1-Azido-3-iodopropane

Applications in Click Chemistry

Click chemistry refers to a set of powerful reactions that allow for the rapid and efficient formation of covalent bonds. 1-Azido-3-iodopropane is particularly useful in:

• Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) : This reaction involves the reaction of azides with terminal alkynes to form 1,2,3-triazoles. The use of this compound facilitates the synthesis of various triazole derivatives, which have applications ranging from drug development to materials science .

Bioconjugation and Protein Labeling

This compound is employed for bioconjugation processes, particularly in labeling proteins with fluorescent tags. For instance, bovine serum albumin (BSA) can be modified with azide groups using this compound, allowing for subsequent labeling with fluorophores through click chemistry . This method is advantageous due to its specificity and efficiency.

Case Study: Fluorescent Labeling of Proteins

A study demonstrated the use of this compound to label BSA with fluorescent dyes. The process involved:

• Treating BSA with this compound in a TRIS buffer.
• Irradiating the mixture to facilitate the reaction.
• Analyzing the resulting fluorescently labeled protein using spectroscopic methods.

This technique highlights the potential for real-time imaging and tracking of proteins in biological systems .

Pharmaceutical Applications

The compound has been explored for its potential in developing new pharmaceuticals. Its ability to form stable triazole linkages makes it a candidate for synthesizing bioactive compounds.

Case Study: Antifungal Activity

Research has indicated that derivatives synthesized from this compound exhibit antifungal properties. A series of compounds were prepared through click chemistry involving this azide, leading to promising results against various fungal strains .

Material Science Applications

In material science, this compound is utilized for modifying surfaces and creating functional materials. Its reactivity allows for the incorporation of azide functionalities into polymers, which can then undergo click reactions to create crosslinked networks or functionalized surfaces.

Case Study: Surface Functionalization

A study demonstrated the functionalization of polymer surfaces with azide groups using this compound, followed by subsequent reactions with alkyne-functionalized compounds. This approach enabled the creation of bioactive surfaces suitable for tissue engineering applications .

Cu(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC)

The azido group undergoes regioselective 1,3-dipolar cycloaddition with terminal alkynes under Cu(I) catalysis, forming stable 1,4-disubstituted 1,2,3-triazoles. This reaction is central to click chemistry applications .

Example Reaction:

Substrates : 1-Azido-3-iodopropane + Terminal alkyne (e.g., phenylacetylene)
Conditions :

• Catalyst: CuI (0.1–1.0 equiv)

• Base: Triethylamine (TEA) or DIPEA

• Solvent: THF, room temperature
  Product : 1,4-Disubstituted triazole (e.g., 1-(3-iodopropyl)-4-phenyl-1,2,3-triazole)
  Yield : 74–82%

Key Observations:

• Anti-Markovnikov selectivity dominates .

• Competing 5-iodo-triazole formation occurs under oxidative conditions (e.g., air exposure or NBS) .

Formation of 5-Iodo-1,2,3-Triazoles

Under oxidative conditions, electrophilic iodine species participate in cycloadditions, yielding 5-iodo-1,4,5-trisubstituted triazoles .

Example Reaction:

Substrates : this compound + Ethynyl-BODIPY
Conditions :

• Catalyst: CuI (1.0 equiv)

• Oxidant: N-Bromosuccinimide (NBS, 1.2 equiv)

• Base: DIPEA (1.0 equiv)

• Solvent: THF, inert atmosphere
  Product : 5-Iodo-1,4,5-trisubstituted triazole
  Yield : 69%

Mechanistic Insight:

Oxidation of iodide (I⁻) to electrophilic iodine (I⁺) enables iodination at the triazole’s 5-position .

One-Pot Cycloaddition-Sonogashira Coupling

Integrated CuAAC and Pd-catalyzed Sonogashira coupling enables synthesis of 1,4,5-trisubstituted triazoles with alkynyl substituents .

Example Reaction:

Substrates : this compound + 1-Ethynylpyrene
Conditions :

• Catalysts: CuI (0.2 equiv) + Pd(PPh₃)₂Cl₂ (0.1 equiv)

• Solvent: THF, 16 h
  Product : 1,4,5-Trisubstituted triazole (e.g., 1-(3-iodopropyl)-4-(pyren-1-yl)-5-ethynyl-1,2,3-triazole)
  Yield : 7–27%

Comparative Reaction Pathways

Substitution Reactions

The iodo group participates in nucleophilic substitution (SN2), enabling derivatization .

Example Reaction:

Substrate : this compound
Reagent : Sodium azide (NaN₃)
Conditions : DMF, 60°C
Product : 1,5-Diazidopentane (via intermediate displacement)
Yield : 87%

Basic Research Questions

Q. What are the established protocols for synthesizing 1-Azido-3-iodopropane, and how can reproducibility be ensured across laboratories?

• Methodology : Follow factorial design principles to optimize reaction parameters (e.g., temperature, solvent ratio, catalyst loading). Document purification steps (e.g., column chromatography, distillation) and characterize intermediates using NMR or IR spectroscopy. Reproducibility requires explicit reporting of solvent purity, reaction time, and quenching methods, as per standardized experimental sections in peer-reviewed journals .
• Example Table :

Q. Which spectroscopic/chromatographic methods are most effective for characterizing this compound, and how should conflicting spectral data be resolved?

• Methodology : Use $^1$H/$^13$C NMR to confirm molecular structure, IR for azide (2100 cm$^{-1}$) and iodide (500 cm$^{-1}$) groups. For purity, employ GC-MS or HPLC with a polar stationary phase. Conflicting data (e.g., unexpected peaks) should be addressed via spiking experiments, deuterated solvent controls, or repeating analyses under inert atmospheres to rule out degradation .

Q. What safety protocols are critical when handling this compound due to its reactive functional groups?

• Methodology : Conduct small-scale reactions in fume hoods with blast shields. Use secondary containment for azide-containing waste. Monitor thermal stability via DSC (Differential Scanning Calorimetry) to identify decomposition thresholds. Emergency protocols should include dilute sodium thiosulfate solutions for iodide neutralization .

Advanced Research Questions

Q. How can computational methods like DFT elucidate reaction mechanisms involving this compound in click chemistry?

• Methodology : Perform density functional theory (DFT) calculations using software like Gaussian or ORCA. Optimize geometries at the B3LYP/6-31G* level, and calculate transition states with intrinsic reaction coordinate (IRC) analysis. Validate results against experimental kinetics (e.g., Arrhenius plots) to confirm mechanistic pathways .

Q. What experimental designs are optimal for assessing the thermal and photolytic stability of this compound under varying storage conditions?

• Methodology : Use accelerated stability studies with controlled variables (temperature, UV exposure). Apply Arrhenius modeling to predict shelf life. For photolysis, employ quartz reactors with monochromatic light sources (e.g., 254 nm). Monitor degradation via in-situ FTIR or Raman spectroscopy .

Q. What statistical approaches resolve contradictions in yield or selectivity data for reactions using this compound?

• Methodology : Conduct root-cause analysis using Fishbone diagrams to identify variables (e.g., impurity profiles, moisture levels). Apply ANOVA to compare datasets across labs. Use Bayesian inference to assess the likelihood of outlier results being systematic vs. random .

Q. How can this compound be strategically utilized in multi-step syntheses to construct complex heterocyclic or polymeric architectures?

• Methodology : Employ azide-alkyne cycloaddition (CuAAC) for regioselective triazole formation. Optimize stoichiometry via Design of Experiments (DoE) to balance reactivity and steric effects. For polymers, use RAFT polymerization with iodopropyl initiators, characterized by GPC and MALDI-TOF .

Q. What validation strategies are recommended when using molecular dynamics (MD) simulations to predict solvent interactions of this compound?

• Methodology : Simulate solvation in explicit solvents (e.g., water, DMSO) using GROMACS or AMBER. Validate force fields by comparing simulated radial distribution functions with experimental X-ray scattering data. Calibrate dielectric constants against empirical measurements .

Q. Methodological Notes

• Data Contradictions : Cross-validate findings using orthogonal techniques (e.g., XRD for crystallinity vs. DSC for thermal behavior) .
• Experimental Design : Prioritize fractional factorial designs to reduce variable combinations while maintaining statistical power .
• Computational Validation : Always benchmark computational results against experimental controls to ensure predictive accuracy .

Comparison with Structurally Similar Compounds

1-Azido-3-chloropropane (C₃H₆ClN₃)

• Synthesis : Prepared directly from 1-bromo-3-chloropropane and NaN₃ via nucleophilic substitution .
• Reactivity : The chlorine atom exhibits lower leaving-group ability compared to iodine, making it less reactive in SN₂ substitutions. However, it serves as an intermediate for synthesizing 1-azido-3-iodopropane via halogen exchange .
• Applications: Primarily used as a precursor for the iodo analog. Limited direct applications in click chemistry due to slower reaction kinetics.

Key Differences :

3-Azidopropylamine (C₃H₈N₄)

• Structure : Contains an azide and a primary amine (-NH₂) group.
• Reactivity : The amine enables conjugation with carboxylic acids or carbonyl groups, expanding utility in bioconjugation.
• Applications : Used in click chemistry for synthesizing peptide-fluorescent dye conjugates .

Key Differences :

1-Azidopropane (C₃H₇N₃)

• Structure : A simpler analog lacking the iodine atom.
• Reactivity: Limited utility in substitution reactions due to the absence of a leaving group.
• Applications : Used in strain-promoted azide-alkyne cycloaddition (SPAAC) where steric bulk is minimized .

Key Differences :

1-Iodopropyne (C₃H₃I)

• Structure : An alkyne with a terminal iodine atom.
• Reactivity : Participates in Cadiot-Chodkiewicz coupling for carbon-carbon bond formation .
• Applications : Key intermediate in synthesizing acetylenic natural products.

Key Differences :

1-Azido-2,3-epoxypropane (C₃H₅N₃O)

• Structure : Combines an azide with an epoxide ring.
• Reactivity : The epoxide enables ring-opening reactions with nucleophiles (e.g., amines, thiols).
• Applications : Used in polymer chemistry and crosslinking agents .

Key Differences :