Synthesizing compounds is one of the main concepts in organic chemistry. Knowing how and why compounds interact in different manners allows chemists to create new compounds. Drugs, fertilizers, and fuels are some of the few ways synthesized compounds are used; however, synthesizing compounds has its challenges. Questions of efficiency, orientation, and effectiveness must be assessed. Efficiency involves using methods that increase product yield without jeopardizing product purity or enantiomeric excess. Spatial orientation, or stereochemistry of compounds is especially important when synthesizing biologically active compounds1. Biological molecules, such as protein, DNA, and amino acids have specific structures that are formed through specific folding and bonding patterns for particular purposes. These specific structural components are crucial for life, allowing for specially structured compounds to bind and signal body responses. Thus, it is useful to use stereospecific mechanisms when synthesizing biologically significant compounds. The Buchwald-hartwig reaction is a useful in synthesizing compounds requiring a specific orientation.
■ CHEMISTRY OF THE BUCHWALD-HARTWIG AMINATION
The Buchwald-hartwig reaction is often used as a cross-coupling reaction to add an amine group to a benzene ring. Cross coupling reactions place specific groups on the desired compound by directing a desired group to a specific position. The adding of the amine group is called amination, and is a useful step in that it is used to direct successive reactions. Directing is determined by the nature of the substituted groups on the original compound2. The position to which an addition or substitution reaction is directed relates to the stability of resonance structures of benzene derivatives. Substituents on the benzene ring can be classified as electron-withdrawing or electron-donating. Most electron-withdrawing substituents direct to the meta position in benzene and its derivatives, while electron-donating groups direct to ortho and para positions. Amine groups are electron donating, as they contain an unshared pair of electrons, which contribute to resonance (Figure 1). The resonance forms of aniline demonstrate why the ortho and para positions are preferred for further chemistries, as these respective positions contain nucleophilic carbons; therefore, electrophiles will attack at the nucleophilic sites.
The Buchwald-hartwig reaction is used prior to the directing chemistries to place the amine group on the ring. The benzene derivative has a halogen substituent, allowing nucleophilic substitution to occur (Figure 2). A 1˚ or 2˚ amine acts as the nucleophile and attacks the halogen. In addition, a base and palladium catalyst are used. The base acts in two different ways depending on the polarity of the solvent3. With polar solvents, the palladium catalyst and base form a complex that is stable in the resting state. With nonpolar solvents, the palladium and amine form a complex, which the base deprotonates.
The palladium catalyst is used to increase efficiency of the product yield and decrease reaction time; increased efficiency using the catalyst does not sacrifice selective location of the chemistry4. In addition, copper catalysts have also been shown to have similar outcomes as palladium, though is less effective in systems with primary and secondary amines with aryl bromides.
The Buchwald-hartwig reaction has biological significance, as many synthesized molecules have coupled the Buchwald-hartwig with other reactions to investigate many biological problems including inhibitors for infections commonly found in AIDS patients5 and cancer cell inhibitor compounds6.
Figure 1. Resonance structures of aniline. The resonance structure of aniline demonstrates the ortho and para directing mannerism of amino groups. The ortho and para positions are possibilities for nucleophilic addition in amino substituted benzene derivatives as the resonance structures show the ortho and para positions are nucleophilic carbons.
Figure 2. General Buchwald-hartwig reaction. An aryl halide is combined with a 1˚ or 2˚ amine under basic conditions with a palladium catalyst and the amine group is attached to the ring.
■ DIPEPTIDE HYBRIDS USING BUCHWALD-HARTWIG REACTION6
The purpose of Pájátas’s research was to synthesize biologically active molecules using amino acid and peptide derivatives and test their effectiveness in attacking cancer cells6. Flavone and chromone alkaloids are found in nature and have properties that inhibit cell regulation. It is important to note the amine nitrogen in these natural compounds is not directly linked to the aromatic carbon. Other research has used these naturally occurring compounds as models to create synthetic versions of the compounds, which have also been effective in inhibiting the proteins that regulate the cell cycle. However, it is important to note amine nitrogens can be directly bonded to the aromatic ring, giving more specificity to which cells are regulated, especially malignant cells. Direct attachment of the amine to the aromatic ring is accomplished by using amino acid esters or peptide derivatives. Amino acid esters have a reputation for being biologically active and were thus used to investigate their practicality. Past methods have been ineffective in synthesizing stereospecific compounds, as the conditions were nonregioselective. Using the Buchwald-hartwig reaction the nitrogen sources were added to the bromoflavone yielding specific orientations and followed with additional chemistries directed via the amine. The research was done to synthesize unique flavone-amino acid hybrid compounds that could be tested for cytotoxicity.
The main focus of the experiment was to maximize product yield while not sacrificing enantiomeric excess. When performing synthesizing experiments, it is important to balance the effects of product yield versus enantiomeric excess. Product yield can be high, however a low enantiomeric excess is not useful when synthesizing biologically active compounds, as the body requires specific orientations. The article delves into the process in which it took to develop a synthetic compound by modifying different components of the reaction. The process was divided into different steps in which each part of the reaction was targeted and optimized. Each step targeted can be viewed as a system of controls and variables. Only one variable was assessed at a time so the optimization could be monitored. The base, solvent, time, temperature, catalyst, and phosphane content were varied in order to achieve maximum percent yield and maximum enantiomeric excess.
One specific variable that is an important factor for many experiments is temperature and reaction time. Despite having all the ratios of reagents and solvents, time and temperature greatly effect yield and enantiomeric excess. In this specific synthesis, lower temperatures and faster reaction time yielded better product results. For this reason, catalysts were used to lower activation energy and decrease reaction time.
As two types of reagents, either amino acid esters or dipeptide esters, were added to the bromoflavones, several different R groups were assessed to look at increasing enantiomeric excess. As previously mentioned, it is important to have specific stereochemistry for biologically active molecules. For amino acids esters, different amino acids, differing by R groups, were used. It was found that amino acids that made the carbanion more stable decreased enantiomeric excess, as it was less selective for specific positioning.
After synthesizing methodology was optimized, the Buchwald-hartwig reaction was coupled to other chemistries to produce the hybrid compounds. Coupling reactions allows for directing of additions or substitutions to specific places without disrupting orientation that needs to be retained. The amine group directed chemistry to ortho and meta positions. These steps are important when synthesizing biologically active compounds as not only does the appropriate reagent attack at a specified spot, but also will yield correct orientation.
This article provided not only the optimal production methodology of the unique compounds, but also commented on biological activity results. Cytotoxic activity of the synthesized compounds was assessed to see how each of the compounds effected an array of cancer cell lines. Several of the synthesized compounds were deemed active in cytotoxic activity.
This article provided a detailed description of steps and variations required in synthetic chemistry. The Buchwald-hartwig is a useful reaction in synthesis of biologically significant molecules as the amine group provides directing activity that retains desired groups and predicts orientation.
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