Experimental Judgment for CMPI in Carboxylic Acid Activation: Applicable Tasks, Base Matching, and Workup Burden

Overview

2-Chloro-1-methylpyridinium iodide, abbreviated as CMPI, is a representative member of Mukaiyama-type carboxylic acid activation reagents and is often referred to as a Mukaiyama reagent; more precisely, it is one of the classic representatives of Mukaiyama-type 2-halo-1-methylpyridinium activators. In 1975, the Mukaiyama group successively reported that 1-methyl-2-halopyridinium salt reagents promote the esterification of carboxylic acids with alcohols and the amidation of carboxylic acids with amines; in 1976, related conditions were further applied to the lactonization of hydroxy acids. In organic synthesis, the experimental value of CMPI lies mainly in the direct activation of free carboxylic acids, its side-reaction profile being different from that of carbodiimide systems, and its relatively clear dependence on the base, the state of the nucleophile, and the workup protocol. When making a selection judgment, it is more important first to clarify the substrate type, the reactivity of the nucleophile, whether the base is properly matched, and whether the purification route is acceptable.

1. Mode of Action and Applicable Tasks of CMPI in Carboxylic Acid Activation

CMPI belongs to the class of 1-alkyl-2-halopyridinium salt activators. According to Mukaiyama’s 1979 review, after reacting with a carboxylic acid, this class of reagents can generally be described as forming a 2-acyloxypyridinium-type activated intermediate, which is then intercepted by an alcohol, an amine, or an intramolecular nucleophilic site to give an ester, an amide, or a lactone. Its activation pathway differs from that of carbodiimide systems, and it also differs from routes that first prepare an acid chloride or an acyl imidazole and then proceed by substitution.

From the standpoint of experimental use, the mature applications of CMPI are mainly concentrated in three categories.

Application Task	Literature Basis	Role of CMPI in This Type of Task
Esterification of carboxylic acids with alcohols	1975 esterification paper	In the presence of a tertiary amine, directly activates a free carboxylic acid, which is then trapped by an alcohol to form an ester
Amidation of carboxylic acids with amines	1975 amidation paper	Under relatively mild conditions, promotes the direct coupling of a free carboxylic acid with an amine to form an amide
Intramolecular lactonization of hydroxy acids	1976 lactonization paper	Directly drives a hydroxy acid to intramolecular ring closure to form a lactone

The 1975 esterification paper showed that free carboxylic acids and alcohols can be directly converted to esters in the presence of 1-methyl-2-halopyridinium salts and two equivalents of tributylamine; the amidation paper from the same year showed that free carboxylic acids and amines can rapidly form amides under related conditions; the 1976 paper further extended this route to the direct conversion of hydroxy acids into lactones. For systems that aim to move directly from a free carboxylic acid into a subsequent transformation, CMPI is an activating reagent suited to relatively mild, nonaqueous, organic-phase conditions and can be used for esterification, amidation, or lactonization.

2. Three Factors That Should Be Evaluated First Under CMPI-Mediated Carboxylic Acid Activation Conditions

In CMPI systems, before beginning small-scale trials, the carboxylic acid, the nucleophile, and the base should first be evaluated separately. The first two determine whether the activated intermediate can be formed smoothly and intercepted in time, while the third affects not only the acid-base balance but may also directly alter the activation process.

2.1 | Three Factors That Should Be Evaluated First Under CMPI Conditions

Factor to Evaluate	What to Confirm First	Main Effect on the Reaction Outcome	What to Examine First Experimentally
Carboxylic acid side	Whether steric hindrance is obviously large, whether side reactions are likely, and whether functional groups affecting acid-base balance are present	Directly affects the activation rate and the stability of the activated intermediate	First check whether the carboxylic acid is consumed smoothly, and whether this is accompanied by accumulation of the activated intermediate or an increase in byproducts
Nucleophile side	Whether it is an alcohol or an amine, how strong its nucleophilicity is, and whether the amine is introduced as a salt	Determines whether the activated intermediate can be intercepted promptly	First check whether product formation rises in step with acid consumption, or whether the system remains at the stage of intermediates and byproducts
Base	Whether it serves simply as an acid scavenger or also affects the activation pathway; whether the base loading must also cover liberation of the free amine from an amine salt	Affects the carboxylic acid activation equilibrium, the effective concentration of the amine, and the composition of byproducts	First check whether changing the base or increasing its amount leads to a clear improvement in the reaction

Among these three factors, the one most easily underestimated is the base. In the original esterification and amidation papers, tertiary amines were used under explicitly defined stoichiometric conditions, showing that this route depended on base participation from the outset; later studies further showed that certain nitrogen-containing bases not only alter the acid-base balance but may also directly rewrite the activation process.

3. Differences in Experimental Judgment Among Esterification, Amidation, and Lactonization Under CMPI Conditions

Under CMPI conditions, esterification, amidation, and lactonization all begin with carboxylic acid activation, but the limiting factors that affect the outcome are not the same in the three types of transformations. At this stage, the factors most likely to influence reaction progress and purification outcome in each task should be evaluated separately.

3.1 | Items That Need to Be Checked Separately in the Three Types of Transformations

Transformation Type	Which Step First Governs Reaction Progress	Common Limiting Factors in This Type of Task	What Needs to Be Checked Separately
Esterification of carboxylic acids with alcohols	Whether the activated acyl group can be intercepted promptly by the alcohol	Conversion can be slower for highly hindered carboxylic acids, and polar byproducts increase the separation burden	Whether activation on the carboxylic acid side is sufficient, and whether product formation is synchronized with carboxylic acid consumption
Amidation of carboxylic acids with amines	Whether the effective concentration of the amine and the base matching are appropriate	Insufficient liberation of the free amine from amine salts, high product polarity, and tailing during workup/purification	Whether the amine is in the free-base form or introduced as a salt, and whether the amount of base covers release of the free amine from the amine salt
Intramolecular lactonization of hydroxy acids	Whether intramolecular attack can dominate	For lactonization to larger ring sizes, additional attention is usually needed for intermolecular side reactions and purification burden	In particular, whether ring size, reaction concentration, and mode of addition favor intramolecular ring closure

4. Situations Where CMPI Is Applicable, Its Limitations, and the Burden of Workup

Whether CMPI is worth including among the initial candidate conditions usually depends simultaneously on substrate type, reaction medium, and workup method. The table below groups together situations that may reasonably be tried first and those that require cautious evaluation.

4.1 | Common Situations Where CMPI May Be Considered First and Situations Requiring Cautious Evaluation

Judgment on CMPI	Common Situation	Basis for the Judgment
Can be considered first	Routine esterification, routine amidation, and lactonization of hydroxy acids	The original literature foundation is relatively solid, and fairly mature application routes already exist for these tasks
Can be considered first	When one wants to avoid acid chloride conditions or does not want to deal with urea byproducts from carbodiimide routes	The activation pathway and byproduct profile of CMPI differ from those systems
Requires cautious evaluation	Highly aqueous systems or homogeneous aqueous-phase coupling	CMPI has limited compatibility with water, and its activity can be affected by halide exchange
Requires cautious evaluation	Carboxylic acids with large steric hindrance combined with weak nucleophiles	Both activation and subsequent interception may be slow, making the upper limit of the reaction more constrained
Requires cautious evaluation	Target products with high polarity that are already difficult to separate	Polar byproducts and residual salts may further increase the purification burden
Requires cautious evaluation	Cases where the reaction only advances clearly after addition of a more strongly nucleophilic nitrogen-containing base	The system may no longer mainly reflect the reaction characteristics of classical CMPI conditions

The burden of workup is one of the most easily underestimated factors in CMPI selection. In the traditional workup for esterifications using Mukaiyama reagents, precipitated 1-methyl-2-pyridone often has to be filtered off before further purification; a 2021 process-metrics analysis of Muk-mediated esterification conditions also showed that, in the systems examined in that study, the high process mass intensity arose mainly from the large amount of solvent consumed during workup and separation. Whether CMPI should remain under consideration cannot be judged only by whether the main reaction can be completed; one must also consider whether the separation is practically worthwhile.

Another issue that is easily overlooked is the effective state of the reagent in nucleophilic solvents and under specific ionic conditions. A 2021 study showed that, under the methanol-containing conditions examined in that work, Mukaiyama reagents may react directly with methanol to form deactivated derivatives; therefore, in systems involving methanol, if conversion is abnormally low, this deactivation pathway deserves early investigation. A 2022 study, in discussing applicability in water, pointed out that CMPI is insoluble in water and that its chlorine atom can undergo nucleophilic displacement by iodide, thereby lowering its activity. When abnormally low conversion or large fluctuations in results are encountered experimentally, these factors should also be included in the troubleshooting process.

5. Differences Between CMPI and Common Carboxylic Acid Activation Systems

Common carboxylic acid activation systems differ markedly in activation pathway, byproduct profile, and workup burden. Considering these differences together makes it easier to judge the place of CMPI in a specific task.

5.1 | Main Differences Between CMPI and Common Carboxylic Acid Activation Systems

Activation System	Characteristics of the Activation Pathway	Main Advantages	Main Limitations
CMPI	Pyridinium salt activation, with acyl transfer proceeding through a 2-acyloxypyridinium-type intermediate	Free carboxylic acids can proceed directly to subsequent esterification, amidation, or lactonization; does not pass through a carbodiimide-type intermediate	Sensitive to the base and the reaction medium; often forms polar byproducts, so the workup burden cannot be ignored
DCC / DIC	Carbodiimide activation, proceeding through an O-acylisourea intermediate	Broad applicability and extensive practical experience in routine esterification and amidation	Readily generates urea byproducts; O-acylisourea-related side reactions may also occur, making separation burdensome
EDC	Water-soluble carbodiimide activation, usually used together with additives	More convenient for operation in water-containing systems; byproduct handling differs from DCC	In many cases requires additives and base to be used together; the system composition is more complex, and condition optimization is more dependent on fine tuning
CDI	The carboxylic acid is first converted to an acyl imidazole, which is then attacked by the nucleophile	The intermediate is relatively well defined and is suited to a “pre-activate first, then add the nucleophile” mode of control	Sensitive to substrate, order of addition, and moisture; the activation pathway is clearly different from that of CMPI
Acid chlorides / mixed anhydrides	The carboxylic acid is first converted to an acid chloride or mixed anhydride, followed by subsequent acyl transfer	For highly hindered or less reactive substrates, reaction advancement is often more direct	The pre-activation step is harsher, so functional-group compatibility must be evaluated separately; operation and workup burden are usually higher

The 2021 Green Chemistry study also provided a very concrete comparative background. In the design stage of the high-throughput screening, the authors did not include DCC because large amounts of urea precipitate readily formed during the reactions, making it unsuitable for high-throughput HPLC analysis; the same paper also identified Mukaiyama reagents and EDC·HCl as alternative systems worthy of particular attention. This does not mean that CMPI is generally superior to DCC or EDC, but rather that in practical selection, byproduct form, analytical convenience, and overall process burden are often just as important as the efficiency of the main reaction.

6. Result Items Recommended for Simultaneous Recording During CMPI Small-Scale Trials

In small-scale comparison experiments under CMPI conditions, it is not enough to record only conversion or crude yield. For this type of activation system, whether a given set of conditions should continue to be retained often also depends on the form of the byproducts, extraction difficulty, whether obvious tailing appears, and whether the base or nucleophilic nitrogen-containing base has changed the behavior of the system. The original 1975 papers, the 2021 esterification-condition study, and the 2022 study on related water-soluble activating reagents all show that judgment on this route cannot rely only on whether the main reaction occurs.

6.1 | Items Recommended for Simultaneous Recording in CMPI Small-Scale Comparison Experiments

Item to Record	Recommended Recording Content	What It Can Be Used to Judge Later
Whether starting material consumption and product formation are synchronized	Record the rate of decrease of the carboxylic acid, the rate of increase of the target product, and whether the two are synchronized	Distinguish whether the problem is insufficient activation or insufficient interception after activation
Appearance changes in the reaction mixture	Record whether solids precipitate, whether the mixture becomes cloudy, whether it thickens markedly, and whether stirring stops	Judge byproduct precipitation, mass-transfer limitations, and workup burden
Polar tailing in the crude product	Record whether obvious tailing, broad peaks, or difficult-to-elute impurities appear on TLC or in LC analysis	Judge whether polar byproducts, salts, or base-related residues have already become the main problem
Whether results change significantly after changing the base	Record whether conversion, selectivity, and purification difficulty change significantly after changing the type or amount of base	Judge whether the base is serving only as an acid scavenger or has already begun to affect the activation pathway
Difference between amine salts and free amines	Record whether reaction progress differs significantly when the amine is added as a salt versus in free-base form	Judge whether the limiting factor arises from insufficient liberation of the free amine from the amine salt
Workup consumption	Record whether multiple water washes, acid washes, base washes, filtrations, or column chromatography are required	Judge whether this route loses its practical advantage at the separation stage

7. Product Navigation Table for CMPI-Related Carboxylic Acid Activation, Base Matching, and Workup Considerations (Choose Table 1-Table 3 by Research or Experimental Goal)

Research or Experimental Goal	Recommended Table to Read First	Why Start with This Table	Recommended Table(s) to Read in Combination	Reason for Cross-Reference
To first clarify the core reagent framework of this route, distinguishing which compounds are CMPI itself, which are related pyridinium activators, and which are key reference compounds for workup	Table 1	Table 1 places CMPI, related halopyridinium activators, and 1-methyl-2-pyridone together, making it suitable for first establishing a basic understanding of what the main activator is, what related alternatives are available, and what should be watched in workup	Table 2	After identifying the main activator, Table 2 should be consulted next so that issues such as slow reaction progress, substrate sensitivity, or insufficient release of free amine from amine salts can be translated into questions of base selection
With a carboxylic acid and an alcohol or amine already in hand, to first judge whether the next small-scale trial should begin by changing the base or by changing the activator	Table 2	Table 2 focuses on acid-scavenging bases, hindered bases, and nitrogen-containing bases that can alter the activation pathway, making it the most suitable starting point for judging whether the current problem lies in base matching	Table 1	If changing the base still gives unsatisfactory results, Table 1 can then be consulted to compare related pyridinium activators and judge whether substitution should first be attempted within this activator family
To compare differences among different halopyridinium activators and decide whether screening should be expanded from CMPI to related reagents	Table 1	Table 1 already places the chloro-, fluoro-, and bromo-substituted related activators together, allowing direct comparison of how leaving-group changes affect activation and workup	Table 2	Screening of related activators usually needs to be considered together with base conditions, and consulting Table 2 helps avoid mistaking “base mismatch” for “the activator itself is unsuitable”
The reaction proceeds, but conversion is slow, and you want to judge whether the problem is insufficient carboxylic acid activation, slow interception by the nucleophile, or the base diverting the pathway	Table 2	For this type of problem, the first question is whether the base is serving only as an acid scavenger or has already participated in activation and altered intermediate distribution, so Table 2 is the most suitable place to begin	Table 3	If the problem is confirmed not to come from the base, Table 3 can then be consulted to compare CMPI with carbodiimide, imidazole-type activators, mixed anhydride routes, or acid chloride routes, and to judge whether the system itself should be changed directly
The reaction gives acceptable yield, but workup is difficult, with polar tailing, incomplete washing, or heavy column chromatography burden, and you want to identify the source of the problem first	Table 1	Table 1 includes 1-methyl-2-pyridone, a key byproduct reference compound, making it suitable for first judging purification difficulties from common residues in the CMPI system itself	Table 2	If large amounts of byproducts and salt residues are confirmed, Table 2 can then be consulted to check whether the type or amount of base is further amplifying the workup burden
To compare CMPI in parallel with DCC, DIC, EDC, CDI, HATU, HBTU, mixed anhydride, or acid chloride routes	Table 3	Table 3 summarizes the carboxylic acid activation systems most commonly compared in parallel with CMPI, making it suitable for direct side-by-side evaluation in terms of activation pathway, byproduct profile, and separation burden	Table 2	After identifying candidate activation systems, Table 2 should then be consulted for base conditions so that “changing the reagent” and “changing the base” can truly be separated into two different types of adjustment
The current substrate is sterically hindered, or the nucleophile is weak, and you want to judge whether CMPI is still worth pursuing	Table 3	Such tasks often require comparison of CMPI with stronger activation routes, so Table 3 is more suitable for first judging whether the case has already entered the range where the system should be changed	Table 1	If you still wish to retain the pyridinium route, return to Table 1 to compare whether a more suitable related substitute may still exist within the same activator family
To design a relatively complete CMPI research scheme, not looking only at a single main reagent, but also laying out related activators, base effects, and control systems together in one set	Table 1	Begin with Table 1 to establish the main framework of CMPI and related pyridinium activators, making it easier to define the starting point of the study	Table 2, Table 3	Then consult Table 2 and Table 3 together to incorporate both base effects and external control systems, so that a complete comparative scheme covering activators, bases, and alternative routes can be constructed

Table 1 | CMPI Itself, Related Pyridinium Activators, and Byproduct Reference Compounds

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Core pyridinium carboxylic acid activator	14338-32-0	C154059	2-Chloro-1-methylpyridinium Iodide	≥98%(T)	A classical Mukaiyama-type carboxylic acid activator that can be used directly for coupling carboxylic acids with alcohols, amines, or intramolecular hydroxyl groups, and is often used as the starting point of the main route in small-scale trials.
Fluorinated related pyridinium activator	58086-67-2	F139031	2-Fluoro-1-methylpyridinium p-toluenesulfonate	≥98%	Also a halopyridinium activator, suitable as a related comparison object for CMPI to compare how leaving-group differences affect activation efficiency, reaction rate, and workup.
Chlorinated related pyridinium activator	7403-46-5	C134736	2-Chloro-1-methylpyridinium p-Toluenesulfonate	≥98%	Belongs to the same class of activation system as CMPI and is suitable for comparing activation performance, system stability, and purification burden under different counteranion conditions.
Brominated related pyridinium activator	52693-56-8	B961955	2-Bromo-1-methylpyridin-1-ium iodide	≥95%	Suitable for comparing the relative activation strength and byproduct characteristics of different halopyridinium salts, and useful for replacement screening within the same reagent family.
Pyridone byproduct reference compound	694-85-9	M158822	1-Methyl-2-pyridone	≥99%(GC)	A common workup reference compound for this class of pyridinium activators, suitable for identifying polar byproducts, elution tailing, and sources of purification burden.

Table 2 | Common Bases, Nucleophilic Nitrogen-Containing Additives, and Pathway-Modulating Factors under CMPI Conditions

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
General tertiary amine acid-scavenging base	121-44-8	T140677	Triethylamine	Anhydrous grade, ≥99.5%, Water≤50 ppm	A commonly used acid-scavenging base that neutralizes the acid generated during the reaction and maintains the basic environment needed for carboxylic acid activation and nucleophilic attack, making it suitable as a starting point for routine small-scale trials.
Hindered tertiary amine acid-scavenging base	7087-68-5	D109322	N,N-Diisopropylethylamine	Distilled grade, ≥99.5%	A more sterically hindered tertiary amine base, suitable for comparison with triethylamine to observe changes in activation efficiency, substrate stability, and side reactions after changing the base.
Hindered pyridine base	108-48-5	L431380	2,6-Lutidine	Distilled grade, ≥99%	A hindered pyridine base with relatively moderate basicity and nucleophilicity, suitable for comparative use when the substrate is sensitive or when side reactions need to be suppressed.
Nucleophilic nitrogen-containing base	616-47-7	M109227	1-Methylimidazole	≥99%	Strongly nucleophilic and capable of clearly influencing the distribution of activated intermediates, making it suitable for judging whether the base has shifted from an acid-scavenging role to participation in activation.
Acyl transfer promoter and nucleophilic base	1122-58-3	D109207	4-Dimethylaminopyridine	≥99%	A commonly used acyl transfer promoter and nucleophilic base that often changes reaction rate and pathway, suitable for comparing whether stronger nucleophilic promotion is needed.

Table 3 | Common Control Carboxylic Acid Activation Systems and Representative Reagents

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product Features and Applications
Representative reagent for the acid chloride route	79-37-8	O434200	Oxalyl chloride	Reagent grade, superior grade, ≥99%	Commonly used to convert carboxylic acids into acid chlorides, suitable for comparison with CMPI in terms of conversion rate and functional-group tolerance under stronger activation conditions.
Representative reagent for the acid chloride route	7719-09-7	T433841	Thionyl chloride	Superior grade, reagent grade, ≥99.5%, low iron	A classical acid chlorination reagent, suitable for comparing preformed acid chloride routes with direct activation routes such as CMPI in terms of operational intensity, substrate compatibility, and workup.
Carbodiimide-type coupling reagent	538-75-0	D106074	N,N′-Dicyclohexylcarbodiimide	≥99%	A classical carbodiimide coupling reagent, suitable for comparison with CMPI in terms of activation efficiency, handling of urea byproducts, and separation mode.
Imidazole-type carboxylic acid activator	530-62-1	C109315	N,N'-Carbonyldiimidazole (CDI)	≥99%	Can first convert a carboxylic acid into an acyl imidazole intermediate and is suitable for comparing how different activation pathways affect substrate compatibility and order of addition relative to CMPI.
Highly active uronium-type coupling reagent	148893-10-1	H109327	HATU	≥99%	A highly active coupling reagent, suitable for comparison with difficult-to-couple substrates or chiral substrates, allowing observation of differences between highly active systems and CMPI in yield, workup, and side reactions.
Highly active uronium-type coupling reagent	94790-37-1	H106174	HBTU	≥99%	Commonly used for amide bond formation and peptide coupling, suitable for comparing coupling efficiency and purification burden under different activation strengths relative to CMPI.
Carbodiimide-type coupling reagent	693-13-0	N420184	N,N'-Diisopropylcarbodiimide	≥98.5%	A commonly used carbodiimide coupling reagent, suitable for comparison with CMPI in terms of reaction progress, physical form of urea byproducts, and convenience of separation under liquid-reagent conditions.
Water-soluble carbodiimide coupling reagent	25952-53-8	E106172	N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride	≥98%	A water-soluble carbodiimide coupling reagent, suitable for comparing coupling performance and workup differences between organic-phase and water-containing conditions relative to CMPI.
Coupling additive for carbodiimide systems	3849-21-6	E138773	Ethyl (hydroxyimino)cyanoacetate	≥98%	Commonly used together with carbodiimides, suitable for comparing additive-assisted activation routes with the direct CMPI activation route in terms of efficiency, side reactions, and workup.
Representative reagent for the mixed anhydride route	543-27-1	I105738	Isobutyl chloroformate	≥98%	A representative reagent for mixed anhydride routes, suitable for comparing the efficiency, temperature requirements, and side-reaction control of pre-activation followed by coupling relative to CMPI.
Representative reagent for the mixed anhydride route	3282-30-2	T109597	Trimethylacetyl chloride	≥98%	Commonly used to convert carboxylic acids first into more reactive mixed anhydrides, suitable for comparing reaction-driving ability with CMPI for sterically hindered or difficult coupling substrates.
Coupling additive for carbodiimide systems	123333-53-9	H106176	1-Hydroxybenzotriazole Monohydrate	≥97%	Commonly used as an additive in carbodiimide systems and suitable for comparing additive-assisted activation with direct CMPI activation in terms of reaction cleanliness and side-reaction control.

Note: The above are representative Aladdin products. For more product specifications, search the Aladdin website by “product name/CAS/catalog number”.

References

[1] Mukaiyama T, Usui M, Shimada E, Saigo K. A Convenient Method for the Synthesis of Carboxylic Esters. Chemistry Letters. 1975;4(10):1045-1048. doi:10.1246/cl.1975.1045.

[2] Bald E, Saigo K, Mukaiyama T. A Facile Synthesis of Carboxamides by Using 1-Methyl-2-Halopyridinium Iodides as Coupling Reagents. Chemistry Letters. 1975;4(11):1163-1166. doi:10.1246/cl.1975.1163.

[3] Mukaiyama T, Usui M, Saigo K. The Facile Synthesis of Lactones. Chemistry Letters. 1976;5(1):49-50. doi:10.1246/cl.1976.49.

[4] Mukaiyama T. New Synthetic Reactions Based on the Onium Salts of Aza-Arenes. Angewandte Chemie International Edition in English. 1979;18(10):707-721. doi:10.1002/anie.197907073.

[5] Valeur E, Bradley M. Amide Bond Formation: Beyond the Myth of Coupling Reagents. Chemical Society Reviews. 2009;38(2):606-631. doi:10.1039/B701677H.

[6] Jordan A, Whymark KD, Sydenham J, Sneddon HF. A Solvent-Reagent Selection Guide for Steglich-type Esterification of Carboxylic Acids. Green Chemistry. 2021;23:6405-6413. doi:10.1039/D1GC02251B.

[7] Nguyen HD, Tran TV, Taylor CR, Campbell DT, Harkins DI, Do LH. 2-Azaaryl-1-methylpyridinium Halides: Aqueous-Soluble Activating Reagents for Efficient Amide Coupling in Water. ACS Sustainable Chemistry & Engineering. 2022;10(39):12968-12974. doi:10.1021/acssuschemeng.2c04989.

[8] Dunetz JR, Magano J, Weisenburger GA. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Organic Process Research & Development. 2016;20(2):140-177. doi:10.1021/op500305s.

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