Reactions and Applications of 3,3-Difluoroallyl Sulfonium Salts (DFASs): Small-Molecule gem-Difluoroallylation, Selective Peptide Modification, and Subsequent Functionalization
Reactions and Applications of 3,3-Difluoroallyl Sulfonium Salts (DFASs): Small-Molecule gem-Difluoroallylation, Selective Peptide Modification, and Subsequent Functionalization
Introduction
Introducing fluorinated groups into organic molecules generally requires simultaneous consideration of three questions: whether the fluorinated fragment can be conveniently prepared and stored, whether a new chemical bond can be formed at the intended position, and whether the reaction product can be used in subsequent synthesis.
3,3-Difluoroallyl sulfonium salts (DFASs) integrate these functions into a single class of reagents. DFASs can transfer a carbon fragment containing a gem-difluoromethylene unit and a carbon–carbon double bond. Under copper-catalyzed conditions, they form carbon–carbon bonds with organozinc reagents, and under aqueous conditions, they can also form oxygen–carbon or sulfur–carbon bonds with the phenolic hydroxyl group of tyrosine or the thiol group of cysteine.[1,3,4]
The carbon–carbon double bond retained after the DFASs reaction, together with functional groups such as alkynes and azides preinstalled at the β-position of the allylic framework or within its substituents, can further participate in click conjugation, radical addition, and other chemical transformations. The role of DFASs is therefore not limited to introducing a CF₂ unit; they also install a fluorinated linkage that can undergo further derivatization.
1 What Are DFASs?
DFASs are not a single compound, but a series of reagents containing a 3,3-difluoroallyl sulfonium salt framework. Their structures can be divided into three interrelated components.
1.1 Sulfonium Component: Providing Activation and Leaving-Group Ability
The sulfur atom in a sulfonium salt carries a positive charge and is connected to the fluorinated allylic framework. This structure increases the electrophilic reactivity of the attached carbon framework, enabling it to react with organometallic reagents, phenoxide species, or sulfur nucleophiles.
During bond formation, the fluorinated allylic fragment is transferred to the substrate, while the sulfur-containing portion leaves as a neutral sulfide. Changing the substituents on the sulfur atom can regulate the reactivity and regioselectivity of the sulfonium salt.[3,4]
1.2 CF₂ Component: Establishing a Fluorinated Linkage
DFASs do not transfer fluoride ions; instead, they transfer an intact gem-difluoroallyl fragment. Depending on the reaction substrate and reaction conditions, the major or targeted regioisomers reported in the literature can contain:
· a carbon–CF₂ bond;
· an oxygen–CF₂ bond;
· a sulfur–CF₂ bond.
The CF₂ unit can alter the electronic distribution, conformation, and hydrophobic properties around the linkage site. However, its specific effects depend on the overall molecular structure and the position of modification and therefore require subsequent experimental evaluation.
1.3 Carbon–Carbon Double Bond and β-Substituents: Retaining Sites for Subsequent Transformation
The carbon–carbon double bond is generally retained after the DFASs reaction. This double bond can subsequently participate in metathesis, dihydroxylation, oxidation, radical addition, and other reactions.
Aryl, alkyl, and other substituents can also be introduced at the β-position of the DFASs allylic framework, while alkynes, azides, or other functional structures can be preinstalled at the β-position or within its substituents. The resulting products therefore contain both a CF₂ unit and functional groups that can be used for subsequent conjugation.[1,3,4]
1.4 Structure and Functional Modules of a Representative 3,3-Difluoroallyl Sulfonium Salt (DFAS)
Taking (3,3-difluoroallyl)(methyl)(p-tolyl)sulfonium triflate (CAS 2839167-38-1) as an example, this compound consists of a positively charged 3,3-difluoroallyl sulfonium cation and a triflate counterion. The sulfonium cation contains a transferable 3,3-difluoroallyl fragment. After the reaction, the CF₂ unit in this fragment forms a fluorinated linkage, while the carbon–carbon double bond is generally retained and can continue to participate in functional-group transformations or bioconjugation. The triflate anion primarily balances the charge of the sulfonium cation and is generally not transferred to the substrate.
2 How DFASs Construct C–C Bonds
A 2022 study first established the copper-catalyzed cross-coupling of DFASs with organozinc reagents. The study used DFASs prepared from 3,3,3-trifluoropropene and reacted them with arylzinc, primary alkylzinc, secondary alkylzinc, and tertiary alkylzinc reagents to obtain the corresponding gem-difluoroallylated products.[1]
This reaction can be summarized as follows:
Organozinc reagent provides an aryl or alkyl fragment → DFAS provides a gem-difluoroallyl fragment → copper catalysis promotes coupling between the two carbon fragments → a new C–CF₂ bond is formed
This method can be used to construct C(sp²)–CF₂R- and C(sp³)–CF₂R-type structures. The former refers to a CF₂ unit connected to an sp²-hybridized carbon, such as an aryl carbon, whereas the latter refers to a CF₂ unit connected to an sp³-hybridized carbon, such as an alkyl carbon.
2.1 Copper Catalysis Controls the Bond-Forming Position
The allylic framework of DFASs contains multiple positions that may undergo nucleophilic attack. The copper catalytic system promotes carbon-fragment coupling between the organozinc reagent and the DFAS and helps achieve high regioselectivity.
The original study showed that various aryl and alkyl organozinc reagents could participate in the reaction, indicating that this method can accommodate carbon fragments with different hybridization states and steric demands.[1]
2.2 gem-Difluoroallylated Products Can Undergo Further Transformation
The carbon–carbon double bond in the coupling product is not consumed during the reaction and can subsequently undergo:
① olefin metathesis;
② dihydroxylation;
③ oxidation;
④ other olefin functionalization reactions.
This reaction therefore simultaneously constructs a C–CF₂ bond and installs an olefinic reaction site, providing opportunities for subsequent carbon-chain extension, ring construction, or the introduction of heteroatom-containing functional groups.[1]
3 How Reaction Mode and Order of Addition Regulate the Formation of BCPs or Cyclobutanes
Bicyclo[1.1.1]pentane (BCP) is a strained cage-like framework composed of five carbon atoms. [1.1.1]Propellane contains a distinctive bridgehead carbon–carbon bond and can be converted into BCP derivatives following attack by nucleophiles, radicals, or organometallic species.
A 2024 study combined [1.1.1]propellane, DFASs, and organometallic reagents. By using either stepwise reactions or one-pot three-component reactions and controlling the order of addition, the researchers selectively obtained gem-difluoroallylated BCPs or gem-difluoroallylated cyclobutanes.[2]
Reaction mode | Reaction sequence | Major product |
Stepwise reaction | The organometallic reagent first adds to [1.1.1]propellane, followed by copper-catalyzed coupling with a DFAS | gem-Difluoroallylated BCP |
One-pot three-component reaction | The organozinc reagent, [1.1.1]propellane, and DFAS react in the same reaction system under copper catalysis and in an optimized order of addition | gem-Difluoroallylated cyclobutane |
3.1 The Stepwise Reaction Retains the BCP Framework
In the stepwise route, a Grignard reagent or organozinc reagent first adds to the bridgehead carbon–carbon bond of [1.1.1]propellane, forming a BCP-type organometallic intermediate. This intermediate then undergoes copper-catalyzed cross-coupling with a DFAS, introducing a gem-difluoroallyl group at the BCP bridgehead position.
Because the BCP framework is formed before the DFAS participates in the reaction, the subsequent reaction primarily completes the coupling between the bridgehead carbon and the fluorinated fragment.
3.2 The One-Pot Three-Component Reaction Mainly Forms Cyclobutanes
In the one-pot reaction, the organozinc reagent, [1.1.1]propellane, and DFAS react in the same reaction system under copper catalysis and in an optimized order of addition. The paper describes this process as a copper-catalyzed three-component carbene-transfer reaction. This route forms two new carbon–carbon bonds and one quaternary carbon center and mainly affords gem-difluoroallylated cyclobutanes.[2]
The original study and reaction-condition screening showed that the order of addition significantly changes the proportions of BCP and cyclobutane products. The authors proposed that different orders of addition may alter the intermediates initially formed among the organozinc reagent, copper species, and [1.1.1]propellane, thereby directing the reaction into different bond-forming pathways.
This study demonstrates that the same basic reactants do not necessarily generate the same framework. The order in which intermediates are formed and the sequence in which the catalyst contacts the different reactants are also important factors controlling product structure.[2]
4 Why DFASs Can Also Be Used for Peptide Modification
Small-molecule cross-coupling reactions generally require anhydrous organic solvents and organometallic reagents, whereas peptides contain multiple functional groups, including amino, carboxyl, hydroxyl, thiol, amide, and heterocyclic groups. Peptide modification must also account for aqueous solubility, acid–base stability, and competing reactions among amino acid side chains.
DFASs have relatively strong electrophilic reactivity. Under suitable basic conditions, they can therefore react with the phenolic hydroxyl group of tyrosine or the thiol group of cysteine without requiring organometallic reagents or metal catalysts.[3,4]
However, the acidity and nucleophilicity of these two amino acid side chains differ, and the required reaction conditions and applicable substrate ranges are therefore also different.
5 O-gem-Difluoroallylation of Tyrosine
The tyrosine side chain contains a phenolic hydroxyl group. A 2024 study used DFASs to achieve O-gem-difluoroallylation of phenol-containing molecules and tyrosine residues in peptides in a mixed medium composed of a basic carbonate buffer and dimethyl sulfoxide. The optimized buffer had a pH of 11.6, and the reaction did not require a metal catalyst.[3]
5.1 Site Selectivity Arises from the Reactivity of the Phenolic Hydroxyl Group
The basic buffer promotes deprotonation of the phenolic hydroxyl group, generating a more nucleophilic phenoxide species. After reacting with a DFAS, this species mainly forms a regioisomer in which the oxygen atom is connected to the CF₂ carbon.
Among the substrates tested in the paper, residues such as tryptophan, histidine, methionine, and threonine tolerated the reaction conditions. Cyclic peptides containing disulfide bonds also afforded the corresponding tyrosine-modified products.[3]
The study also examined arbutin, esculin, and phenol-containing molecules bearing nucleoside structures. The reaction occurred at the phenolic hydroxyl groups in these molecules rather than at the ordinary alcoholic hydroxyl groups on the sugar rings or nucleosides. These results therefore demonstrate that the reaction tolerates sugar and nucleoside structures and does not represent general selective fluoroalkylation of sugar or nucleoside hydroxyl groups.
5.2 The Reaction Conditions Impose Limitations on Substrates
A pH of 11.6 facilitates activation of the phenolic hydroxyl group. However, for peptides containing base-sensitive functional groups or conformationally sensitive structures, the reaction time, racemization, hydrolysis, and retention of biological activity must be evaluated separately.
The original study also indicated that free cysteine, free lysine side chains, and unprotected N-terminal amines were incompatible with the current conditions. These nucleophilic groups may compete with the intended reaction with DFASs or affect the product composition. This method is therefore more suitable for tyrosine-containing substrates that do not contain free competing thiol or amino groups.[3]
6 S-gem-Difluoroallylation of Cysteine
The cysteine side chain contains a thiol group, and its sulfur atom is generally more nucleophilic than the oxygen atom of a phenolic hydroxyl group. Another 2024 study exploited this difference to achieve S-gem-difluoroallylation of cysteine residues in unprotected peptides under aqueous, mildly basic conditions at room temperature.[4]
Typical conditions used a mixed solvent composed of water and either N,N-dimethylformamide or dimethyl sulfoxide, together with a small amount of sodium carbonate. The reaction formed a product in which the sulfur atom was connected to the CF₂ carbon, while retaining the olefin and other functional groups at the β-position of the DFAS.
6.1 Chemoselectivity Arises from the Stronger Nucleophilicity of the Thiol Group
In competition experiments, residues such as tyrosine, histidine, tryptophan, serine, proline, lysine, methionine, and glutamine did not significantly inhibit cysteine modification.
Substrates including unprotected glutathione, cyclic peptides containing an arginine–glycine–aspartic acid sequence, and β-amyloid peptide fragments also afforded the corresponding S-gem-difluoroallylated products.[4]
The selectivity primarily arises from the nucleophilicity of the cysteine thiol group and its deprotonated form rather than from recognition of a specific peptide sequence by the DFAS.
6.2 Sulfonium Substituents Regulate Regioselectivity
Early reaction conditions produced two regioisomers simultaneously. After the researchers changed the substituents on the sulfur atom of the DFAS, the regioselectivity for the target product improved substantially.
The authors attributed this phenomenon to regulation of the leaving-group ability of the sulfonium salt by the sulfur substituents and proposed that the reaction mainly proceeds through an S_N2′-type allylic nucleophilic substitution pathway.[4]
In addition, the researchers proposed that an aryl group at the β-position of the DFAS allylic framework can activate the gem-difluoroalkene, thereby facilitating attack by sulfur nucleophiles. Different substituents can be introduced at the β-position, and functional groups such as alkynes and azides can be preinstalled within the corresponding substituents. Brominated groups or alkyl groups can also be introduced to regulate product structure and subsequent conjugation pathways.
6.3 Major Differences Between the Two Peptide-Modification Reactions
Comparison item | Tyrosine modification | Cysteine modification |
Reactive side chain | Phenolic hydroxyl group | Thiol group |
Main bond-forming atom | Oxygen | Sulfur |
Newly formed linkage | Mainly an O–CF₂ linkage | Mainly an S–CF₂ linkage under optimized conditions |
Typical conditions | pH 11.6 carbonate buffer, organic cosolvent, no metal catalyst | Room temperature, aqueous mildly basic mixed solvent, no metal catalyst |
Origin of selectivity | Formation of a phenoxide species after deprotonation of the phenolic hydroxyl group | Strong nucleophilicity of the thiol group and sulfur nucleophilic species |
Validated substrates | Phenol-containing bioactive molecules and various oligopeptides | Protected and unprotected cysteine-containing peptides |
Issues requiring attention | Free cysteine, lysine, and N-terminal amines may undergo competing reactions | Substrates containing multiple cysteine residues may require control over the number and positions of modifications |
7 Why the gem-Difluoroallyl Group Is Suitable for Further Chemical Transformation
The structure remaining after DFAS transfer is not an inert fluorinated substituent, but a unit containing both a CF₂ group and a carbon–carbon double bond. Some DFASs also contain preinstalled alkynes or azides at the β-position. The first reaction can therefore achieve site-selective installation, after which other functional groups can be used to connect additional molecules in a second step.
7.1 Click Conjugation Using β-Position Functional Groups
After tyrosine or cysteine modification with alkyne- or azide-containing DFASs, sugars, fluorophores, biotin, or drug molecules can be attached through azide–alkyne cycloaddition.
In the tyrosine study, an alkyne-containing DFAS was used to attach an azide-functionalized sugar and to prepare a fluorescently labeled etoposide derivative. In the cysteine study, an azide-containing modified peptide was connected to a fluorophore and a camptothecin derivative through copper-free strain-promoted azide–alkyne cycloaddition.[3,4]
7.2 Radical Addition to the gem-Difluoroallyl Double Bond
The double bond in the gem-difluoroallyl group can act as a radical acceptor. Both the tyrosine and cysteine studies used redox-active esters under blue-light irradiation in the presence of a Hantzsch ester to add carbon fragments containing biotin, amino acids, bile acids, or sugar structures to this double bond.[3,4]
Under the conditions reported in the literature, the double bond in the gem-difluoroallyl group can undergo radical addition, providing a second conjugation pathway for fluorinated modified products.
7.3 The Two Types of Conjugation Reactions Can Be Performed Sequentially
When the same modified product contains both an azide group and a gem-difluoroallyl double bond, click conjugation can first be performed at the azide group, followed by radical addition at the double bond.
The cysteine study used this strategy to construct a peptide–sugar–biotin chimeric conjugate. The two reactions use different functional groups, and the first step retains the reactive site required for the second step, allowing two types of functional molecules to be attached sequentially to the same peptide chain.[4]
8 What Determines the Selectivity of DFAS Reactions?
DFASs can form C–C, O–C, or S–C bonds because reagent structure, reactant properties, and reaction conditions jointly alter the bond-forming process.
8.1 The Reactant Determines the Bond-Forming Atom
① Organozinc reagents provide carbon nucleophilic fragments, forming C–C bonds.
② Phenoxide species attack through oxygen atoms, forming O–C bonds.
③ Cysteine-derived sulfur nucleophiles attack through sulfur atoms, forming S–C bonds.
8.2 The Catalyst and pH Determine the Reaction Mode
Copper catalysts mediate carbon-fragment coupling between organozinc reagents and DFASs. Tyrosine and cysteine modification do not require metal catalysts; instead, a base regulates the degree of deprotonation and the nucleophilicity of the phenolic hydroxyl or thiol group.
8.3 Sulfonium Substituents Affect Reactivity and Regioselectivity
Substituents on the sulfur atom alter the leaving-group ability of the sulfonium salt. The cysteine study showed that this change can significantly affect the ratio of the two regioisomers.
8.4 The β-Position and Its Substituents Affect Structural Diversity and Subsequent Applications
A β-aryl group can alter the electronic properties of the olefin. Alkynes and azides preinstalled at the β-position or within its substituents can be used for click conjugation, while other substituents can adjust the spatial structure and hydrophobicity of the product.
8.5 Reaction Mode and Order of Addition Affect the Strained-Ring Reaction Pathway
In reactions involving [1.1.1]propellane, formation of a BCP-type organometallic intermediate before DFAS coupling mainly preserves the BCP framework, whereas reaction of the three components in the same system under copper catalysis mainly affords cyclobutanes. The reaction mode and order of addition may influence the final framework by changing the distribution of the intermediates formed first.[2]
9 Scope and Limitations of Current Research
Validated by the original studies | Areas requiring further investigation |
DFASs can undergo copper-catalyzed coupling with various aryl and alkyl organozinc reagents | General applicability to other types of organometallic reagents and nucleophilic carbon reagents |
Stepwise and one-pot reactions can selectively afford specific BCPs and cyclobutanes | Applicability to other propellanes and strained-ring frameworks |
Tyrosine in phenol-containing molecules and oligopeptides can be modified at pH 11.6 | Effects on the structure, activity, and conformation of large proteins |
Cysteine in unprotected peptides can be modified under aqueous, mildly basic conditions | Methods for controlling a single modification site in proteins containing multiple cysteine residues |
Olefins, alkynes, and azides can be used for subsequent conjugation | Systematic evaluation of biological activity, metabolic behavior, and cytocompatibility after multistep modification |
Fluorescently labeled products and multicomponent peptide conjugates have been prepared | Reaction efficiency under intracellular, in vivo, and clinically relevant conditions |
DFASs provide a synthetic method for investigating the effects of CF₂ units on molecular properties. However, current studies have not demonstrated that gem-difluoroallylation universally improves peptide membrane permeability, metabolic stability, or biological activity. The outcome depends on the modification site, peptide sequence, molecular conformation, and linkage group and must therefore be experimentally evaluated for each specific product.
10 Classification and Research Applications of Chemicals Related to DFAS-Based Organometallic Coupling, Strained-Ring Construction, Selective Peptide Modification, and Subsequent Conjugation
Note: The following products cover the preparation of organozinc and Grignard reagents, copper-catalyzed gem-difluoroallylation, transformation of the [1.1.1]propellane framework, selective modification of tyrosine and cysteine, as well as click conjugation and subsequent radical transformations. These products are primarily used for organic synthesis, reaction-condition screening, peptide modification, mechanistic studies, or analytical controls. This does not mean that every product has been directly used as a substrate in every reaction reported in the original studies.
Table 1 Products Related to Copper-Catalyzed Cross-Coupling, Organometallic Reagents, and Strained-Ring Construction
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Salt for organozinc reagent preparation | 7646-85-7 | Zinc chloride | GR, ≥98% | Used for transmetalation of Grignard reagents, preparation of organozinc reagents, and investigation of reaction conditions for copper-catalyzed cross-coupling between DFASs and organozinc reagents. | |
Metal for organozinc reagent preparation | 7440-66-6 | Zinc granules | AR, ≥99% | Used for preparing organozinc reagents through direct insertion into organic halides, comparing zinc-activation conditions, and preparing substrates for gem-difluoroallylation. | |
Alkyl organozinc reagent | 557-20-0 | D684313 | Diethylzinc solution | 2 M in toluene | Used to study the reactivity of alkyl organozinc reagents, copper-mediated transmetalation, and conditions for DFAS-based carbon–carbon bond formation. |
Copper catalyst | 7787-70-4 | Copper(I) bromide | PrimorTrace™, ≥99.99% metals basis | Used for cross-coupling between organozinc reagents and DFASs, as well as the copper-catalyzed construction of gem-difluoroallylated bicyclo[1.1.1]pentanes and cyclobutanes. | |
Metal for Grignard reagent preparation | 7439-95-4 | M109153 | Magnesium powder (explosive precursor) | AR, ≥99.5% | Used for preparing aryl and alkyl Grignard reagents, nucleophilic addition to [1.1.1]propellane, and studying bicyclo[1.1.1]pentane organometallic intermediates. |
Primary alkyl Grignard reagent | 925-90-6 | Ethylmagnesium bromide solution | 40% in 2-methyltetrahydrofuran | Used to study addition to the bridging bond of [1.1.1]propellane, formation of ethyl-substituted bicyclo[1.1.1]pentane intermediates, and subsequent coupling with DFASs. | |
Methyl Grignard reagent | 75-16-1 | M130050 | Methylmagnesium bromide | 3.0 M solution in diethyl ether | Used for methyl nucleophilic addition, comparison of strained-ring opening pathways, and construction of methyl-substituted fluorinated frameworks. |
Secondary alkyl Grignard reagent | 1068-55-9 | I107831 | Isopropylmagnesium chloride | 2.0 M in THF | Used to study the reactivity of secondary alkyl organometallic reagents, steric effects, and [1.1.1]propellane addition–coupling routes. |
Aryl Grignard reagent | 100-58-3 | P103163 | Phenylmagnesium bromide | 1.0 M in THF | Used for preparing aryl-substituted bicyclo[1.1.1]pentane intermediates, nucleophilic addition to strained rings, and subsequent cross-coupling with DFASs. |
Aryl organozinc reagent | 1078-58-6 | Diphenylzinc | ≥99% | Used to study aryl organozinc transmetalation, construction of aryl–gem-difluoroallyl carbon–carbon bonds, and comparison of substrate types. | |
Core strained-ring substrate | 35634-10-7 | (1.1.1)Propellane | ≥95% | Used to study divergent construction of bicyclo[1.1.1]pentane and cyclobutane frameworks, addition to the bridging bond, three-component reactions, and the effects of the order of addition. |
Table 2 Products Related to Selective Tyrosine and Cysteine Modification and Bioactive Substrates
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Tyrosine-modification model | 60-18-4 | L-Tyrosine | Animal-free, ≥99%, fermentation-derived | Used to study O-selective gem-difluoroallylation of phenolic hydroxyl groups, activation under basic conditions, regioselectivity, and the reactivity of amino acid residues. | |
Cysteine-modification model | 52-90-4 | L-Cysteine | UltraBio™, ≥98.5% (RT) | Used for studies of cysteine thiol reactivity, sulfur-containing structural controls, and related analytical investigations. | |
Thiol-protection and reducing reagent | 51805-45-9 | Tris(2-carboxyethyl)phosphine hydrochloride (TCEP HCl) | ≥98% | Used for disulfide-bond reduction, generation of free thiols, pretreatment of cysteine-containing peptides, and investigation of compatibility with DFAS reactions. | |
Unprotected thiol-containing tripeptide model | 70-18-8 | Glutathione, reduced | PharmPure™, European Pharmacopoeia (Ph. Eur.) | Used to study cysteine-site modification in unprotected tripeptides, amino acid side-chain tolerance, and analysis of S-gem-difluoroallylated products. | |
Disulfide-bond structural control | 56-89-3 | L-Cystine | Moligand™, ultrapure grade, ≥99.5% | Used to compare the reactivity of disulfide bonds and free thiols, evaluate modification efficiency before and after reduction, and provide a structural control for sulfur-containing amino acids. | |
Tyrosine-containing cyclic peptide model | 177943-89-4 | Dotatate acetate | Moligand™, ≥99% | Used for late-stage O-gem-difluoroallylation of tyrosine-containing cyclic peptides, evaluation of compatibility with complex peptide substrates, and functional conjugation studies. | |
Phenol-containing bioactive molecule model | 33419-42-0 | Etoposide | Moligand™, ≥98% | Used for late-stage O-gem-difluoroallylation of phenol-containing drug molecules, introduction of an olefinic interface, and subsequent attachment of fluorescent or functional groups. | |
Phenol-containing glycoside model | 497-76-7 | Arbutin | Moligand™, ≥98% | Used to study selective modification of phenolic hydroxyl groups, tolerance of glycoside structures, and comparison of the reactivity of ordinary alcoholic hydroxyl groups and phenolic hydroxyl groups. | |
Phenol-containing coumarin glycoside model | 531-75-9 | Aesculin hydrate | ≥98% | Used for late-stage modification of phenol-containing glycosidic bioactive molecules, evaluation of sugar-structure compatibility, and investigation of phenolic hydroxyl site selectivity. |
Table 3 Products Related to Basic Buffer Systems and Organic Reaction Media
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Base for phenolic hydroxyl activation | 497-19-8 | Sodium carbonate | Anhydrous, GR, suitable for analysis | Used to prepare basic aqueous reaction systems, increase the proportion of tyrosine phenoxide species, promote cysteine thiol reactions, and screen pH conditions. | |
Carbonate-buffer component | 144-55-8 | Sodium bicarbonate | Anhydrous, reagent grade, high purity, ≥99.5% | Can be combined with sodium carbonate to prepare carbonate buffer systems with different pH values for screening reaction pH and substrate stability. | |
Solvent for Grignard reactions | 60-29-7 | D1506340 | Diethyl ether (controlled precursor chemical) | Anhydrous, ACS | Used for preparing Grignard reagents, organometallic reactions under low-moisture conditions, addition to [1.1.1]propellane, and dissolution of reactants. |
Solvent for organometallic reactions | 109-99-9 | T1491789 | Tetrahydrofuran (THF) | Anhydrous, ≥99.9%, unstabilized, H₂O ≤30 ppm | Used for preparing Grignard and organozinc reagents, copper-catalyzed cross-coupling, strained-ring reactions, and control of anhydrous conditions. |
Organic cosolvent for peptide modification | 67-68-5 | Dimethyl sulfoxide (DMSO) | Anhydrous, ≥99.9% | Used to dissolve DFASs and hydrophobic bioactive substrates, perform aqueous peptide modification, and investigate reaction-medium composition and substrate compatibility. | |
Organic cosolvent for peptide modification | 68-12-2 | N,N-Dimethylformamide (DMF) | Anhydrous, ≥99.8% | Used to dissolve functionalized DFASs, perform S-selective cysteine modification, prepare aqueous–organic mixed media, and screen peptide-reaction conditions. |
Table 4 Products Related to Click Conjugation and Subsequent Radical Transformations
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Biotin-labeling molecule | 58-85-5 | D-Biotin | Animal-free, Moligand™, suitable as a raw material for culture media and buffers, ≥99% | Used to prepare biotinylated conjugation units, peptide–biotin and peptide–sugar–biotin conjugates, and for affinity labeling and capture studies. | |
Copper source for click conjugation | 7758-99-8 | Copper sulfate pentahydrate | AR, ≥99% | Used to provide Cu(II), which is reduced in situ to Cu(I) to catalyze cycloaddition between alkyne and azide groups. | |
Copper reductant for click conjugation | 134-03-2 | (+)-Sodium L-ascorbate | UltraBio™, ultrapure grade, ≥99% (NT) | Used to reduce Cu(II) to Cu(I) in situ and promote subsequent click conjugation of alkyne- or azide-functionalized peptides. | |
Copper ligand for click conjugation | 510758-28-8 | Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) | ≥95% | Used to stabilize Cu(I) and promote azide–alkyne cycloaddition for attaching sugars, probes, or biotin to DFAS-modified products. | |
Active ester for copper-free click conjugation | 1353016-71-3 | DBCO-NHS ester | ≥97% | Used to introduce a dibenzocyclooctyne group into amino-containing molecules, followed by copper-free cycloaddition with azide-functionalized peptides. | |
Visible-light radical reductant | 1149-23-1 | Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate | ≥98% (HPLC) | Used for electron and hydrogen-atom transfer in visible-light reactions, promoting decarboxylation of redox-active esters and radical addition to gem-difluoroallyl double bonds. | |
Redox-active ester precursor | 524-38-9 | N-Hydroxyphthalimide (NHPI) | ≥98% | Used to prepare redox-active esters and for decarboxylative radical generation and subsequent addition to gem-difluoroallyl double bonds. |
Note: The products listed above are representative Aladdin products related to scientific and formulation research. Additional product specifications, grades, and certificate of analysis information can be retrieved from the Aladdin website using the product name, CAS number, or catalog number.
References
[1] Feng, X.-T.; Ren, J.-X.; Gao, X.; Min, Q.-Q.; Zhang, X. 3,3-Difluoroallyl Sulfonium Salts: Practical and Bench-Stable Reagents for Highly Regioselective gem-Difluoroallylations. Angew. Chem. Int. Ed. 2022, 61, e202210103. DOI: 10.1002/anie.202210103.
[2] Feng, X.-T.; Min, Q.-Q.; Zeng, X.; Zhao, H.-Y.; Zhang, X. Controllable Diverse Construction of gem-Difluoroallylated Bicyclo[1.1.1]pentanes and Cyclobutanes from [1.1.1]Propellane via Copper Catalysis. ACS Catal. 2024, 14, 5879–5887. DOI: 10.1021/acscatal.4c00281.
[3] Zhou, M.; Ren, J.-X.; Feng, X.-T.; Zhao, H.-Y.; Fu, X.-P.; Min, Q.-Q.; Zhang, X. Late-Stage gem-Difluoroallylation of Phenol in Bioactive Molecules and Peptides with 3,3-Difluoroallyl Sulfonium Salts. Chem. Sci. 2024, 15, 2937–2945. DOI: 10.1039/D3SC06302J.
[4] Ren, J.-X.; Zhou, M.; Feng, X.-T.; Zhao, H.-Y.; Fu, X.-P.; Zhang, X. Site-Selective S-gem-Difluoroallylation of Unprotected Peptides with 3,3-Difluoroallyl Sulfonium Salts. Chem. Sci. 2024, 15, 10002–10009. DOI: 10.1039/D4SC02681K.
For more related articles, see below:
Oxetane: Property-Window Optimization and a Building-Block Selection Guide (Tables 1–4)
Cyclic isomers--Azabicyclic molecular building blocks to aid drug design
N-Heterocyclic Carbene (NHC) Ligands
危险品化学品经营许可证（带存储）