Substitution Reactions

By James Ashenhurst

Common Blind Spot: Intramolecular Reactions

Last updated: May 23rd, 2021 |

So I bought a belt today (pleather, 75 cents at the Goodwill).  and decided to show it off. This is me putting it together.

belt analogy for intramolecular nucleophilic substitution reactions

This is what it looks like now:

image of two belts together

At this point you’re probably saying WTF: that’s not what a belt is supposed to look like when you put it together. That’s because I linked it together with my other belt.

I say: broaden your horizons of how nucleophiles and electrophiles can meet.

*****

Here’s a typical reaction you meet early on in Org 2. Formation of an ether through the addition of an oxygen nucleophile to an alkyl halide. This is the Williamson ether synthesis.

formation of ethers from alcohol and alkyl halide in presence of base is williamson ether reaction

Makes some sense, right? Nucleophile, electrophile: give the product.

Here’s the same reaction. Exactly the same. But a lot of students I talk to will look twice at it the first time they see it,  not quite sure what to do.

sodium hydroxide as base with alcohol alkyl halide leading to cyclic ether

Different example: the Friedel Crafts acylation between aromatic rings and acyl halides.

example of friedel crafts acylation reaction benzene alcl3 intermolecluar

Then, here’s the exact same reaction. Common result: hesitation. What happens?

apply same concepts of intermolecular reaction to intramolecular friedel crafts

Last example: formation of esters from alcohols and carboxylic acids. The Fischer esterification. Once people see this, they usually find it straightforward.

fischer esterification reaction intermolecular

But then hand them this reaction, and it’s a stumper.

fischer projection intramolecular

What do all of these reactions have in common?

When the nucleophile and electrophile are on the same molecule, they form RINGS.

examples of intramolecular reactions sn2 friedel crafts and lactonization

Because you’re probably used to seeing linear molecules – not chains – it looks weird.  But if you think about it, you’re already familiar with an example of this:

closing a belt is an intramolecular reaction


(Advanced) References and Further Reading

Control of intra- vs. inter-molecular reactions is commonly done by dilution. The former are favored at very low concentrations (high dilution), to minimize the probability of the molecule reacting with another molecule of itself.

  1. Ring closure reactions of bifunctional chain molecules
    Gabriello Illuminati and Luigi Mandolini
    Accounts of Chemical Research 1981, 14 (4), 95-102
    DOI:
    1021/ar00064a001
    Fig. 1 in this paper shows that the intramolecular formation of 5- and 6-membered rings is especially favored relative to other ring sizes.
  2. Ring-closure reactions. 22. Kinetics of cyclization of diethyl (.omega.-bromoalkyl)malonates in the range of 4- to 21-membered rings. Role of ring strain
    Maria Antonietta Casadei, Carlo Galli, and Luigi Mandolini
    Journal of the American Chemical Society 1984, 106 (4), 1051-1056
    DOI: 1021/ja00316a039
    Figure 1 in this paper also plots the relationship between ring size and rate of intramolecular cyclization, with a pronounced global maximum for 5-membered rings. The authors state that cyclizations for 9-11 membered rings “should be run at concentrations of less than 10-6 M in order to proceed free from polymerization!”.
  3. Ring-closure reactions. 7. Kinetics and activation parameters of lactone formation in the range of 3- to 23-membered rings
    Carlo Galli, Gabriello Illuminati, Luigi Mandolini, and Pasquale Tamborra
    Journal of the American Chemical Society 1977, 99 (8), 2591-2597
    DOI:
    1021/ja00450a031
    Esterification can also take place intramolecularly to give lactones, and as to be expected, 5-membered rings are the most favored, followed by 4 and 6, then 7, then other ring sizes (see Table I).
  4. Ring-closure reactions. 11. The activation parameters for the formation of four- to six-membered lactones from .omega.-bromoalkanoate ions. The role of the entropy factor in small- and common-ring formation
    Luigi Mandolini
    Journal of the American Chemical Society 1978, 100 (2), 550-554
    DOI: 1021/ja00470a032
    As shown in Fig. 2, DS values for intramolecular cyclizations are fairly negative and of the same magnitude as DH values, which is why it can be difficult to favor intramolecular reactions for large rings.
  5. Cyclization and polymerization of .omega.-(bromoalkyl)dimethylamines
    DeLos F. DeTar and Walter Brooks
    The Journal of Organic Chemistry 1978, 43 (11), 2245-2248
    DOI: 1021/jo00405a033
  6. Quantitative evaluation of steric effects in SN2 ring closure reactions
    DeLos F. DeTar and Narender P. Luthra
    Journal of the American Chemical Society 1980, 102 (13), 4505-4512
    DOI:
    1021/ja00533a033
    Cyclic amines can also be formed via intramolecular reactions and are subject to the same principles – 5- and 6-membered rings form fastest.
  7. Neighboring Group Participation by Carbonyl Oxygen
    J. Pasto and M. P. Serve
    Journal of the American Chemical Society 1965, 87 (7), 1515-1521
    DOI:
    10.1021/ja01085a019
    In this case, a carbonyl oxygen can aid with leaving group departure and form a cyclic ether, which is especially favored if a 5- or 6-membered ring is formed.
  8. Rules for Ring Closure
    Jack E. Baldwin
    Chem. Soc. Chem. Comm. 1976, 734-736
    DOI: 10.1039/C39760000734
    An advanced topic, this introduces ‘Baldwin’s rules for ring closure’, which allows one to predict whether a particular intramolecular ring-closing reaction is favorable based on ring size, the hybridization of the carbon atom at the reaction site, and the relationship (exocyclic or endocyclic) of the reacting bond to the forming ring. These rules are based on empirical observations of ring-closing reactions.

Comments

Comment section

6 thoughts on “Common Blind Spot: Intramolecular Reactions

  1. very interesting to get this web,i am a science teacher at blind school,some times it is very difficult to me to teach my students .big up!!

  2. I despise intramolecular reactions with a white hot passion, particularly when it comes to retrosynthetic analysis. Give me a bunch of rings all stuck together, and I crumple into the fetal position crying for my Mommy. No idea how to tackle them. Generally no idea on what the linking sites on precursors are, or how to systematically approach problems.

    IMHO, it is barely taught at all in organic classes. Most books seem to barely mention intramolecular reactions, let alone scrutinize it as a troublesome area for students. And when it is taught, it isn’t taught very well. Frequently it just seems to pop upon tests for the purposes of destroying students.

    The lack of emphasis on this topic seems utterly bizarre to me considering how incredibly important it is in chemical synthesis and in biochemistry.

    1. “Give me a bunch of rings all stuck together, and I crumple into the fetal position crying for my Mommy.”
      This has my vote as favorite comment of all time. Thank you Thomas

  3. Can you please tell me if there will be ring formation in case of a molecule where the nucleophile and electrophile are at the ends of a very long aklyl chain?

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.