Triphenylphosphine-Involved Carboxylic Acid Activation and Amide Bond Formation: Activation Pathways, Anhydride Competition, and Applicability Scenarios
Triphenylphosphine-Involved Carboxylic Acid Activation and Amide Bond Formation: Activation Pathways, Anhydride Competition, and Applicability Scenarios
Overview
When a carboxylic acid and an amine are used to form an amide bond in a triphenylphosphine-involved system, the first distinction to make is whether the process proceeds through stoichiometric activation or through a catalytic cycle in which triphenylphosphine oxide is reduced in situ to establish a P(III)/P(V) turnover manifold. Stoichiometric activation systems may first be broadly divided, according to their dominant activation tendency, into two categories: one is closer to in situ acyl chloride formation, while the other is often understood as proceeding through acyloxyphosphonium-like activation followed by acyl transfer. Before running the experiment, three points should be clarified first: what type of highly reactive intermediate is formed under the chosen conditions; whether that intermediate is first captured by the target amine or by the carboxylate after activation; and whether the sensitivity to order of addition, the formation of triphenylphosphine oxide as a byproduct, and the associated work-up burden are compatible with the target substrate and the experimental objective.
1. Several Typical Pathways for Triphenylphosphine-Involved Amidation
1.1 The hexachloroacetone/triphenylphosphine system is closer to an in situ acyl chloride pathway
The combination of hexachloroacetone and triphenylphosphine is, in essence, closer to a pathway in which an acyl chloride is generated in situ and then undergoes acyl transfer to the amine. Villeneuve and Chan reported in 1997 that carboxylic acids could be converted into the corresponding acyl chlorides by hexachloroacetone and triphenylphosphine in dichloromethane at −78 °C; under the same conditions, formic acid could also be converted into formyl chloride. This route is fundamentally an in situ acyl chloride pathway, and moisture sensitivity, substrate tolerance, order of addition, and the efficiency of subsequent capture by the amine are all key factors affecting the reaction outcome.
1.2 N-halosuccinimide/triphenylphosphine systems are usually understood in terms of an acyloxyphosphonium-type activation pathway
Frøyen’s 1995 work showed that carboxylic acids and amines could be converted into amides in the presence of stoichiometric triphenylphosphine and N-halosuccinimides; the abstract states that N-chlorosuccinimide and N-bromosuccinimide could be used. Frøyen then reported in 1997 that in situ generated acyloxytriphenylphosphonium salts could serve as chemoselective acylating reagents in their own right. Accordingly, for experimental purposes, this class of routes can often be understood in terms of acyloxyphosphonium-like activation. Within this pathway, whether the activated species is captured promptly by the target amine often directly determines whether the reaction proceeds toward amide formation; if carboxylates, alcohols, or other nucleophiles compete for interception, the reaction outcome can change substantially.
1.3 A catalytic cycle based on in situ regeneration of triphenylphosphine
In 2014, Lenstra, Rutjes, and Mecinović reported a triphenylphosphine-catalyzed carboxylic acid-amine amidation system. This system uses catalytic triphenylphosphine and carbon tetrachloride, and in the presence of diethoxymethylsilane and bis(4-nitrophenyl) phosphate, the triphenylphosphine oxide formed during the reaction is reduced in situ back to triphenylphosphine, thereby establishing a P(III)/P(V) cycle. In this route, triphenylphosphine is regenerated in situ and enters catalytic turnover, so its reaction characteristics differ from those of stoichiometric triphenylphosphine-mediated amidation.
1.4 Several Typical Pathways for Triphenylphosphine-Involved Carboxylic Acid-Amine Amidation
Type | Representative system | Key activating species or pathway | Main focus of experimental judgment |
Stoichiometric in situ acyl chloride pathway | Triphenylphosphine / hexachloroacetone | In situ generation of an acyl chloride | Evaluate substrate tolerance, moisture sensitivity, and subsequent amine capture efficiency using acyl chloride logic |
Stoichiometric acyloxyphosphonium activation pathway | Triphenylphosphine / N-chlorosuccinimide; triphenylphosphine / N-bromosuccinimide | In situ generation of an acyloxyphosphonium-type activated species | Focus on competitive capture by the target amine versus carboxylates, alcohols, or other nucleophiles |
Order-sensitive activation network | Triphenylphosphine / iodine / triethylamine | An order-sensitive network of highly reactive intermediates associated with acyloxyphosphonium salts and related species | Focus on the order of addition, the timing of base addition, and the carboxylate concentration |
Catalytic P(III)/P(V) cycle | Catalytic triphenylphosphine / carbon tetrachloride, combined with an in situ triphenylphosphine oxide reduction system | Triphenylphosphine is regenerated and enters catalytic turnover | Valid only under specifically designed regeneration conditions and cannot substitute for most classical triphenylphosphine systems |
2. Key Experimental Variables Associated with Different Activation Pathways
2.1 Substrate tolerance and timing control in the in situ acyl chloride pathway
Under the in situ acyl chloride pathway, activation is relatively fast and acyl-transfer capability is strong, but control of moisture, sensitive functional groups, and side reactions is also more demanding. In systems such as hexachloroacetone/triphenylphosphine, whether the substrate can tolerate acyl chloride-forming conditions, whether the water content of the system is under control, and whether the amine can enter promptly after activation usually has a direct impact on the reaction outcome.
In systems using N-chlorosuccinimide or N-bromosuccinimide together with triphenylphosphine, once an acyloxyphosphonium-type activated species is formed, competitive interception by the target amine, the carboxylate, an alcohol, or another nucleophile will directly affect yield and selectivity. When entry of the target amine is relatively slow, side pathways are more easily amplified.
2.3 Order effects and anhydride competition in triphenylphosphine/iodine/triethylamine systems
Wangngae and co-workers reported in 2015 that triphenylphosphine/iodine-mediated amidation is highly sensitive to the order of reagent addition. When triethylamine was added to a mixture containing triphenylphosphine, iodine, and a carboxylic acid, the anhydride was generated almost immediately. In contrast, when the triphenylphosphine-iodine mixture was first brought into contact with the amine, followed by addition of the carboxylic acid and then triethylamine, the amide was formed rapidly with high chemoselectivity.
Phakhodee and co-workers further showed in 2016 that under triphenylphosphine/iodine/triethylamine conditions, most aromatic carboxylic acids could be converted into the corresponding anhydrides in high yield within 5 to 10 minutes. However, for nitro-substituted aromatic carboxylic acids, the product isolated after longer reaction times was N,N-diethylamide rather than the corresponding anhydride. The reaction outcome in this system is simultaneously influenced by the substrate’s electronic properties, the order of addition, and the timing of base addition.
2.4 Recognition and troubleshooting points for competing pathways in triphenylphosphine/iodine/triethylamine systems
Observation | Possible corresponding pathway | Experimental points to check first |
The carboxylic acid is consumed rapidly, but the target amide is very low | After activation, the system forms an anhydride first rather than being captured by the amine | Whether a high carboxylate concentration has already been established before amine addition; whether triethylamine was added too early |
Different orders of addition lead to major differences in outcome | The system exhibits pronounced order sensitivity | Examine the order of addition together with reagent ratios, rather than adjusting only equivalents |
In aromatic carboxylic acid systems, a large amount of symmetrical anhydride forms within minutes | Competitive interception of the highly reactive activated species by the carboxylate is rapid | Shorten the exposure time of the activated species and avoid prolonged premixing of the carboxylic acid with the base |
Under PPh3/I2/Et3N conditions, strongly electron-deficient nitro-substituted aromatic acids give N,N-diethylamides at longer reaction times | Substrate electronic effects alter the downstream reaction pathway | Monitor both time-dependent changes and the byproduct profile; do not treat all substrates as following a single side pathway |
3. Applicability Scenarios of Triphenylphosphine Systems in Amidation Screening
Triphenylphosphine-involved amidation is suitable for several types of tasks:
1. substrate pairs for which one needs to quickly test whether a highly reactive carboxylic acid activation pathway can be opened;
2. systems in which the effects of order of addition, competitive interception, and diversion into side pathways need to be compared;
3. projects at the small-scale screening stage that can tolerate stoichiometric byproducts such as triphenylphosphine oxide and allow careful control over order of addition and work-up.
When the screening objective shifts toward reducing stoichiometric waste, simplifying separation, or prioritizing more direct bond-forming routes, direct amidation, transamidation, and nonclassical amide bond-forming methods should usually be included in parallel for comparison.
3.1 Assessment of the suitability of triphenylphosphine systems in amidation condition screening
Research or experimental task | Suitability | Main basis |
Rapidly testing whether a highly reactive carboxylic acid activation pathway is feasible | Relatively suitable | Substrate reactivity can be raised rapidly through in situ acyl chloride formation or acyloxyphosphonium-type activation |
Comparing the effects of order of addition, competitive interception, and diversion into side pathways | Highly suitable | Triphenylphosphine/iodine/triethylamine systems are highly sensitive to order of addition and the timing of base addition |
Involvement of weakly nucleophilic or sterically hindered amines | Requires caution | In some systems, anhydride competition can compress the capture window for the target amine |
Work-up cannot tolerate the separation burden caused by byproducts such as triphenylphosphine oxide | Less suitable | In most classical triphenylphosphine systems, triphenylphosphine participates stoichiometrically and is usually accompanied by the formation of byproducts such as triphenylphosphine oxide, which often imposes a substantial separation and purification burden |
The goal is to reduce waste burden, simplify work-up, or improve scale-up feasibility | Should be compared in parallel with other methods | Under such objectives, direct amidation, transamidation, and other lower-burden bond-forming methods generally deserve higher priority in comparison |
4. Work-Up Evaluation of Triphenylphosphine Systems Before Scale-Up
Before a triphenylphosphine system enters scale-up or further route development, one should evaluate not only whether the reaction can proceed, but also the separation and purification burden associated with byproducts such as triphenylphosphine oxide.
4.1 Key points for evaluating work-up and separation before scale-up of triphenylphosphine systems
Observation or project characteristic | Potential problem | Experimental points to confirm first |
High content of triphenylphosphine oxide in the crude product | More purification steps are required, and the separation burden increases upon scale-up | Whether the triphenylphosphine oxide content can first be reduced by precipitation, filtration, recrystallization, or complexation |
The target amide and triphenylphosphine oxide have similar polarity | Separation by column chromatography or recrystallization is difficult, and yield loss is amplified | Whether the existing solvent system is suitable for selective precipitation, removal by complexation, or phase-separation-based handling |
Pure material can only be obtained on small scale by relying on column chromatography | Poor scalability and difficult process translation | Whether a chromatography-free purification route exists; if not, other amidation routes should be compared as early as possible |
The project emphasizes low waste, simplified work-up, or scale-up feasibility | The overall burden of the triphenylphosphine route is relatively high | Whether direct amidation, transamidation, or other lower-burden bond-forming methods should be compared in parallel |
The target product is highly polar and remains in the high-polarity region together with byproducts | Impurities in the crude material are difficult to separate, increasing downstream purification pressure | Whether different extraction, crystallization, and solvent-switching schemes need to be tested already at the small-scale stage |
5. Product Navigation Table for Experimental Method Selection in Triphenylphosphine-Involved Carboxylic Acid Activation and Amidation (Choose Table 1–Table 4 by Research or Experimental Objective)
Research or experimental objective | Which table to consult first | Why consult this table first | Which table to cross-reference | Reason for cross-reference |
To first distinguish whether triphenylphosphine functions in this type of reaction as the core activating reagent, a precursor to a preformed activated species, or a regenerable phosphorus source in a catalytic cycle | Table 1 | Table 1 brings together triphenylphosphine, polymer-supported triphenylphosphine, triphenylphosphine oxide, dichlorotriphenylphosphorane, dibromotriphenylphosphorane, and catalytic-cycle-related components, making it suitable for first clarifying the role of the phosphorus center and the basic framework of different systems | Table 2 | Table 2 then adds paired reagents such as iodine, NCS, NBS, hexachloroacetone, and carbon tetrabromide, helping further distinguish which activation pathway each phosphorus-based system tends to follow |
To compare whether PPh3/I2, PPh3/NCS(NBS), and PPh3/hexachloroacetone each more closely correspond to a given carboxylic acid activation mode | Table 2 | Table 2 focuses on different paired activators, key bases, and byproduct identifiers, making it suitable for directly comparing iodine-based activation, N-halosuccinimide-based activation, and the in situ acyl chloride pathway | Table 1, Table 3 | First cross-reference Table 1 for phosphorus reagents and preformed activated species, then Table 3 to examine differences in the behavior of different carboxylic acid substrates entering these pathways |
To focus on why anhydride competition appears under PPh3/I2/Et3N conditions instead of the reaction remaining cleanly on the amide pathway | Table 3 | Table 3 places benzoic acid, 4-nitrobenzoic acid, 4-methoxybenzoic acid, phenylacetic acid, and benzoic anhydride together, making it convenient to compare the effects of carboxylic acid electronics and the anhydride side pathway | Table 2 | Iodine, triethylamine, and DIPEA in Table 2 are the key condition components for studying anhydride competition and order-of-addition effects, and are suitable for joint evaluation of base effects and activation mode differences |
To compare differences in reactivity when different carboxylic acid substrates enter triphenylphosphine activation systems, and to decide how aromatic acids, aliphatic acids, and benzylic acids should each be screened | Table 3 | Table 3 is organized by carboxylic acid type and electronic effects, and is suitable for first establishing a framework for how substrate differences influence activation efficiency, acyl transfer, and side reactions | Table 2, Table 4 | Table 2 helps identify which type of activator and base should be paired, while Table 4 helps compare how different amine substrates match with these carboxylic acids |
To compare the interception ability of primary amines, secondary amines, and aromatic amines in triphenylphosphine activation systems, and determine which types of amines more readily enter the desired amide pathway | Table 4 | Table 4 focuses on benzylamine, cyclohexylamine, aniline, morpholine, piperidine, and N,O-dimethylhydroxylamine hydrochloride, making it suitable for directly comparing differences in amine nucleophilicity and structural type | Table 2, Table 3 | Cross-referencing Table 2 shows the corresponding activation conditions, while cross-referencing Table 3 shows the reaction windows for pairing different carboxylic acid substrates with these amines |
To perform a Weinreb amide route and compare differences between ordinary triphenylphosphine and polymer-supported triphenylphosphine in work-up and handling | Table 4 | N,O-Dimethylhydroxylamine hydrochloride in Table 4 is the direct amine source for Weinreb amides and is a suitable starting point for this route | Table 1, Table 2 | Table 1 further compares ordinary triphenylphosphine with polymer-supported triphenylphosphine, while Table 2 supplements the route with commonly used supporting conditions such as iodine and DIPEA |
To compare the difference between the two approaches of “forming the acyl chloride in situ and then coupling” and “forming the amide directly in the activation system” | Table 2 | Table 2 includes both hexachloroacetone and benzoyl chloride, making it convenient to compare the in situ acyl chloride pathway and a preformed acyl chloride reference within the same framework | Table 3, Table 4 | Table 3 can then be used to choose different carboxylic acid models, while Table 4 can be used to compare how different amines capture acyl chloride-type activated species |
To focus on work-up and byproduct identification, and to see which components are most likely to affect separation, purification, and interpretation of the results | Table 1 | Triphenylphosphine oxide and polymer-supported triphenylphosphine in Table 1 directly correspond to phosphorus-related byproduct burden and differences in work-up | Table 2, Table 3 | Table 2 supplements the analysis with byproduct identifiers such as succinimide and triethylamine hydrochloride, while benzoic anhydride in Table 3 corresponds to interpretation of outcomes arising from the anhydride side pathway |
To start from a “truly catalytic triphenylphosphine amidation” system rather than remaining at the level of stoichiometric phosphorus activation | Table 1 | Table 1 already lists bis(4-nitrophenyl) phosphate and diethoxymethylsilane, which are relevant to the catalytic cycle and suitable as an entry point for catalytic-cycle studies | Table 2 | The carbon tetrachloride analytical reference in Table 2 can be considered alongside the catalytic PPh3/CCl4 route, helping distinguish the catalytic cycle from traditional activation systems |
Table 1 | Core Phosphine Reagents, Preformed Activated Species, and Catalytic-Cycle Components
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Core phosphine activating reagent | 603-35-0 | Triphenylphosphine | ≥99%(GC) | A core phosphorus source for carboxylic acid activation. It can be paired with iodine, N-chlorosuccinimide, N-bromosuccinimide, hexachloroacetone, and related reagents to form different activation systems, and is suitable for comparing acyloxyphosphonium-type, halogenation-type, and in situ acyl chloride pathways. | |
Polymer-supported phosphine activating reagent | 39319-11-4 | Triphenylphosphine, polymer-bound | 100-200 mesh, labeling range: ~3.0 mmol/g loading, 2% cross-linked with divinylbenzene | A polymer-supported phosphorus source suitable for screening conventional amide and Weinreb amide preparations under PPh3/I2 conditions, while allowing convenient removal of phosphorus-related byproducts by filtration. | |
Phosphine oxide byproduct reference | 791-28-6 | Triphenylphosphine oxide | ≥98% | A typical oxidation byproduct in triphenylphosphine activation systems, suitable for reaction monitoring, purification analysis, and evaluating the impact of phosphorus-related byproducts on work-up. | |
Preformed chlorophosphorane activating species | 2526-64-9 | Dichlorotriphenylphosphorane | ≥95% | A preformed halophosphorane activating species suitable for comparing differences in reactivity and side-reaction behavior between preformed activated species and in situ activation systems. | |
Preformed bromophosphorane activating species | 1034-39-5 | Triphenylphosphine dibromide | ≥95% | A preformed bromophosphorane activating species suitable for comparison with in situ bromination-based activation conditions such as NBS and carbon tetrabromide, in order to examine the reactivity of bromination-type phosphorus activation states. | |
Catalytic-cycle regeneration-promoting component | 645-15-8 | Bis(4-nitrophenyl) phosphate | ≥99% | A key regeneration-promoting component reported in the literature on catalytic triphenylphosphine amidation, suitable for use with hydrosilanes to examine regeneration of triphenylphosphine from triphenylphosphine oxide. | |
Catalytic-cycle reducing silane | 2031-62-1 | Diethoxymethylsilane [Hydrosilylating Reagent] | ≥95%(GC) | Suitable for use together with bis(4-nitrophenyl) phosphate in studies of phosphine oxide reduction and regeneration in catalytic systems. | |
Carbon tetrachloride analytical reference | 56-23-5 | Carbon tetrachloride Standard | 2000 ug/ml in Purge and Trap Methanol | An analytical standard related to carbon tetrachloride, suitable for paired-reagent identification, analysis, or methodological reference in catalytic PPh3/CCl4 routes. It is not suitable for direct use as a representative synthetic reagent for catalytic PPh3/CCl4 amidation. |
Table 2 | Paired Reagents for Carboxylic Acid Activation, Key Bases, and Byproduct Identifiers
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Key acid-binding base for order effects | 121-44-8 | Triethylamine | Anhydrous, ≥99.5%, Water≤50 ppm | A key acid-binding base in PPh3/I2 systems, suitable for examining how the timing of base addition influences amide formation versus anhydride competition. | |
Post-acid-binding salt-form identifier | 554-68-7 | Triethylamine hydrochloride | Chromatography HPLC grade, ≥99% | A common salt-form reference in pathways involving acyl chlorides or hydrogen halides, suitable for identifying the acid-binding process and work-up state. | |
Sterically hindered tertiary amine acid-binding base | 7087-68-5 | N,N-Diisopropylethylamine | Distilled grade, ≥99.5% | A more sterically hindered tertiary amine base, suitable for screening conventional amide and Weinreb amide preparations under PPh3/I2 conditions and for comparing its base effects with those of triethylamine. | |
Iodination-based activation paired reagent | 7553-56-2 | I434868 | Iodine | High purity, reagent grade, ≥99.8%(T) | Forms an order-sensitive activation system with triphenylphosphine and is suitable for examining diversion between the amide pathway and the anhydride pathway when the order of addition is changed. |
Chlorination-based activation paired reagent | 128-09-6 | N-Chlorosuccinimide | ≥98% | One of the classical conditions for carboxylic acid activation and amidation when paired with triphenylphosphine, suitable for establishing a benchmark route under relatively mild conditions. | |
Bromination-based activation paired reagent | 128-08-5 | N-Bromosuccinimide (NBS) | AR, ≥99% | Can form a highly active acyl-transfer system when paired with triphenylphosphine, and is suitable for comparing differences between bromination-type and chlorination-type activation conditions relative to NCS. | |
Acyl chloride pathway activation paired reagent | 116-16-5 | Hexachloroacetone | ≥99% | In combination with triphenylphosphine, this system more closely follows an in situ acyl chloride pathway and is suitable for comparing “direct acyl transfer” with “initial acyl chloride formation followed by amine capture.” | |
Strong bromination activation paired reagent | 558-13-4 | Carbon Tetrabromide | ≥99% | Forms a relatively strong bromination-based activation system with triphenylphosphine and is suitable for comparing reactivity and byproduct burden against paired conditions such as iodine, NCS, and NBS. | |
N-Halosuccinimide byproduct reference | 123-56-8 | Succinimide | ≥99% | A direct byproduct reference for NCS/NBS routes, suitable for monitoring N-halosuccinimide conversion and identifying byproducts during purification. | |
Preformed acyl chloride reference | 98-88-4 | Benzoyl chloride | AR, ≥99% | A representative preformed acyl chloride reference, suitable for comparing reaction efficiency and work-up differences against the in situ acyl chloride pathway based on hexachloroacetone/triphenylphosphine. |
Table 3 | Carboxylic Acid Substrate Models and Anhydride Competition References
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Electron-deficient aromatic carboxylic acid model | 62-23-7 | 4-Nitrobenzoic acid | Suitable for synthesis | An electron-deficient aromatic carboxylic acid model, suitable for comparing how changes in carboxylic acid electronic effects influence activation rate and amine capture efficiency. | |
Benchmark aromatic carboxylic acid model | 65-85-0 | Benzoic acid | Suitable for synthesis | A benchmark aromatic carboxylic acid substrate, suitable for establishing baseline conditions for PPh3/I2, PPh3/NCS(NBS), and in situ acyl chloride pathways. | |
Aliphatic carboxylic acid model | 64-19-7 | Acetic acid | Moligand™, anhydrous, ≥99%, without molecular sieves, water≤50 ppm | An aliphatic carboxylic acid model, suitable for comparison with aromatic carboxylic acids to evaluate how carboxylic acid class affects activation efficiency and side-reaction control. | |
Benzylic carboxylic acid model | 103-82-2 | P1506271 | Phenylacetic acid | AR,≥99.0% | A benzylic carboxylic acid model, suitable for comparing how substrate structures different from benzoic acid affect activation pathways and side-reaction behavior. |
Electron-rich aromatic carboxylic acid model | 100-09-4 | 4-Methoxybenzoic acid | ≥98% | An electron-rich aromatic carboxylic acid model, suitable for paired comparison with 4-nitrobenzoic acid to examine the influence of electronic effects on carboxylic acid activation and subsequent acyl transfer. | |
Anhydride competition product reference | 93-97-0 | Benzoic anhydride | ≥98% | A representative reference for the anhydride competition product under PPh3/I2/Et3N conditions, suitable for identifying whether the system is preferentially diverting toward the anhydride pathway. |
Table 4 | Amine Substrate Models, Weinreb Amide Amine Source, and Target Product Reference
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Secondary alicyclic amine model | 110-89-4 | P1506346 | Piperidine | Biotechnology grade, ≥99.5% | A secondary alicyclic amine model, suitable for evaluating the interception ability of relatively strongly nucleophilic, more basic amines toward activated acyl intermediates. |
Secondary heterocyclic amine model | 110-91-8 | Morpholine | Distilled grade, ≥99.5% | A six-membered heterocyclic secondary amine model, suitable for comparing the amidation behavior of secondary amines versus primary amines in triphenylphosphine activation systems. | |
Aromatic primary amine model | 62-53-3 | Aniline | Standard for GC, ≥99.9%(GC) | A weakly nucleophilic aromatic amine model, suitable for testing the ability of highly active carboxylic acid activation conditions to drive less nucleophilic amine substrates. | |
Aliphatic primary amine model | 108-91-8 | Cyclohexylamine | Moligand™, Standard for GC, ≥99.5%(GC) | An aliphatic primary amine model, suitable for establishing the conventional reaction baseline for primary amine substrates under different activation modes. | |
Benzylic primary amine model | 100-46-9 | Benzylamine | AR, ≥99% | A benzylic primary amine model, suitable for comparing the capture efficiency of relatively reactive primary amines toward acyloxyphosphonium-type and acyl chloride-type activated species. | |
Weinreb amide amine source | 6638-79-5 | N,O-Dimethylhydroxylamine Hydrochloride | ≥98% | A direct amine source for Weinreb amides, suitable for constructing Weinreb amides under PPh3/I2 or polymer-supported triphenylphosphine/iodine conditions. | |
Target amide endpoint reference | 55-21-0 | Benzamide | Sublimed grade, ≥99.5% | A representative endpoint amide reference, suitable for establishing retention behavior and purification references for the target product in the “carboxylic acid → amide” transformation. |
Note: The above are representative Aladdin products. More product specifications can be searched on the Aladdin official website using the “product name/CAS/catalog number.”
References
[1] Montalbetti, C. A. G. N.; Falque, V. Amide bond formation and peptide coupling. Tetrahedron 2005, 61(46), 10827-10852. doi:10.1016/j.tet.2005.08.031.
[2] Valeur, E.; Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 2009, 38(2), 606-631. doi:10.1039/B701677H.
[3] Lanigan, R. M.; Sheppard, T. D. Recent developments in amide synthesis: direct amidation of carboxylic acids and transamidation reactions. Eur. J. Org. Chem. 2013, (33), 7453-7465. doi:10.1002/ejoc.201300573.
[4] Lenstra, D. C.; Rutjes, F. P. J. T.; Mecinović, J. Triphenylphosphine-catalysed amide bond formation between carboxylic acids and amines. Chem. Commun. 2014, 50, 5763-5766. doi:10.1039/C4CC01861C.
[5] Wangngae, S.; Duangkamol, C.; Pattarawarapan, M.; Phakhodee, W. Significance of reagent addition sequence in the amidation of carboxylic acids mediated by PPh3 and I2. RSC Adv. 2015, 5(33), 25789-25793. doi:10.1039/C5RA03184B.
[6] Phakhodee, W.; Duangkamol, C.; Wangngae, S.; Pattarawarapan, M. Acid anhydrides and the unexpected N,N-diethylamides derived from the reaction of carboxylic acids with Ph3P/I2/Et3N. Tetrahedron Lett. 2016, 57(3), 325-328. doi:10.1016/j.tetlet.2015.12.009.
[7] Frøyen, P. The conversion of carboxylic acids into amides via NCS/triphenylphosphine. Synth. Commun. 1995, 25(7), 959-968. doi:10.1080/00397919508012657.
[8] Frøyen, P. Phosphorus in organic synthesis. Acyloxyphosphonium salts as chemoselective acylating reagents. Tetrahedron Lett. 1997, 38(30), 5359-5362. doi:10.1016/S0040-4039(97)01172-6.
[9] Villeneuve, G. B.; Chan, T. H. A rapid, mild and acid-free procedure for the preparation of acyl chlorides including formyl chloride. Tetrahedron Lett. 1997, 38(37), 6489-6492. doi:10.1016/S0040-4039(97)01511-6.
[10] de Figueiredo, R. M.; Suppo, J.-S.; Campagne, J.-M. Nonclassical routes for amide bond formation. Chem. Rev. 2016, 116(19), 12029-12122. doi:10.1021/acs.chemrev.6b00237.
For more related articles, see below:
危险品化学品经营许可证（带存储）