Chemical Ligation Chemical Ligation by Click Chemistry Native Chemical Ligation Staudinger Ligation Organic Azides and Azide Sources Functionalized Alkynes Vol. 8, No. 1 Diphenylphosphinemethanethiol: efficacious reagent for traceless Staudinger ligation
More and more researchers face the task of selectively combining large molecules, attaching molecular probes, or covalently immobilizing substrates on surfaces. In particular when biopolymers and bioconjugates are involved there is an urgent need for mild and biocompatible reaction conditions. A toolbox of several powerful chemical ligation techniques already exists and is continually being expanded. In this issue of ChemFiles, we provide an overview of modern chemical ligation methods and introduce highly innovative and unique new tools for research at the interface between chemistry and biology. The most prominent chemical ligation techniques (click chemistry, native chemical ligation, and Staudinger ligation) will be discussed. A comprehensive listing of available organic azides and functionalized alkynes rounds off this issue of ChemFiles with valuable building blocks for click chemistry or Staudinger ligation. - Click Chemistry - Native Chemical Ligation - Staudinger Ligation - Azides - Alkynes
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Transcript
Chemical Ligation
Chemical Ligation by Click Chemistry
Native Chemical Ligation
Staudinger Ligation
Organic Azides and Azide Sources
Functionalized Alkynes
Vol. 8, No. 1
Diphenylphosphinemethanethiol: efficacious reagent for traceless Staudinger ligation
�
Vol. 8 No. 1
Aldrich Chemical Co., Inc. Sigma-Aldrich Corporation6000 N. Teutonia Ave.Milwaukee, WI 53209, USA
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IntroductionMore and more researchers face the task of selectively combining large molecules, attaching molecular probes, or covalently immobilizing substrates on surfaces. In particular when biopolymers and bioconjugates are involved there is an urgent need for mild and biocompatible reaction conditions. A toolbox of several powerful chemical ligation techniques already exists and is continually being expanded.
In this issue of ChemFiles, we provide an overview of modern chemical ligation methods and introduce highly innovative and unique new tools for research at the interface between chemistry and biology. The most prominent chemical ligation techniques (click chemistry, native chemical ligation, and Staudinger ligation) will be discussed. A comprehensive listing of available organic azides and functionalized alkynes rounds off this issue of ChemFiles with valuable building blocks for click chemistry or Staudinger ligation.
If you are unable to find the specific reagent you need, “Please Bother Us.” with your suggestions at [email protected], or contact your local Sigma-Aldrich® office (see back cover).
The cover structure depicts diphenylphosphinemethanethiol, the most efficacious reagent known today to induce traceless Staudinger ligations (Raines ligation reagent). Diphenylphosphinemethanethiol can be obtained easily from the shelf-stable precursor 670359 by removing the acetyl and borane protective groups.
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Chemical Ligation by Click Chemistry—A “Click” Away from Discovery
In an extensive study Finn and co-workers only recently showed that tris(2-benzimidazolylmethyl)amines (general structure in Figure 2) are the most promising family of accelerating ligands for the Cu catalyzed azide-alkyne cycloaddition reaction from among more than 100 mono-, bi-, and polydentate candidates.10 Under both preparative (high concentration, low catalyst loading) and dilute (lower substrate concentration, higher catalyst loading) conditions, these tripodal benzimidazole derivatives give substantial improvements in rate and yields, with convenient workup to remove residual Cu and ligand.
A new reagent developed by Carolyn R. Bertozzi and co-workers eliminates the toxicity to living cells that is usually associated with the copper catalyzed Huisgen 1,3-dipolar cycloaddition.11 By using a difluorinated cyclooctyne (Figure 3) instead of the usual terminal alkyne a rapid cycloaddition reaction takes place even without a catalyst. The ring strain and the electron-withdrawing difluoro group activate the alkyne for copper-free click chemistry. This method was used to attach fluorescent labels to cells with azide-containing sialic acid in their surface glycans. Thus, it was possible to study the dynamics of glycan trafficking in living cells over the course of 24 hours with no indication that the reaction or the labels perturb the process. This is an impressive example of how copper-free click chemistry can be used as a biologically friendly method to label and track biomolecules in living cells.
Sigma-Aldrich® proudly offers a choice of catalysts and ligands for the Huisgen cycloaddition reaction. Later sections in this issue present a comprehensive overview of available organic azides, azide sources, and alkynes that may be applied in click chemistry.
If you want to learn about hot new product additions to the click chemistry universe and other innovative areas of chemical synthesis as soon as they become available, please check our regularly updated product highlights at sigma-aldrich.com/chemicalsynthesis.
References: (1) For recent reviews, see: (a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128. (b) Kolb, H. C. et al. Angew. Chem. Int. Ed. 2001, 40, 2004. (2)(a) Rostovtsev, V. V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W. et al. J. Org. Chem. 2002, 67, 3057. (3)(a) Manetsch, R. et al. J. Am. Chem. Soc. 2004, 126, 12809. (b) Lewis, W.G. et al. Angew. Chem. Int. Ed. 2002, 41, 1053. (4) Speers, A. E. J. Am. Chem. Soc. 2003, 125, 4686. (5) Wolfbeis, O.S. Angew. Chem. Int. Ed. 2007, 46, 2980. (6) Gierlich, J.; Burley, G.A.; Gramlich, P.M.E.; Hammond, D.M.; Carell, T. Org. Lett. 2006, 8, 3639. (7) Bock, V.D.; Perciaccente, R.; Jansen, T.P.; Hiemstra, H.; Maarseveen, J.H. Org. Lett. 2006, 8, 919. (8) Lutz, J.-F. Angew. Chem. Int. Ed. 2007, 46, 1018. (9) Chan, T.R. et al. Org. Lett 2004, 6, 2853. (10) Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y.-H.; Finn, M. G. J. Am. Chem. Soc. 2007, 129, 12696. (11) Baskin, J.M.; Prescher, J.A.; Laughlin, S.T.; Agard, N.J.; Chang, P.V.; Miller, I.A.; Lo, A.; Codelli, J.A.; Bertozzi, C.R. PNAS 2007, 104, 16793.
Ch
em
ical Lig
atio
n
by C
lick C
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The traditional process of drug discovery based on natural secondary metabolites has often been slow, costly, and labor-intensive. Even with the advent of combinatorial chemistry and high-throughput screening in the past two decades, the generation of leads is dependent on the reliability of the individual reactions to construct the new molecular framework.
Click chemistry is a newer approach to the synthesis of drug-like molecules that can accelerate the drug discovery process by utilizing a few practical and reliable reactions. Sharpless and co-workers have defined what makes a click reaction: one that is wide in scope and easy to perform, uses only readily available reagents, and is insensitive to oxygen and water. In fact, water is in several instances the ideal reaction solvent, providing the best yields and highest rates. Reaction work-up and purification uses benign solvents and avoids chromatography.1
Of the reactions comprising the click universe, the “perfect” example is the Huisgen 1,3-dipolar cycloaddition of alkynes to azides to form 1,4-disubsituted-1,2,3-triazoles (Scheme 1). The copper(I)-catalyzed reaction is mild and very efficient, requiring no protecting groups and no purification in many cases.2 The azide and alkyne functional groups are largely inert towards biological molecules and aqueous environments, which allows the use of the Huisgen 1,3-dipolar cycloaddition in target guided synthesis3 and activity-based protein profiling,4 or the ligation of biopolymers to probes or surfaces.5 For example, Carell and co-workers demonstrated the labelling of alkyne modified DNA oligomers with fluorescence probes by click chemistry.6
The triazole has similarities to the ubiquitous amide moiety found in nature. Thus triazole formation was used for the otherwise difficult macrocyclization of a cyclic tetrapeptide analog to a potent tyrosinase inhibitor.7
Additionally triazoles are nearly impossible to oxidize or reduce. This is a main reason why material science has discovered Huisgen cycloadditions as major ligation tools in diverse areas such as polymer science or nanoelectronics.8
Using Cu(II) salts with ascorbate has been the method of choice for the preparative synthesis of 1,2,3-triazoles, but it is problematic in bioconjugation applications. However, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TBTA (Figure 1), has been shown to effectively enhance the copper-catalyzed cycloaddition without damaging biological scaffolds.9
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
Native Chemical Ligation
Introduction: Chemical Synthesis of Peptides and ProteinsDespite competition by recombinant DNA techniques, the synthetic preparation of peptides and proteins offers approaches to protein engineering that are beyond the realm of biology and the limitations of the genetic code. Unlike nature, purely synthetic methods allow the design of peptides entirely from scratch and the furnishing of protein analogs with virtually any unnatural residue.
Chemical peptide synthesis faces certain limitations though. Solution-phase synthesis methods are suitable for peptides with a chain length of up to ten amino acids (Figure 1). Solid-phase peptide synthesis (SPPS) broadens the range of accessible peptides by dramatically enhancing speed and efficiency of the synthesis. Still the maximum chain length of the peptides prepared by SPPS is limited to about 50 amino acid residues.
The development of chemoselective reactions to give a native peptide bond at the site of ligation allows the synthesis of proteins by joining smaller peptides synthesized previously by SPPS. The challenge of this approach is to form an amide bond chemoselectively in the presence of amino acid side chains presenting free amines (Lys) and carboxylates (Glu/Asp). Ideally, no protecting groups should be used and all chemical transformations should take place under mild conditions that are compatible with biological environments. The most powerful technique of this kind is Native Chemical Ligation (NCL) that was introduced by Kent and co-workers in 1994 (Scheme 1).12 Prior to this work, Wieland had observed the condensation of peptide thioesters in early, pioneering investigations.13 Meanwhile, Native Chemical Ligation has enabled the synthesis of many moderate-size proteins and glycoproteins, culminating in the assembly of a 203 amino acid HIV protease covalent dimer.14 Some innovative applications and improved procedures for NCL will be presented later in this chapter.
Expressed Protein Ligation (EPL) finally combines the strengths of molecular biology and chemical synthesis by filling the gap between chemistry and biology. A protein expressed by recombinant DNA techniques can be extended with synthetic peptide fragments post-translationally. In recent examples, Cole and co-workers used EPL for the C-terminal attachment of a small phosphorylated synthetic peptide.15 Waldmann, Goody, and co-workers demonstrated the EPL synthesis of an azide-modified N-Ras protein and its site-specific immobilization onto a phosphine-functionalized glass surface by means of the Staudinger ligation.16
Native Chemical LigationNative Chemical Ligation allows the combination of two unprotected peptide segments by the reaction of a α-thioester with a cysteine-peptide (Scheme 1). The result of this reaction is a native amide bond at the ligation site, rendering this method highly attractive for the synthesis of large peptides. Usually, α-alkylthioesters are used because of their ease of preparation. Since they are rather unreactive, the ligation reaction is catalyzed by in situ transthioesterification with thiol additives. The most common thiol catalysts to date have been either a mixture of thiophenyl/benzyl mercaptan, or 2-mercaptoethanesulfonate (MESNa). In a recent study, it was shown that MESNa is a poor catalyst, requiring reaction times of typically 24–48 hours. It is outperformed by far by certain aryl thiols. Using 4-mercaptophenylacetic acid (MPAA), proteins can be synthesized much more rapidly (Figure 2). Chemical ligations are typically complete in less than an hour and with high yields.17
Native chemical ligation usually relies on the location of suitable Xaa–Cys ligation sites, spaced at intervals no greater than about 40 residues in the target amino acid sequence. However, Xaa–Cys sites in a protein’s polypeptide chain are often limiting: Cys residues are rare or even absent in many proteins, or only present in an unsuitable position. Yan and Dawson introduced an approach that allows Xaa–Ala ligation sites, with a Cys residue used in place of the native Ala residue. Subsequent desulfurization of the ligation product with freshly prepared Raney nickel produces the native target sequence.18 Recently, this methodology has been extended by Kent and co-workers to the synthesis of Cys-containing peptides by ligating fragments at Xaa–Ala junctions.19 Using acetamidomethyl (Acm) side chain protecting groups for Cys residues other than the ligation site, efficient and selective desulfurization of the ligation site is feasible.
Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
Staudinger Ligation
IntroductionThe reaction between an azide and a phosphine forming an aza-ylide was discovered almost a century ago by Nobel Prize laureate Herrmann Staudinger. It has found widespread application in chemical synthesis, but only recently its value as a highly chemoselective ligation method for the preparation of bioconjugates has been recognized.20 Both reactive functionalities involved in this reaction are bioorthogonal to virtually all naturally existing functionalities in biological systems and readily combine at room temperature tolerating an aqueous environment. These ideal conditions make it possible to exploit the Staudinger ligation even in the complex environment of living cells.
Staudinger and Meyer first reported in 1919 that azides react smoothly with triaryl phosphines to form iminophosphoranes after elimination of nitrogen (Scheme 1).21 This imination reaction proceeds under mild conditions, almost quantitatively, and without noticeable formation of any side products.
The resulting iminophosphorane with its highly nucleophilic nitrogen atom can also be regarded as an aza-ylide (Scheme 2). It may be intercepted with almost any kind of electrophilic reagent. Common pathways include aqueous hydrolysis forming a primary amine and a phosphine(V) oxide in the so-called Staudinger reduction. Quenching with aldehydes or ketones yields imines, which is known as the aza-Wittig reaction. Even carbonyl electrophiles with low reactivity, like amides or esters, react with iminophosphoranes, especially if the reaction can take place intramolecularly (Scheme 3).
P + N N N P +N N2
Scheme 1
R3P NR'
R3P NR'
Scheme 2
PRR
RN
R1
H2OR2 R3
O
R2 NH
OR3
R2 N C O
R1NH
H R1NR2
R3
R1NR2
HN R3R2 N C N R1
- R3PO
Scheme 3
Nontraceless Staudinger LigationBertozzi et al. pioneered the application of the Staudinger reaction as a ligation method for bioconjugates. In the course of their studies on the metabolic engineering of cell surfaces they designed a phosphine with an ester moiety as an intramolecular electrophilic trap. After formation of the iminophosphorane from the newly designed phosphine reagent and an azide, the ester moiety captures the aza-ylide in a fast intramolecular cyclization reaction before hydrolysis with water can occur. This process ultimately produces a stable amide bond.22
The phosphine reagent can be synthesized from aminoterephthalic acid methyl ester by diazotization, followed by iodination and subsequent Pd-catalyzed phosphinylation (Scheme 4).
The free acid moiety allows the easy attachment of a wide choice of molecular probes to the phosphine reagent by standard esterification or amidation procedures. Thus, a fluorescence label or different detection probe can be linked to any biomolecule that has been equipped with an azide function by the Staudinger ligation even in living cells (Scheme 5).
The following paragraph shows how GlycoProfile™ azido sugars can be incorporated into glycan structures in vivo, and be used to attach a FLAG® phosphine probe chemically.
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.
Sta
ud
ing
er
Lig
ati
on
N-Azidoacetylmannosamine, Acetylated 8
ManNaz
O
RO
RO
OR OR
HN
ON3
R = * CH3
O
C16H22N4O10 FW 430.37
A7605-1MG 1 mg
A7605-5MG 5 mg
N-Azidoacetylgalactosamine, Acetylated 8
GalNaz
O
HN
RO
O
OR
N3
OROR
R = * CH3
O
C16H22N4O10 FW 430.37
A7480-1MG 1 mg
A7480-5MG 5 mg
N-Azidoacetylglucosamine, Acetylated 8
GlcNaz O
HN
O
RO
OR ORR = * CH3
O
N3
RO
C16H22N4O10 FW 430.37
A7355-1MG 1 mg
A7355-5MG 5 mg
GlycoProfile™ Azido SugarsThe GlycoProfile™ Azido Sugar portfolio consists of three peracetylated azido sugars that may be incorporated into glycan structures chemically or by using existing biosynthetic pathways of mammalian cells.23 Orthogonally to chemical and biological carbohydrate or peptide synthesis, the azide moiety offers an ideal anchor to attach the modified glycan to surfaces, labels, peptides, or proteins. Labelling even works in vivo by using an alternative metabolic-system approach. The acetyl groups increase cell permeability and allow the unnatural sugars to easily pass through the cell membrane. Carboxyesterases remove the acetyl groups once the monosaccharide is in the cell. Cells metabolize the azido sugars using glycosyltransferases and express the sugars on the terminus of a glycan chain both intracelullarly and on the cell surface, leaving the azido group unreacted. N-Azidoacetylmannosamine may also be introduced into the sialic acid biosynthesis pathway. A phosphine probe containing a detection epitope such as the FLAG® peptide can be selectively bound to the glycan by Staudinger Ligation, resulting in a post-translationally modified glycoprotein that is detected in vivo by using a FLAG®-specific antibody. This approach permits the analysis of pathways that are regulated by particular glycan post-translational modifications as well as the monitoring of the intracellular glycosylation process itself.
NH
O
OAcO
OAc
AcO OAc
N3
O
O
P
CH3
FLAGR
R
FLAG-Phosphine
Staudingerligation
cellMetabolic labeling
GalNAz
NH
O
OAcO
OAc
AcOO
N3
NH
OAcO
OAc
AcOO
O
H ON
O
PFLAGR
Labeled glycoprotein
..
Profiling O-type glycoproteins by metabolic labeling with an azido GalNAc analog (GalNAz) followed by Staudinger ligation with a phosphine probe (FLAG-phosphine).
Reference: (23)(a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Saxon, E.; Bertozzi, C. R. Annu. Rev. Cell. Dev. Biol. 2001, 17, 1. (c) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357. (d) Dube, D. H.; Prescher, J. A.; Quang, C. N.; Bertozzi, C. R. Proc. Natl. Acad. Sci 2006, 103, 4819.
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Whether you are an expert in carbohydrate biology and chemistry or just getting started in glycomics, the Glycobiology Analysis Manual provides the products and methods you need to solve your glycomics puzzle!
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Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com.
Traceless Staudinger LigationAlthough the previously described methods for Staudinger ligations work well even in biological environments, a modification forming a native amide bond without leaving the unnatural phosphine oxide moiety in the product would be more attractive yet. In 2000, the groups of Bertozzi and Raines simultaneously introduced alternative ligation strategies.24 Based on the same working principle as the nontraceless Staudinger Ligation the auxiliary phosphine reagent can be cleaved from the product after the ligation is completed leaving a native amide bond. Thus, the total chemical synthesis of proteins and glycopeptides is enabled overcoming the limitations of native chemical ligation (NCL) of a Cys residue at the ligation juncture.
Among the suitable phosphine reagents for traceless Staudinger ligations, diphenylphosphinemethanethiol (Figure 1), developed by Raines and co-workers, exhibits the best reactivity profile and has already found widespread application. This Raines ligation reagent is first acylated. Treatment with an azide leads to the formation of an aza-ylide. The nucleophilic nitrogen atom of the aza-ylide then attacks the carbonyl group, cleaving the thioester. Hydrolysis of the rearranged product finally produces a native amide and liberates the auxiliary as its phosphine(V) oxide (Scheme 6).25
It’s recommended to use a freshly prepared Raines ligation reagent because it has only a limited stability. In this issue of ChemFiles, Sigma-Aldrich® proudly introduces new product 670359 as a shelf-stable, convenient source for this highly useful reagent (sold under license for research and development purposes only. U.S. Patent 6,974,884 and related patents apply). In the acetylthiomethyldiphenylphosphine borane complex 670359, the thiol and phosphine moiety are protected as acetyl ester and borane adduct, respectively. The active Raines ligation reagent can be liberated easily by treatment with DABCO® at 40 °C followed by basic ester cleavage (Scheme 7). Hackenberger and co-workers showed that acidic deprotection of the phosphine-borane was advantageous in glycopeptide and cyclopeptide preparations.26 In the latter case, a linear peptide with terminal azide and phosphine-borane groups was synthesized by SPPS. 95% TFA was used to deprotect the phosphine and the amino acid side chains simultaneously in a single step. Diisopropylethylamine (DIPEA) was then added to trigger the peptide macrocyclization by traceless Staudinger ligation, yielding cyclic Microcin J25 with 21 amino acids.
Other Staudinger ligation induced macrocyclizations have been published previously by Maarseveen and co-workers, who successfully used the Raines ligation reagent for the synthesis of a series of medium-sized lactams.27 Wong and co-workers reported the synthesis of 14 different glycopeptides through the traceless Staudinger Ligation.28 For this work, they also developed a protease-catalyzed method to selectively introduce an N-terminal azido group into an unprotected polypeptide, as it was needed for the subsequent ligation reaction.
Most recently, Raines and co-workers introduced a water-soluble variant of their reagent carrying dimethylamino groups (Figure 2). This substrate mediates the rapid ligation of equimolar substrates in water. In a pilot experiment, traceless Staudinger ligation was integrated with expressed protein ligation (EPL), revealing future opportunities in modern protein chemistry.29
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.
Organic Azides and Azide SourcesSince the preparation of the first organic azide, phenyl azide, by Peter Griess in 1864 this energy-rich and versatile class of compounds has enjoyed considerable interest. In more recent years, completely new perspectives have emerged, notably the use of organic azides for peptide synthesis, combinatorial synthesis, heterocycle synthesis, and the ligation or modification of biopolymers.30 The most prominent fields of application today are Huisgen 1,3-dipolar cycloadditions, and different variants of the Staudinger ligation.
The azido group can also be regarded as a protecting group for coordinating primary amines, especially in sensitive substrates like complex carbohydrates or peptidonucleic acids (PNA).31 For example, it is stable to alkene metathesis conditions.32
Sigma-Aldrich® is offering a broad range of organic azides for your research. Additionally a wide choice of azide sources facilitates the preparation of tailor-made organic azides.
An elegant way to produce organic azides from unactivated olefins was recently reported by Carreira and co-workers. A catalyst, that is easily prepared from Co(BF4)2 · 6H2O and a Schiff base, allows hydroazidation with p-toluenesulfonyl azide (TsN3) to yield alkyl azides. Mono-, di-, and trisubstituted olefins are tolerated in this reaction, and complete Markovnikov selectivity is observed (Scheme 1).33
TO ORDER: Contact your local Sigma-Aldrich office (see back cover), or visit sigma-aldrich.com/chemicalsynthesis.
Functionalized AlkynesAlkynes contain a highly versatile functional group that may be utilized for numerous reactions such as electrophilic additions of hydrogen, halogens, hydrogen halides, or water; metathesis; hydroboration; oxidative cleavage; C–C coupling; and cycloadditions. Terminal alkynes may be transformed into metal acetylides and can then be submitted to nucleophilic substitution with alkyl halides, forming new C–C bonds, or nucleophilic addition, e.g., the Favorskii reaction.
Sigma-Aldrich® furnishes a broad portfolio of alkynes consisting of more than 250 products. To see the full listing, please visit the organic building blocks section on Chem Product Central at: sigma-aldrich.com/chemprod.
From the class of cycloaddition reactions that can be performed with alkynes, the Huisgen 1,3-dipolar cycloaddition stands out and has found tremendous interest in recent years as the best representative of a “click” reaction. Alkyne building blocks with a second functionality are particularly useful in click chemistry. The second functional group allows the attachment of a molecule of interest that subsequently can be “clicked” conveniently to the target azide. The following product list contains alkynes with a free or protected hydroxyl functional group, halogen-bearing alkynes, and miscellaneous other alkynes with an additional functional group.
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