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Journal of the Mexican Chemical Society

versión impresa ISSN 1870-249X

J. Mex. Chem. Soc vol.68 no.4 Ciudad de México oct./dic. 2024  Epub 03-Mar-2025

https://doi.org/10.29356/jmcs.v68i4.2238 

Reviews

Molecular Insights on Coffee Components as Chemical Antioxidants

Luis Felipe Hernández-Ayala1 

Eduardo Gabriel Guzmán-López1  2 

Adriana Pérez-González1 

Miguel Reina2 

Annia Galano1  * 

1Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Sección, Alcaldía Iztapalapa, Mexico City 09310, México.

2Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, México.

Abstract.

Coffee is not only a delicious beverage but also an important dietary source of natural antioxidants. We live in a world where it is impossible to avoid pollution, stress, food additives, radiation, and other sources of oxidants that eventually lead to severe health disorders. Fortunately, there are chemicals in our diet that counteract the hazards posed by the reactive species that trigger oxidative stress. They are usually referred to as antioxidants; some of them can be versatile compounds that exert such a role in many ways. This review summarizes, from a chemical point of view, the antioxidant effects of relevant molecules found in coffee. Their mechanisms of action, trends in activity, and the influence of media and pH in aqueous solutions, are analyzed. Structure-activity relationships are discussed, and the protective roles of these compounds are examined. A particular section is devoted to derivatives of some coffee components, and another one to their bioactivity. The data used in the analysis come from theoretical and computational protocols, which have been proven to be very useful in this context. Hopefully, the information provided here will pro-mote further investigations into the amazing chemistry contained in our morning coffee cup.

Keywords: Free radicals; scavengers; reaction mechanisms; kinetics; trends in activity; coffee components

Resumen.

El café no solo es una bebida deliciosa, sino también una importante fuente dietética de antioxidantes naturales. Vivimos en un mundo donde es imposible evitar la contaminación, el estrés, los aditivos alimentarios, la radiación y otras fuentes de oxidantes que eventualmente conducen a trastornos de salud graves. Afortunadamente, existen sustancias químicas en nuestra dieta que contrarrestan los peligros planteados por las especies reactivas que desencadenan el estrés oxidativo. Por lo general, se les denomina antioxidantes; algunos de ellos pueden ser compuestos versátiles que ejercen dicho papel de muchas maneras. Este artículo de revisión resume, desde un punto de vista químico, los efectos antioxidantes de moléculas relevantes encontradas en el café. Se analizan sus mecanismos de acción, tendencias en la actividad y la influencia del medio y el pH en soluciones acuosas. Se discuten las relaciones estructura-actividad, y se examinan los roles protectores de estos compuestos. Se dedica una sección particular a los derivados de algunos componentes del café, y otra a su bioactividad. Los datos utilizados en el análisis provienen de protocolos teóricos y computacionales, que han demostrado ser muy útiles en este contexto. Se espera que la información proporcionada aquí promueva investigaciones futuras sobre la química contenida en nuestra taza de café matutina.

Palabras clave: Radicales libres; depuradores; mecanismos de reacción; cinética; tendencias de actividad; componentes del café

Introduction

Since ancient times, natural products have been widely appreciated by humankind. The main reason is that they are beneficial for health issues and our general well-being. However, only in the last centuries technology and science developments have allowed to pass empiricism and deepened into the knowledge about the bioactive substances found in natural products, as well as on their specific functions and medicinal effects.

Regarding coffee, its origin has been traced to Ethiopia,[1] currently the fifth producer worldwide.[2] The legend says that goat herders noticed their animals restless at night after eating the berries of the coffee plant. After trying the fruit, they felt energized and became accustomed to consuming it. Such a stimulating effect is still one of this beverage’s appeals, albeit coffee is much better understood and more widely consumed today than twelve centuries ago. In fact, coffee currently ranks as one of the most consumed beverages and stands as the second commodity worldwide.[3]

According to the annual review (2021/23) of the International Coffee Organization, the Arabica variety represents 57 % of the coffee production, and Robusta the other 43 % (Fig. 1). The top producers are Brazil, Vietnam and Colombia, in that order, with approximately 61, 32 and 12 billion bags of 60 kg, respectively. On the other hand, the leading consumers are the USA, Brazil, Germany, Japan and France (27, 22, 8.7, 7.2 and 6.2 billion bags of 60 kg, respectively).

Based on the data obtained from the Scopus database (Fig. 2), the number of scientific publications on coffee has grown exponentially over the years. The same trend is followed by its antioxidant properties. Today, many of the chemical components of coffee have been identified and a large proportion of them have been investigated. For example, there are 68,971 reports on caffeine, 2,641 of them published last year. The oldest record found in the search for antioxidative properties of coffee dates back to 1940.[4] It dealt with the “antioxygens” produced by roasting and considered several species. Among them, pyrrole, proline, thioglycolic acid, and caffeic acid were identified as those with the highest protection factor against rancidity.

Fig. 1 Coffee production and consumption stats (in million bags of 60 kg), according to the annual review (2022/23) of the International Coffee Organization. https://www.icocoffee.org/documents/cy2023-24/cmr-0224-e.pdf, accessed March 7, 2023. 

Antioxidants are inherently appealing substances, both from scientific and pragmatic points of view. They help counteracting the dangerous effects of oxidative stress (OS), which arises from the imbalance between production and consumption of oxidants in living systems. OS is considered a chemical stress and has been associated with multiple health issues, including neurodegeneration, [5-16] cancer,[17-28] cardiovascular diseases,[29-38] diabetes,[39-46] rheumatoid arthritis,[47-51] renal [52-60] and pulmonary[61-66] failures, ocular disorders,[67-72] preeclampsia and fetal development complications.[73-77]

Fig. 2 Number of published researches on coffee and coffee + antioxidant, according to Scopus, consulted on March 7, 2024. 

Antioxidant protection is one of the many health benefits attributed to coffee, [78-99] and other natural products. However, not all its components exhibit such activity, and those that do, have diverse mechanisms of action and efficiency. Phenolic compounds, in general, are recognized as highly efficient for counteracting the deleterious effects of OS. Phenolic acids, in particular, are among the most potent antioxidants present in coffee.[100-106] Other components identified as efficient antioxidants include melanoidins,[107-110] heterocycles[111,112] Maillard reaction products,[100,112-114] and some volatile compounds.[111,112,115-119] Regarding caffeine, some studies suggest that it acts as an antioxidant, [110,120] while others indicate that the antioxidant properties of coffee are not directly related to caffeine but to the presence of other components.[121-123]

Quantifying antioxidant activity is a challenging task. This is probably because there is no universal assays to do it,[124] and because the available ones depend on the reaction mechanism, which can vary from one antioxidant to another. In fact, they have been classified as electron transfer and hydrogen atom transfer-based assays. In addition, some of these assays are meant to estimate the antioxidant capacity of total phenols lacking the specificity to differentiate among various phenolic compounds. Complicating matters further, conflicting trends may be obtained when different experimental techniques are employed to evaluate the antioxidant activity of phytochemicals.[125]

When using theoretical and computational chemistry, other difficulties arise. Probably, the most important ones are: (i) the unavoidable use of simplified models for mimicking chemical environments; (ii) the necessary balance between accuracy and computing time that must be taken into account when a particular level of theory is chosen; (iii) the fact that for establishing reliable trends, calculations must be performed using the same methodology and approximations; (iv) the importance of considering all the possible mechanisms and sites of reaction.[126] Therefore, it becomes evident that assessing antioxidant activity is a complex task, regardless of if it is pursued using experimental or theoretical approaches.

Previous publications, where experimental techniques were used to evaluate the antioxidant activity of coffee and its components in vitro, have been reviewed thoroughly. [78,127] Therefore, molecular insights on such activity are the main focus of the analyses and discussion here. The data used to do that derived from computational and theoretical strategies, that have been demonstrated to be useful and reliable to study the antioxidant chemistry. Several aspects are considered, including structure-activity relationships, the influence of solvent and pH, reaction mechanisms, and the influence of redox metals. Trends in antioxidant activity are proposed for several coffee components and compared with Trolox as a reference. The reviewed data is expected to contribute to enhance the current knowledge on the chemical aspects related to the antioxidant effects of coffee, thereby promoting further investigations into the chemistry of this beverage.

Chemical overview

Chemical components are responsible for the taste, aroma and bioactivities of coffee. However, its chemical composition is complex and depends on the variety, growing conditions, and processing.[128] Nevertheless, it has been reported that the main components of raw coffee beans include carbohydrates, which account for about 60 % of their total weight. [129] They also have significant amounts of cellulose, grease, proteins, amino acids, tannic acid, and starch. In addition, there is a diversity of other minor and trace substances in coffee beans. There are numerous publications providing detailed information on the chemical composition of coffee. [129-133] A brief summary of this composition is provided in Table 1.

Table 1 Chemical compounds present in coffee beans.  

Family Compounds Ref.
Alkaloids Caffeine, Theobromine, Theophylline, Trigonelline. [134-139]
Amino acids Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamate, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine. [140-144]
Carotenoids α-Carotene, β-Carotene, Antheraxanthin, Lutein, Neoxanthin, Violaxanthin, Zeaxanthin. [135,145, 146]
Fatty acids Arachidic, Docosanoic, Eicosenoic, Lauric, Linoleic, Linolenic, Myristic, Oleic, Palmitic, Stearic, Tetracosanoic, Tricosanoic Acids. [141,142, 144,147]
Flavonoids Apigenin, Catechin, Delphinidin, Epicatechin, Epicatechin Gallate, Fisetin, Hyperoside, Isoquercitrin, Kaempferol, Luteolin, Myricetin, Patuletin, Quercetin, Quercitrin, Rutin. [135,145]
Organic acids Acetic, Butyric, Citric, Formic, Lactic, Malic, Oxalic, Quinic, Succinic, Tartaric Acids. [136,144, 145,148-150]
Phenolic acids 3-OH-Benzoic, Benzoic, Caffeic, Caftaric, Chlorogenic, Cinnamic, Dicaffeoylquinic, Dihydrocaffeic, Ferulic, Gallic, Gentisic, p-Coumaric, p-Hydroxybenzoic, Protocatechuic, Sinapic, Syringic, Vanillic Acids and Caffeic Phenylester. [129,135-137,139,145,149,151-155]
Sugars Arabinose, Fructose, Glucose, Saccharose, Sucrose. [135,139, 150,154,156,157]
Terpenes 16-O-Methylcafestol, Atractyligenin, Cafestol, Caffarolides, Caffruones, Cofarysloside, Ent-kaurane Diterpenoid, Kahweol, Mascarosides, Paniculoside, Triterpenoids, Tricalysiolides, Ursolic Acid, Villanovane. [135,158-164]
Volatiles Alcohols, Alkanes, Aldehydes, Carboxylic acids, Esters, Fatty acids, Furans, Ketones, Lactones, Oxazols, Pyrazines, Pyrimidines, Pyrroles, Terpenes, Thiazoles, Thiophenes, 4-Ethylguaiacol, 4-Vinylguaiacol, Caffeol, Eugenol, Furfural, Furaneol, Guaiacol, Phenol. [135,139, 144,148,153,165-170]
Xanthone Isomangiferin, Mangiferin [135,143]
Phytosterol Sitosterol [135]

Bioactivity overview

The versatile bioactivity of coffee has also been thoroughly reviewed. [171-176] Coffee has numerous health benefits from its chemical composition, provided that it is moderately consumed. Some of them are summarized in Table 2. However, as is the case with almost everything, amounts mediate the balance between benefits and harms. It has been pointed out that high consumption of coffee may compromise coronary health, posing risks for pregnant and postmenopausal women, and has the potential for addiction, where withdrawal could trigger muscle fatigue and related problems. [171]

Table 2 Some health benefits of coffee components.  

Benefits Key components Ref.
Antibacterial

  • caffeic acid

  • caffeic acid phenethyl ester

  • chlorogenic acids

  • eugenol

  • ferulic acid

  • furaneol

  • guaiacol

  • isoeugenol

  • protocatechuic acid

  • scopoletin

  • vanillic acid

Anticarcinogenic

  • 4-vinylguaiacol

  • cafestol and kahweol

  • caffeic acid

  • caffeic acid phenethyl ester

  • chlorogenic acids

  • eugenol

  • ferulic acid

  • quercetin

  • mangiferin

  • protocatechuic acid

  • tannic acid

  • theobromine

  • vanillic acid

  • vanillin

Antidiabetic

  • cafestol

  • caffeic acid

  • caffeol

  • chlorogenic acids

  • isoeugenol

  • scopoletin

  • trigonelline

Antifungal

  • caffeine

  • eugenol

  • furaneol

  • isoeugenol

  • vanillin

Anti-inflammatory effects

  • 4-ethylguaiacol

  • caffeine

  • dicaffeoylquinic acids

  • dihydrocaffeic acid

  • eugenol

  • ferulic acid

  • flavonoids

  • mangiferin

  • phenolic acids and

  • pyrocatechol

  • p-coumaric acid

  • rutin

  • theophylline

  • vanillic acid

  • vanillin

  • vanillyl alcohol

Anti-obesity

  • chlorogenic acids

  • kahweol

Cardioprotection

  • caffeic acid

  • chlorogenic acids

  • dihydrocaffeic acid

  • ferulic acid

Cognitive enhancement

  • paraxanthine

  • protocatechuic acid

  • theobromine

  • vanillic acid

Gastroprotection

  • chlorogenic acids

  • vanillin

Hepatoprotection

  • caffeic acid

  • chlorogenic acids

  • dihydrocaffeic acid

  • paraxanthine

  • theobromine

  • vanillin

Immunoregulation

  • p-coumaric acid

  • protocatechuic acid

Kidney protection

  • protocatechuic acid

  • theobromine

Neuroprotection

  • caffeine

  • caffeic acid

  • chlorogenic acids

  • dihydrocaffeic acid

  • eugenol

  • ferulic acid

  • isoeugenol

  • paraxanthine

  • protocatechuic acid

  • quercetin

  • scopoletin

  • tannic acid

  • theobromine

  • trigonelline

  • vanillin

  • vanillic acid

  • vanillyl alcohol

Lipid-Lowering Effects

  • caffeic acid

  • chlorogenic acids

Based on the data reported in Table 2, it becomes evident that moderate consumption of coffee, i.e., one to four cups a day,[176] may provide beneficial effects. In particular, for inflammation, obesity, diabetes, cancer, cardiovascular diseases, microbial infections, and neurodegeneration. It seems worthwhile noticing that the health benefits mentioned in Table 2 are not necessarily attributed to antioxidant activity. In fact, many of them involve direct interaction with enzymes and other biotargets. Antioxidant activity is not included in this table because it is the main focus of this review, thus a whole section has been entirely devoted to it (section 5).

Derivatives

Considering the myriad of benefits offered by coffee components, it is not surprising that many investigations have been devoted to design and synthesize derivatives based on their molecular frameworks. Many of them keep the bioactivity of the parent molecules, and many others have shown new and improved effects. Albeit a detailed analysis of this point escapes the purpose of this review, it seems worthwhile summarizing (Table 3) some of the great efforts made so far to obtain new molecules from coffee components. Thus, the interested reader can get more comprehensive information on this topic from the provided references.

Table 3 Some previous studies on derivatives based on antioxidants found in coffee. 

Parent molecule Ref.
caffeic acid [395, 548-559]
caffeine [560-568]
chlorogenic acid [569-576]
eugenol [577-596]
ferulic acid [252, 254, 597-629]
guaiacol [630-632]
isoeugenol [337, 633-636]
isoferulic acid [637, 638]
p-coumaric acid [359, 639-645]
protocatechuic acid [646-652]
scopoletin [326, 653-664]
theobromine [665-673]
theophylline [674-695]
vanillic acid [696-702]
vanillin [703-729]
xanthine [730-753]

Theoretical and computational chemistry plays an important role in the design of new compounds. There are numerous tools available that allow evaluating important properties of derivatives, particularly when they are meant to be used as medical drugs. Some useful descriptors in this context are those known as ADME (Absorption, Distribution, Metabolism y Excretion) properties. They comprise the octanol/water partition coefficient (logP), molecular weight, number of H bond donors, number of H bond acceptors, molar refractivity, number of non-hydrogen atoms, and polar surface area. There are other important properties to consider such as synthetic accessibility and toxicity. Using computational strategies allows building candidates, sampling the chemical space and evaluating the potential of the new molecules for the intended purpose. In addition, these strategies save time, resources, and even animal testing. Thus, they have become relevant tools for the development of new formulations with health benefits.

Antioxidant activity

Theoretical and computational chemistry plays an important role in the design of new compounds. There are numerous tools available that allow evaluating important properties of derivatives, particularly when they are meant to be used as medical drugs. Some useful descriptors in this context are those known as ADME (Absorption, Distribution, Metabolism y Excretion) properties. They comprise the octanol/water partition coefficient (logP), molecular weight, number of H bond donors, number of H bond acceptors, molar refractivity, number of non-hydrogen atoms, and polar surface area. There are other important properties to consider such as synthetic accessibility and toxicity. Using computational strategies allows building candidates, sampling the chemical space and evaluating the potential of the new molecules for the intended purpose. In addition, these strategies save time, resources, and even animal testing. Thus, they have become relevant tools for the development of new formulations with health benefits.

Table 4 Some antioxidants found in coffee. 

Common name Structure IUPAC name Ref.
4-ethylguaiacol

4-ethyl-2-methoxyphenol [754-756]
4-vinylguaiacol

4-ethenyl-2-methoxyphenol [757-759]
caffeic acid

(E)-3-(3,4-dihydroxyphenyl)prop-2-enoic acid [312,391,760-772]
caffeine

1,3,7-trimethylpurine-2,6-dione [450,773-776]
chlorogenic acid

(1S,3R,4R,5R)-3-[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy-1,4,5-trihydroxycyclohexane-1-carboxylic acid [96,391,760,777-788]
dihydrocaffeic acid

3-(3,4-dihydroxyphenyl)propanoic acid [789-791]
eugenol

2-methoxy-4-prop-2-enylphenol [349,350,578,792-805]
ferulic acid

(E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid [354,355,481,758,806-813]
guaiacol

2-methoxyphenol [814,815]
isoeugenol

2-methoxy-4-[(E)-prop-1-enyl]phenol [190,202,816]
isoferulic acid

(E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoic acid [817-820]
mangiferin

1,3,6,7-tetrahydroxy-2-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]xanthen-9-one [821]
paraxanthine

1,7-dimethyl-3H-purine-2,6-dione [822]
p-coumaric acid

(E)-3-(4-hydroxyphenyl)prop-2-enoic acid [357,766,823-827]
protocatechuic acid

3,4-dihydroxybenzoic acid [204,828-841]
quercetin

2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one [842]
scopoletin

7-hydroxy-6-methoxychromen-2-one [843-848]
tannic acid

[2,3-dihydroxy-5-[[(2R,3R,4S,5R,6S)-3,4,5,6-tetrakis[[3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl) oxybenzoyl]oxy]oxan-2-yl]methoxycarbonyl]phenyl] 3,4,5-trihydroxybenzoate [849-859]
theobromine

3,7-dimethylpurine-2,6-dione [860,861]
theophylline

1,3-dimethyl-7H-purine-2,6-dione [861-863]
vanillic acid

4-hydroxy-3-methoxybenzoic acid [864-868]
vanillin

4-hydroxy-3-methoxybenzaldehyde [432,756,865,869-873]
vanillyl alcohol

4-(hydroxymethyl)-2-methoxyphenol [874,875]
xanthine

3,7-dihydropurine-2,6-dione [822,860]

Antioxidant activity (AOx) can arise from a variety of processes. This review focuses on chemical ones, albeit there are other protection routes that involve enzymatic systems. From a chemical point of view, AOx can be roughly grouped into the following categories.

AOX-I (or primary AOX, or chain braking, or free radical scavenging activity).

It involves the direct reaction with oxidants, mainly free radicals yielding less reactive species or ending the radical chain process. During such a process, the antioxidant acts as a sacrificial target that prevents the oxidation of crucial biomolecules, such as DNA, proteins, and lipids. However, the amounts of these biomolecules in living organisms are significantly higher than those of chemical antioxidants that might be consumed in the diet or as dietary supplements. Consequently, to be efficient as a primary antioxidant, a molecule must react with oxidants faster than the biological target. This makes imperative to establish some quantitative thresholds that allow identifying a particular chemical as a primary antioxidant. The rate constants of the •OOH damage to polyunsaturated fatty acids have been proposed to that purpose.[126] It ranges from 1.18(103 to 3.05(103 M-1s-1,[876] at acid pH values, i.e. when the molar fraction of HOO( is (1. Since lipids are the most easily oxidized among the biomolecules mentioned above, i.e., those reacting the fastest with free radicals, it is expected that any molecule capable of protecting them from oxidation would also be capable of protecting proteins and DNA.

Important points arise from this analysis. The first one is that kinetics is a key aspect when evaluating free radical scavenging activity. In addition, it is also important to consider the nature of the free radical. •OH is so reactive that it would react with almost any molecule, usually at diffusion-limited rates. In fact, it might be assumed that •OH will react with the first molecule it finds near its production site. It has been known for over a decade that peroxyl radicals are among the oxidants likely to be efficiently scavenged to counteract oxidative stress.[877-880] Thus they are a logical counterpart of chemicals when analyzing AOX-I. This kind of AOX, will be further discussed in the sections 5.1 to 5.3. The other categories are briefly summarized next.

AOX-II (or secondary AOX, or preventing, or OIL behavior).

It may involve diverse chemical routes besides direct free radical scavenging processes. Among them, probably the most relevant one is usually referred to as OH-inactivating ligands (OIL) behavior.[881,882] It involves metal chelation and may occur by sequestering metal ions from reductants or by deactivating OH radicals as soon as they are produced via Fenton-like, or Haber-Weiss recombination, processes. The metal chelation step can take place, at least, through two pathways. Namely, by the direct chelation mechanism (DCM) or by the coupled deprotonation-chelation mechanism (CDCM). The latter may become the most important one for antioxidants acid protons.

AOX-III (or tertiary AOX, or fixing AOX, or repairing AOX).

Preventing biomolecules from oxidative damage is not always possible. Therefore, repairing them after damage is an important way of preserving their chemical integrity. The routes involved in such a process depend on the nature of the damage. Formal hydrogen atom transfer (f-HAT) restores allylic hydrogens to lipids. The same mechanism is involved when the most frequent lesions on Cys, Tyr, Leu, Met, and His are fixed, while single electron transfer (SET) repairs oxidized Tyr and Trp. DNA damage, on the other hand, may occur in at least three different ways, and, logically, the repairing route depends on the kind of damage. One electron loss from guanine, the nucleobase most easily oxidizable, [883] is repaired by SET from the antioxidant. One H loss from the deoxyribose units, yielding C-centered radicals; [884-887] is repaired by f-HAT from the antioxidant. Particular attention deserves the formation of the 8-OH-dG adduct by addition of an OH radical, which in turn yields the most abundant DNA lesion, i.e., 8-oxo-7,8-dihydro-2′-deoxyguanosine. [888]. The latter is considered a biomarker of oxidative stress, [1243,1244] and it has been proposed that such a damage can be fixed via sequential hydrogen atom transfer followed by dehydration (SHATD). [889]

AOX-IV (or versatile AOX, or multifunctional AOX, or multipurpose AOX).

This would apply to molecules capable of exerting their antioxidant activity through two or more of the above-described mechanisms, or by one of them and triggering enzymatic AOX.

AOX-I chemical routes

Free radical scavenging processes in living organisms occur in complex chemical environments. Numerous species are present in biological media, which may influence or be involved in competing reactions. In addition, antioxidants’ reactivity depends on their chemical nature and may be modulated by the polarity of the environment and pH. Some of the most common chemical routes that may contribute to the observable AOX-I activity are detailed in Table 5.

Table 5 Some of the most common chemical routes that may contribute to the observable AOX-I activity (HnAntiox and •R represent the antioxidant and the free radical, respectively). 

Single Step Mechanisms

  • Radical Adduct Formation (RAF)

  • HnAntiox + •R → [HnAntiox-R]•

  • Relevant for antioxidants with multiple bonds and electrophilic free radicals. Viable in polar and non polar media.

  • Examples:

  • Carotenoids + •OOH, [890] or benzylperoxyl [891] or alkyl, alkoxyl, and alkylperoxyl radicals. [892]

  • •OH scavenging activity of caffeine, [123] gentisic acid, [893] hydroxybenzyl alcohols, [894] edaravone, [895,896] melatonin,[897] and its metabolites, [898,899] carnosine, [900] and rebamipide. [901]

  • Single Electron Transfer (SET)

  • HnAntiox + •R → HnAntiox +• + R-

  • Relevant for electrophilic free radicals and antioxidants that are good electron donors. Viable in polar media.

  • Examples:

  • For antioxidants curcumin,[902] and highly galloylated tannin fractions.[903]

  • Edaravone derivatives + •OH, •OCCl3 and CH3COO•.[904]

  • Resveratrol with oxygen radical.[905]

  • Catechin analogues with ROO•. [906]

  • Carotenoids with CCl3OO• [907,908] and •NO2 [909,910].

  • Formal Hydrogen Atom Transfer

  • (f-HAT)

  • HnAntiox + •R → Hn-1Antiox• + HR

  • Relevant for antioxidants with labile H atoms. Viable in polar and non-polar media.

  • Examples:

  • Polyphenols, [911] chlorogenic acids, [912] procyanidins, [913] chalcones,[914] cynarine, [912] orientin, [915] capsaicin, [916] silybin, [912] α-mangostin, [917] fisetin, [918] hydroxychalcones, [919] baicalein, [918] ellagic acid, [920]

  • Lipoic acids, [921] glutathione, [922] tryptophan, [923], N-acetylcystein amide.[924]
Multiple Step Mechanisms

  • Sequential Proton Loss Electron Transfer (SPLET)

  • HnAntiox → Hn-1Antiox- + H+

  • Hn-1Antiox- + •R → Hn-1Antiox• + R-

  • Relevant for antioxidants with acid protons. Viable in polar and protic solvents.

  • Examples:

  • Curcumin, [925, 926] esculetin, [927] alizarin, [928] deoxybenzoins,[929] hydroxybenzoic acids, [930-933] resveratrol, [934, 935] fraxetin, [936] piceatannol, [937] morin, [938] hydroxychalcones, [939-941] xanthones, [942] flavonoids, [943] quercetin, [944] kaempferol, [945] gallic acid, [946] Trolox, [947] isoflavonoids, [948,949] baicalein, [950] purpurin.[951]

  • Sequential Electron Proton Transfer (SEPT)

  • HnAntiox + •R → Hn-1Antiox•+ + R(

  • Hn-1Antiox•+ → Hn-1Antiox• + H+

  • Relevant for antioxidants that are good electron donors. Viable in polar and protic solvents.

  • Examples:

  • Baicalein, [952] astaxanthin, [953] quercetin, in the presence of bases that have HOMO energies lower than that of the SOMO of its radical cation.[954]

  • DPPH and galvinoxyl radical scavenging activity of vitamin E models. [955]

  • The theroxyl radical-scavenging process of α-tocopherol.[956]

  • Sequential Proton Loss Hydrogen Atom Transfer (SPLHAT)

  • HnAntiox → Hn-1Antiox( + H+

  • Hn-1Antiox( + •R → Hn-2Antiox•( + HR

  • Relevant for antioxidants with acid protons and labile H atoms. Viable in polar and protic solvents.

  • Examples:

  • α-mangostin, [917] ellagic acid, [957] propyl gallate, [958] caffeic and other phenolic acids. [959]

  • Esculetin + •OOCH3 and •OOCHCH2 radicals. [927]

  • Gallic acid + •OH. [960]

Trends in activity

As previously mentioned, kinetics is crucial to assess free radical scavenging activity. Therefore, this analysis will be based on rate constants. However, for trends to be fair, it is essential to consider reactions with the same radical and that the rate constants (k) are estimated with the same methodology, and under the same conditions. Those reported in Table 6 correspond to reactions between coffee components and the HOO( radical, in non-polar media that mimic lipid environments. Those reported in Table 7 correspond to the same reactions but in aqueous solution, at physiological pH, i.e., pH=7.4. To facilitate comparisons, their log(k) values have been plotted in Fig. 3. Trolox has been included as a referent antioxidant. The main metabolites of caffeine are also included in the analyses.

Table 6 Overall, or apparent, rate constants (k) of the reactions between coffee components (and Trolox as reference) and HOO(, in non-polar environments. 

Component k (M-1 s-1, at 298 K) Ref.
caffeic acid 3.93E+04 [101]
caffeine 3.19E+01 [123]
dihydrocaffeic acid 4.95E+04 [101]
eugenol 2.49E+03 [961]
ferulic acid 9.13E+03 [101]
guaiacol 1.55E+03 [961]
mangiferin 7.74E+03 [101]
p-coumaric acid 4.35E+03 [101]
paraxanthine 1.05E+00 [962]
protocatechuic acid 5.14E+03 [963]
quercetin 4.39E+03 [101]
theobromine 5.34E+01 [962]
theophylline 4.21E+00 [962]
Trolox 3.40E+03 [947]
vanillin 9.75E+01 [961]
vanillic acid 1.29E+01 [961]
vanillyl alcohol 5.67E+03 [961]

Table 7 Overall, or apparent, rate constants (k) of the reactions between coffee components (and Trolox as reference) and HOO(, in aqueous solution at physiological pH. 

Component k (M-1 s-1, at 298 K, pH=7.4) Ref.
caffeic acid 2.69E+08 [101]
caffeine 3.29E-01 [123]
dihydrocaffeic acid 1.04E+08 [101]
eugenol 1.55E+06 [961]
ferulic acid 3.36E+08 [101]
guaiacol 2.38E+06 [961]
mangiferin 5.52E+08 [101]
p-coumaric acid 8.51E+07 [101]
paraxanthine 4.18E-02 [962]
protocatechuic acid 1.26E+07 [963]
quercetin 8.11E+09 [101]
theobromine 2.76E-01 [962]
theophylline 3.86E-02 [962]
Trolox 8.96E+04 [947]
vanillin 1.54E+05 [961]
vanillic acid 1.65E+07 [961]
vanillyl alcohol 4.12E+06 [961]

The values in Tables 6 and 7 were all computed with the Quantum Mechanics-based Test for Overall Free Radical Scavenging Activity (QM-ORSA).[126] This computational protocol was designed to calculate reliable rate constants in solution and was validated by comparisons with experimental data. The electronic calculations necessary to obtain the rate constants reported in Tables 6 and 7 were carried out with the M05-2X Density Functional Theory approach, combined with basis sets 6-31+G(d) to 6-311++G(d,p), and the SMD solvation model to mimic solvent effects. All possible reaction mechanisms and sites were taken into account, and the overall (or apparent) rate coefficients were estimated as the sum of the rate constants of each thermochemical viable reaction path. More details on this protocol can be found elsewhere.[126]

According to the gathered data, dihydrocaffeic acid and ferulic acid are the most efficient HOO• scavengers in non-polar media and aqueous solution, at pH=7.4, respectively. The trend in non-polar environment was found to be dihydrocaffeic acid > caffeic acid > ferulic acid > mangiferin > vanillyl alcohol > protocatechuic acid > quercetin > p-coumaric acid > eugenol > guaiacol > vanillin > caffeine > theobromine > vanillic acid > theophylline > p-xanthine. In aqueous solution such a trend changes to quercetin > mangiferin > ferulic acid > caffeic acid > dihydrocaffeic acid > p-coumaric acid > vanillic acid > protocatechuic acid > vanillyl alcohol > guaiacol > eugenol > vanillin > caffeine > theobromine > p-xanthine > theophylline.

Fig. 3 log(k) for the reactions between coffee components (and Trolox as reference) with HOO•. The red line corresponds to the reaction of HOO• with polyunsaturated fatty acids. 

The threshold above-mentioned, i.e., 103 M-1s-1, corresponds to the reaction of HOO• with polyunsaturated fatty acids, and has been used to identify the coffee components that are expected to be efficient as free radical scavengers in biological systems. It has been marked with a red line in Fig. 3. According to this criterion, dihydrocaffeic, caffeic, ferulic, protocatechuic, and p-coumaric acids, as well as vanillyl alcohol, eugenol, and guaiacol should be capable of preventing peroxyl damage to biomolecules both in lipid and in aqueous environments. For the latter, vanillin and vanillic acid also seem to be suitable for that purpose.

It seems worthwhile mentioning that the reactions of caffeine and its metabolites p-xanthine, theobromine, and theophylline with HOO• are too slow to protect lipids from the oxidative damage caused by this kind of radicals. This is in line with previous works. Šeremet et. al. found that the antioxidant properties of coffee brews do not depend on their caffeine content. [122] Miłek et. al. reported that while ‘specialty’ quality coffees have similar caffeine content as other brands, they significantly surpass them in antioxidant activity. [121] Based on the likeliness of f-HAT and SET mechanisms as protective routes, Petrucci et. al. concluded that caffeine can hardly be considered as an antioxidant. Thus, despite of being the most emblematic coffee component, this brew's antioxidant activity arises from its phenolic species, not from caffeine.

Structure-activity relationships

The reaction mechanism contributing the most to the antioxidant activity of the analyzed coffee components is reported in Tables 8 and 9 for lipid and aqueous environments, respectively. The most reactive site or species are also reported in these tables. The relatively low reactivity of caffeine and its metabolites p-xanthine, theobromine, and theophylline can be attributed to their lack of the phenol moiety. They have not labile H atoms to be involved in f-HAT, nor acid protons that favored deprotonation and, consequently, the SPLET mechanisms, i.e., SET from the anions. Thus, the main chemical route involved in their reactions with HOO( is the radical adduct formation.

Table 8 Main reaction mechanism and most reactive site in the reactions between coffee components and HOO(, in non-polar environments. 

Component Mechanism Site Ref.
caffeic acid f-HAT

[101]
caffeine RAF

[123]
dihydrocaffeic acid f-HAT

[101]
eugenol f-HAT

[961]
ferulic acid f-HAT

[101]
guaiacol f-HAT

[961]
mangiferin f-HAT

[101]
p-coumaric acid f-HAT

[101]
paraxanthine RAF

[962]
protocatechuic acid f-HAT

[963]
quercitin f-HAT

[101]
theobromine RAF

[962]
theophylline RAF

[962]
vanillin f-HAT

[961]
vanillic acid f-HAT

[961]
vanillyl alcohol f-HAT

[961]

Table 9 Main reaction mechanism and most reactive site or species in the reactions between coffee components and HOO(, in aqueous solution at physiological pH. 

Component Mechanism Site or species Ref.
caffeic acid SPLET phenolate anion [101]
caffeine RAF

[123]
dihydrocaffeic acid SPLET phenolate anion [101]
eugenol SPLET phenolate anion [961]
ferulic acid SPLET phenolate anion [101]
guaiacol SPLET phenolate anion [961]
mangiferin SPLET phenolate anion [101]
p-coumaric acid SPLET phenolate anion [101]
paraxanthine RAF

[962]
protocatechuic acid SPLET phenolate anion [963]
quercetin SPLET phenolate anion [963]
theobromine RAF

[962]
theophylline RAF

[962]
vanillin SPLET phenolate anion [961]
vanillic acid SPLET phenolate anion [961]
vanillyl alcohol SPLET phenolate anion [961]

The phenolic structural feature seems to be the key to the high efficiency of coffee components as peroxyl radical scavengers. In lipid media, the OH group acts as H donor leading to AOX-I via f-HAT. In aqueous solution, their acid-base equilibria rule reactivity. At physiological pH, there is enough phenolate fraction, which is excellent as electron donor. Thus, under such conditions, the SPLET mechanism becomes the highest contributor to the antioxidant activity of phenolic compounds in general, and of the phenolic compounds present in coffee.

The solvent also plays an important role in this context. The antioxidant + HOO( reactions are faster in aqueous solution, i.e., polar and protic solvent, than in lipid media (Tables 6 and 7, and Fig. 3). In addition, the fact that water is a polar and protic solvent promotes the SPLET mechanism, which was proposed by Litwinienko and Ingold, [925,964-966] and it is recognized as more efficient than f-HAT, and certainly much more than RAF, when phenols scavenge free radicals.

Perspectives

Albeit much information has been retrieved from the investigations on coffee, some aspects still deserve further research. Some of the many questions to be answered in more detail are:

  • -How much does the presence of redox metals modify the chemistry of the coffee components?

  • -How effective are they as chelating agents?

  • -Would they act as OH inactivating ligands?

  • -Are any of them capable of repairing oxidatively damaged biological targets?

  • -Which of them can be considered multifunctional antioxidants?

  • -Are their derivatives safe enough to be used as medical drugs?

  • -What are the metabolites of these derivatives, and what properties do they have?

Nature gave us coffee. Revealing its chemical wonders is up to us.

Summary

Many natural products are known for their health benefits, but they comprise a large variety of components. Thus, it is essential to identify their bioactive substances as well as the specific functions and medicinal effects of these substances.

Coffee is a complex mixture containing many chemicals, including alkaloids, amino acids, carbohydrates, carotenoids, fatty acids, flavonoids, organic acids, phenolic acids, sugars, terpenes, and volatile compounds. It is also known to have many beneficial properties such as antibacterial, anticarcinogenic, antidiabetic, antifungal, anti-inflammatory, anti-obesity, cardioprotective, gastroprotective, hepatoprotective, and neuroprotective effects, provided that it is consumed in moderate amounts. The chemicals responsible for such valuable effects have been summarized in this review, as well as numerous investigations devoted to the design and synthesis of their derivatives.

The antioxidative protection of coffee has been related to most of its benefits. Several reaction mechanisms contributing to this protection were overviewed. Namely: radical adduct formation (RAF), single electron transfer (SET), formal hydrogen atom transfer (f-HAT), sequential proton loss electron transfer (SPLET), sequential electron proton transfer (SEPT), and sequential proton loss hydrogen atom transfer (SPLHAT). The ones contributing the most to the antioxidant activity of several coffee components were discussed.

The trends in free radical scavenging activity showed that phenolic acids are the ones contributing the most to the antioxidant effects of coffee, while alkaloids are not efficient for that purpose, at least as chemical antioxidants. Thus, despite being the most emblematic coffee component, the antioxidant activity of this brew does not arise from caffeine. In fact, it is not expected to be a good free radical scavenger.

The structure-activity relationships were associated with the main reaction mechanisms and the role of the solvent on the reactivity of the explored compounds. Alkaloids, i.e. caffeine and its metabolites p-xanthine, theobromine, and theophylline, mainly react via RAF, regardless of the solvent nature. Phenolic compounds, on the other hand, mainly react via f-HAT in non-polar media, and via SPLET in aqueous solution, at physiological pH.

Although there are many aspects to be explored in the context of coffee chemistry, this review is meant to provide molecular insights on one of its main effects, i.e., antioxidant protection. The data gathered here demonstrate that computational and theoretical chemistry are very helpful tools to understand the molecular insights of antioxidants, and also for the design of new compounds that combines this behavior with other health benefits. Hopefully, this review will contribute to a better understanding of the chemistry of our morning cup and promote further investigations on this topic.

Acknowledgements

E.G.G.L. acknowledges CONAHCYT for Doctoral fellowship. L.F.H.A thanks to Estancias Posdoctorales por México (2022) CONAHCYT program for postdoctoral grant.

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Received: March 14, 2024; Accepted: May 24, 2024; Published: September 30, 2024

*Corresponding author: Annia Galano, email: agal@xanum.uam.mx

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