mechanism with an intramolecular proton transfer?

    Thanks Josh

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    1. I cheat here and draw “proton transfer” as one step. It’s possible to draw it in several different ways. The explanation in your textbook is probably more correct, but the net result is the same. I drew the alternative mechanism here (at bottom) – https://masterorganicchemistry.com/reaction-guide/conversion-of-carboxylic-acids-to-esters-using-acid-and-alcohols-fischer-esterification/

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14. I have one question with this reaction though James. It seems imperative that only one of the carbonyl groups is protonated. I understand, I think, that the carbonyl is more basic compared to the OH group on the carboxylic acid, but it seems to me, having both molecules(carbonyl functional groups) protonated, would be a problem. So Ive tried to figure out how a chemist would optimize only one of the acids being protonated, and can only come up with a speedy addition of the acid catalyst, to an already under mild reflux conditions. It just seems to make sense, the quicker this reaction can happen, the better. The longer the acid catalyst remains with the molecule in question, the longer it has to protonate both of the carbonyls. Also the acid catalyst and the amount used must play a part in this. Theoretically, we only want half the molar amount of the carboxylic used, but considering how it is being regenerated, perhaps even a much smaller amount would be better, would reduce the amount of carbonyls being protonated, hence that is probably how a chemist would go about this. USE the minimal amount of catalyst. I also thought of what catalyst would be best used. I thought of H2SO4, but need to look at the pKa of this diprotic acid, as the goal is to remove the H2O formed, and not turn it back into an acid, that will play a further role. Anyway, just thinking this though. Thankyou. I have my butanoic to play with, and pretty sure I can work on this.

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15. what I meant was that water remained in the DS trap, and the mix started to drip back into the pot, like you said. Water forming, to me at least proves the mech, so I think this is what has happened.

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16. Yes, for water to of formed, the mechanisms must of worked. The DS reasonably quickly started to fill with two layers. So I’d take it the anhydride would be within the mix of the toluene, carboxylic acid used, and as stated the water is now removed. So the next step is using a good long column, (vigreux – maybe) to separate. Am I making sense, or got things backwards.

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17. Thanks for the response James. So if i am getting this right, the co – solvent and toluene is somewhat bonding well, thus allowing the water to be separated via a DS trap. What I do not understand, and feel I need to, is how can carboxylates bond well with say methyl benzene. I could sort of understand this with butanoic acid,(4 carbons and their H’s, but for acetic acid, which has a methyl group and a carboxylic acid which would H bond with itself, and with water. I am confused. Obviously. Ill look up the use of co solvents(DS traps) with respect to driving of water, and see where I land. This is good, as I am learning via such a problem. etc. Sorry if this is annoying. !!

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    1. Well, water and toluene (as well as water and benzene) form an azeotrope, and boil off together. The distillate ends up in the Dean Stark trap, and the water, being more dense than toluene, settles at the bottom and doesn’t come out. Excess toluene fills the trap, and trickles back down into the reaction flask.

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18. oops, reflux conditions (not concoctions)

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19. I always assumed that the making of anhydrides was a little more trickier than what has been presented here. I assumed that for an eg, acetyl Chlorides were required due to the chloride being a better leaving group. – but hey, Im an undergrad and here to learn. But still surprised to see that latter reaction.

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    1. Well, there are two big ways. The first is the way you mentioned – adding carboxylates to acid halides, and this forms anhydrides. The second is by heating carboxylic acids with acid, which leads to loss of water (hence, “anhydrides”)

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       1. I’d love to experiment with this. I dare say separating water from the formed anhydride from the mix would be necessary. The densities are pretty close, and under reflux concoctions DS would be out, so perhaps just a HCl catalyst, with acetic acid under reflux with a (DRY) CaCl2 drying tube fitted at the end. I wish my chem Professors would allow me to explore this, say with butanoic acid – as stinky as it is, but bypasses the issue of anhydrides and their legalities with respect to acetic and propanoic. Anyway, thankyou for your response.

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          1. It’s not a very broadly useful method since it can only make symmetrical anhydrides, but this almost certainly how commercial acetic anhydride is made.
             Re: butanoic acid, why rule out Dean-Stark? Use benzene or toluene as co-solvent, the water will be driven off, allowing the reaction to go to completion. Although you will probably want to avoid social contact afterwards…..

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20. SIR MY CHEMISTRY IS VERY WEAK
    . I’M 2nd year student plzzzzzzzzzzz help me

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    1. LOL good luck

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21. Hi James,

    In McMurry’s ‘Organic Chemistry’, they give the imine mechanism (and similar ones) like this:

    1. Nucleophilic attack on the carbonyl carbon
    2. Proton transfer from the nitrogen to the carbonyl oxygen
    3. Protonation of the hydroxyl to form a good leaving group
    4. Elimination of water
    5. Deprotonation

    —-

    I’ve read both ways: yours appears in ‘Instant Notes’ and elsewhere.

    So which is correct? Or does it not matter? I’m just wondering, in my exam, if I give one or the other, will it matter?

    Cheers
    Peter

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    1. Good question – it depends on pH. At neutral pH it operates similarly to what you mentioned. It’s also slower. As you go to lower pH, you’ll start to protonate the carbonyl oxygen (through the mechanism mentioned in this post) which results in a faster reaction.

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