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Identification of reactive toxicants: structure-activity relationships for amides
T W Schultz1, J W Yarbrough, S K Koss
1Department of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996-4543, USA. tschultz@utk.edu
Cell Biology and Toxicology
|July 18, 2006
Summary
This study evaluated amide toxicity and reactivity. A model predicted toxicity for many amides, but some highly reactive amides showed greater aquatic toxicity than predicted.
Area of Science:
- Environmental toxicology
- Chemical reactivity
Background:
- Amides are widely used, necessitating an understanding of their environmental impact.
- Predicting aquatic toxicity and chemical reactivity is crucial for risk assessment.
Purpose of the Study:
- To evaluate the aquatic toxicity (IGC50) of various amides using Tetrahymena pyriformis.
- To assess the reactivity of amides with a model thiol nucleophile (glutathione).
- To develop and validate a predictive model for amide toxicity based on hydrophobicity and electrophilicity.
Main Methods:
- Aquatic toxicity assessed via Tetrahymena pyriformis population growth impairment assay.
- Reactivity determined by EC50 with glutathione's thiol group.
- Quantitative Structure-Activity Relationship (QSAR) model developed using hydrophobicity (log Kow) and electrophilicity (E_lumo).
Main Results:
- A hydrophobicity-electrophilicity model accurately predicted toxicity for alkylamides and some halo-substituted amides.
- 2-halo amides and α,β-unsaturated primary amides exhibited higher toxicity than predicted.
- Excess toxicity correlated with the ability to form covalent bonds via SN2 displacement or Michael addition.
- Only amides with excess toxicity were reactive with the thiol nucleophile.
Conclusions:
- The hydrophobicity-electrophilicity model is effective for many amides but requires refinement for specific reactive structures.
- Reactivity with thiol nucleophiles can identify amides with unexpectedly high aquatic toxicity.
- Understanding structure-toxicity relationships is key to predicting and mitigating environmental risks of amides.
Related Concept Videos
01:29Preparation of Amides
Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
01:26Physical Properties of Amines
Amines with low molecular weight are usually gaseous at room temperature, while those with high molecular weight are liquid or solids in nature. Usually, low molecular weight amines have a rotten fish-like smell. Diamines typically have a pungent smell. For instance, cadaverine and putrescine, depicted in Figure 1, are two molecules responsible for decaying tissue.
01:19Amines to Amides: Acylation of Amines
Various carboxylic acid derivatives (such as acid chlorides, esters, and anhydrides) can be used for the acylation of amines to yield amides. The reaction requires two equivalents of amines. The first amine molecule functions as a nucleophile and attacks the carbonyl carbon to produce a tetrahedral intermediate. This is followed by the loss of the leaving group and restoration of the C=O bond.
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary amide...
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary amide...
01:28Amides to Carboxylic Acids: Hydrolysis
Amides can undergo either acid-catalyzed hydrolysis or base-promoted hydrolysis through a typical nucleophilic acyl substitution. Each hydrolysis requires severe conditions.
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
01:13Relative Reactivity of Carboxylic Acid Derivatives
Carboxylic acid derivatives such as acid halides, anhydrides, esters, and amides undergo nucleophilic acyl substitution reactions with varying degrees of reactivity.
A key factor in assessing the reactivity of the acid derivatives is the basicity of the substituent or the leaving group. The lower the basicity of the leaving group, the higher the reactivity of the derivative. The basicity of the leaving group follows this order:
Halide ions < Acyloxy ions < Alkoxy ions < Amine ions
A key factor in assessing the reactivity of the acid derivatives is the basicity of the substituent or the leaving group. The lower the basicity of the leaving group, the higher the reactivity of the derivative. The basicity of the leaving group follows this order:
Halide ions < Acyloxy ions < Alkoxy ions < Amine ions
01:07Acid Halides to Amides: Aminolysis
Aminolysis is a nucleophilic acyl substitution reaction, where ammonia or amines act as nucleophiles to give the substitution product. Acid halides react with ammonia, primary amines, and secondary amines to yield primary, secondary, and tertiary amides, respectively.
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...