Substitution Reactions
Common Blind Spot: Intramolecular Reactions
Last updated: December 6th, 2022 |
So I bought a belt today (pleather, 75 cents at the Goodwill). and decided to show it off. This is me putting it together.
This is what it looks like now:
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.
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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. (See post: The Williamson Ether Synthesis)
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.
Different example: the Friedel Crafts acylation between aromatic rings and acyl halides.
Then, here’s the exact same reaction. Common result: hesitation. What happens?
Last example: formation of esters from alcohols and carboxylic acids. The Fischer esterification. Once people see this, they usually find it straightforward.
But then hand them this reaction, and it’s a stumper.
What do all of these reactions have in common?
When the nucleophile and electrophile are on the same molecule, they form RINGS.
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:
Notes
(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.
- 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. - 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!”. - 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). - 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. - 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 - 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. - 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. - 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.
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!!
Maybe you should mention something about why these reactions usually are favoured kinetically?
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.
“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
U r best. Thanks lord for creating humans like u. It explanations and creativeness are just WOW!!
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?
excuse me but I have a doubt, the cyclic ether reaction is still confusing me a bit because there’s the reagent NaOH and 4-bromobutanol, so to get the butoxide nucleophile I guess the OH- would take off the H from the butanol? But 4-bromobutoxide is a stronger base than OH- [a website said that pKa of 4 bromobutanol is 14.98±0.10(Predicted)], so how would that acid-base reaction occur? This is more a question about Williamson ether synthesis I guess.
The acid-base reaction is an equilibrium. So long as the difference in pKa values is less than 10 or so, there will be a meaningful concentration of the less stable conjugate base, and that can then participate in reactions.
Oh right. Thanks for answering.