Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Nucleophilic Aromatic Substitution: Elimination–Addition01:11

Nucleophilic Aromatic Substitution: Elimination–Addition

2.9K
Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is...
2.9K
Stability of Substituted Cyclohexanes02:30

Stability of Substituted Cyclohexanes

13.3K
This lesson discusses the stability of substituted cyclohexanes with a focus on energies of various conformers and the effect of 1,3-diaxial interactions.
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
13.3K
Relative Stabilities of Alkenes01:59

Relative Stabilities of Alkenes

12.7K
The relative stability of alkenes can be determined by comparing their heats of hydrogenation. The lower heat of hydrogenation indicates the more stable alkene.  The three main factors determining the relative stability of alkenes are i) the number of substituents attached to the double-bond carbon atoms, ii) hyperconjugation, and iii) the stereochemistry of the double bond.
12.7K
SN1 Reaction: Kinetics02:05

SN1 Reaction: Kinetics

8.2K
In an SN2 reaction, the reaction rate depends on both the type of nucleophile and the substrate. A hindered tertiary alkyl halide is practically inert to the SN2 mechanism despite using a strong nucleophile.
However, Sir Christopher Ingold and Edward D. Hughes, who studied the kinetics of various nucleophilic substitution reactions, noticed that a tertiary alkyl halide does undergo a nucleophilic substitution reaction in the presence of a weak nucleophile. While studying the substitution...
8.2K
Radical Substitution: Hydrogenolysis of Alkyl Halides with Tributyltin Hydride01:26

Radical Substitution: Hydrogenolysis of Alkyl Halides with Tributyltin Hydride

1.5K
Radical substitution reactions can be used to remove functional groups from molecules. The hydrogenolysis of alkyl halides is one such reaction, where the weak Sn–H bond in tributyltin hydride reacts with alkyl halides to form alkanes. Here, the reagent Bu3SnH yields tributyltin halide as a byproduct.
The bonds formed in this reaction are stronger than the bonds broken, making it energetically favorable. The reaction follows a radical chain mechanism similar to radical halogenation...
1.5K
Directing and Steric Effects in Disubstituted Benzene Derivatives01:18

Directing and Steric Effects in Disubstituted Benzene Derivatives

3.2K
When disubstituted benzenes undergo electrophilic substitution, the product distribution depends on the directing effect of both substituents. When the directing effects of both substituents reinforce each other, a single product is obtained. For example, bromination of p-nitrotoluene occurs ortho to the methyl group and meta to the nitro group, which is the same position, resulting in a single product. However, if the directing effects of the two groups oppose each other, the...
3.2K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Growth plate cartilage-targeting nanoparticles for pharmacological treatment of hypochondroplasia.

Bioactive materials·2026
Same author

[Association between early fluid overload and critical complications in extremely low birth weight infants].

Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics·2026
Same author

A first-in-human phase 1 clinical study in healthy volunteers to assess the safety, tolerability and pharmacokinetics of EDI048, a novel promising agent to treat enteric cryptosporidiosis.

The Journal of infectious diseases·2026
Same author

Hexokinase 3 promoted cytokine production of monocytes by targeting metabolic reprogramming and histone lactylation in sepsis.

Clinical epigenetics·2026
Same author

Dihydromyricetin Modulates Neuropathic Pain and Depression: A Correlation with Hippocampal Vascular Endothelial Growth Factor in Mice.

Journal of inflammation research·2026
Same author

Raloxifene relaxes the rat aorta via a mitochondria-dependent mechanism.

Scientific reports·2026
Same journal

Semisynthesis of Mycothiazole Analogs having Distinct Bioactivity.

ACS medicinal chemistry letters·2026
Same journal

Investigation on the Cytotoxicity of Hydroxycinnamic and Hydroxybenzoic Acid-Based Natural Antioxidant Conjugated Terpyridine Analogues toward Triple-Negative Breast Cancer.

ACS medicinal chemistry letters·2026
Same journal

Beyond Neddylation Inhibition: X‑ray Structures Reveal Carbonic Anhydrase Isoform Selectivity of Pevonedistat.

ACS medicinal chemistry letters·2026
Same journal

Structure-Guided Discovery of Selective Polo-Like Kinase 3 Inhibitors.

ACS medicinal chemistry letters·2026
Same journal

Controlling Neuroplasticity Across Scales: Constrained Serotonergic Agonists, Neuroplastogens, and Adaptive Neuromodulation.

ACS medicinal chemistry letters·2026
Same journal

Degradation and Detection: Integrating BCL6 Targeted Protein Degradation with Biomarker-Guided BET Inhibition in Cancer.

ACS medicinal chemistry letters·2026
See all related articles

Related Experiment Video

Updated: Apr 28, 2026

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides
07:50

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

Published on: May 26, 2019

8.9K

Metabolically Stable tert-Butyl Replacement.

David Barnes-Seeman1, Monish Jain2, Leslie Bell2

  • 1Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.

ACS Medicinal Chemistry Letters
|June 6, 2014
PubMed
Summary
This summary is machine-generated.

Replacing tert-butyl groups with trifluoromethylcyclopropyl moieties enhances metabolic stability. This novel chemical modification improves drug candidates" resistance to metabolism in both laboratory tests and living organisms.

Keywords:
Metabolic stabilityclearancemetabolismt-butyltert-butyltertiary butyl

More Related Videos

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes
05:34

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Published on: December 16, 2019

5.8K
A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species
08:12

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Published on: August 16, 2018

9.1K

Related Experiment Videos

Last Updated: Apr 28, 2026

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides
07:50

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

Published on: May 26, 2019

8.9K
Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes
05:34

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Published on: December 16, 2019

5.8K
A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species
08:12

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Published on: August 16, 2018

9.1K

Area of Science:

  • Medicinal Chemistry
  • Drug Metabolism
  • Organic Synthesis

Background:

  • The tert-butyl group is frequently used in medicinal chemistry but is susceptible to metabolic degradation.
  • Metabolic instability of drug candidates can limit their therapeutic efficacy and pharmacokinetic profiles.

Purpose of the Study:

  • To develop a strategy for improving the metabolic stability of compounds containing tert-butyl groups.
  • To introduce a novel trifluoromethylcyclopropyl group as a metabolically stable alternative to the tert-butyl group.

Main Methods:

  • Modification of the tert-butyl group by replacing specific C-H bonds with C-F bonds.
  • Increasing the s-character of the remaining C-H bonds to form a trifluoromethylcyclopropyl structure.
  • In vitro and in vivo assays to assess metabolic stability of modified compounds.

Main Results:

  • The newly designed trifluoromethylcyclopropyl group demonstrated increased metabolic stability compared to the tert-butyl group.
  • Analogues containing the trifluoromethylcyclopropyl moiety exhibited consistently higher metabolic stability in both in vitro and in vivo studies.
  • This modification effectively addressed the metabolic liabilities associated with the tert-butyl group.

Conclusions:

  • The trifluoromethylcyclopropyl group is a promising alternative to the tert-butyl group for enhancing metabolic stability in drug discovery.
  • This synthetic approach offers a viable strategy to overcome metabolic challenges posed by tert-butyl containing compounds.
  • The findings have significant implications for the design of more robust and effective pharmaceutical agents.