Optimizing Graphene Dopants for Direct Electrocatalytic Quantification of Small Molecules and Ions

Abstract

This review critically evaluates the recent advancements in graphene dopants for electrocatalytic quantification of small molecules and ions. Emphasizing the enhanced catalytic activity and specificity of doped graphene, the paper delves into the various doping methods, ranging from chemical to physical techniques. It presents a detailed analysis of the mechanisms underlying graphene-based electrocatalysis and its applications in environmental monitoring, health care, and pharmaceuticals. The review also addresses challenges such as the reproducibility and stability of doped graphene, suggesting future research directions. By summarizing the latest findings, this review aims to elucidate the role of doped graphene in improving the sensitivity and selectivity of electrocatalytic processes, bridging the gap between research and practical use.

1. Introduction

Graphene’s emergence as a pivotal material in the field of electrocatalysis has been driven by its unique set of properties, which include high electrical conductivity, large surface area, and exceptional mechanical strength [1]. At the core of its application in electrocatalysis is graphene’s ability to facilitate electron transfer processes, a critical aspect in electrocatalytic reactions [2]. This property, coupled with its two-dimensional structure, offers an ideal platform for the adsorption of reactants and the dispersion of catalytic sites [3]. Unlike traditional metal-based catalysts, graphene provides a more stable and potentially more cost-effective option. Its versatility is further demonstrated in its ability to be functionalized or doped with various atoms or molecules, thereby tuning its electronic properties to suit specific electrocatalytic reactions [4]. This functionalization not only enhances the catalytic activity but also introduces specificity towards particular reactants or reactions [5,6,7,8,9]. Coroş et al. [10] recently reviewed the advancements in graphene-based electrochemical sensors and biosensors. They highlighted the synthesis of graphene and its potential in creating sensitive detection devices. The focus was on the use of graphene materials in sensors for detecting a variety of important substances, including glucose, cholesterol, dopamine, ascorbic acid, uric acid, bisphenol A, cancer biomarkers, and heavy metal ions. They compared different sensors’ sensitivity, detection limits, and stability, emphasizing graphene’s role in enhancing these aspects and its significance in health care and environmental monitoring applications.

The application of graphene in electrocatalysis has shown promise in various domains, particularly in the detection and quantification of small molecules such as glucose [11], dopamine (DA) [12], and environmental pollutants [13]. Its high surface-to-volume ratio allows for a substantial increase in the active sites available for catalysis, thus leading to enhanced sensitivity and lower detection limits in analytical applications. Furthermore, the chemical stability and flexibility of graphene make it an attractive candidate for use in harsh environmental conditions, broadening the scope of its application. The burgeoning interest in graphene-based electrocatalysis is not without challenges: issues such as the reproducibility of graphene synthesis, the control over its doping, and the long-term stability of the modified material remain areas of ongoing research. Nonetheless, the potential of graphene to revolutionize the field of electrocatalysis is undisputed, making it a focal point of scientific exploration and technological innovation.

The detection of small molecules is a cornerstone in various scientific and medical fields, ranging from environmental monitoring to clinical diagnostics [14]. These molecules, often biomarkers or environmental indicators, play crucial roles in understanding biological processes, disease mechanisms, and environmental changes. For instance, glucose and DA are essential in clinical diagnostics, their levels providing critical information on conditions like diabetes and neurological disorders [15,16]. Similarly, the detection of small pollutant molecules in environmental samples is vital for assessing water and air quality [17,18,19]. The ability to accurately and sensitively detect these molecules can lead to early disease diagnosis [20], efficient therapeutic monitoring [21], and the timely implementation of environmental safety measures [22]. The significance of detecting such molecules lies not only in the identification but also in the quantification, which is essential for assessing the severity of a condition or the extent of contamination.

Advancements in detection technologies, particularly those involving electrocatalytic methods using materials like doped graphene, have greatly enhanced the sensitivity and specificity of small-molecule detection. These advancements have opened doors to low-cost, rapid, and on-site detection methods, making it more accessible and practical for a wide range of applications. The focus on optimizing these detection methods reflects the growing need for more reliable and robust diagnostic tools in health care and more stringent environmental monitoring systems. The ability to detect small molecules at lower concentrations and with higher accuracy has profound implications, including improved patient outcomes through early and precise diagnosis, more effective drug monitoring, and a better understanding of environmental pollutants’ impact [23,24,25,26]. In summary, the pursuit of optimized detection methods for small molecules is driven by the need for accuracy, sensitivity, and practicality in both clinical and environmental contexts.

The primary objective of this review is to systematically explore and synthesize the current state of knowledge regarding the optimization of graphene dopants for the direct electrocatalytic quantification of small molecules. The majority of the literature cited and discussed in this review predominantly consists of works published after the year 2015. Figure 1 shows the scheme of content involved in this review. This involves a comprehensive analysis of recent advancements in graphene doping techniques, the mechanistic insights of graphene-based electrocatalysis, and the practical implications of these developments in various fields. The review aims to bridge the gap between fundamental research and practical applications, highlighting the transformative potential of doped graphene in enhancing the sensitivity and selectivity of electrocatalytic processes. Emphasis will be placed on how these advancements can be harnessed for more efficient and accurate detection of small molecules, a critical aspect in fields such as environmental monitoring, health-care diagnostics, and pharmaceuticals. The scope of the review extends to a detailed examination of different types of dopants used in graphene, their impact on the electrocatalytic properties of graphene, and the resulting performance enhancements in the detection of small molecules. It will cover various doping methods, ranging from chemical to physical approaches, and their respective efficiencies. Additionally, the review will discuss the challenges and limitations currently faced in this field, such as reproducibility issues and long-term stability of doped graphene, and will propose future research directions. By providing an in-depth and cohesive overview of the current state of graphene doping for electrocatalysis, this review aims to serve as a valuable resource for researchers and practitioners in the field.

2. Graphene as an Electrocatalyst

2.1. Properties of Graphene Relevant to Electrocatalysis

Graphene’s utility in electrocatalysis is largely derived from its distinct physical and chemical properties, which have been extensively studied and documented in recent research. One of the most critical properties of graphene is its high electrical conductivity, attributed to its sp²-bonded carbon atoms arranged in a honeycomb lattice, facilitating efficient electron transport. The in-plane electrical conductivity of graphene flakes is a critical factor in determining the maximum possible conductivity for macroscopic graphene. This in-plane conductivity can be assumed to be around 100 MS/m [27]. This characteristic is essential in electrocatalysis, where rapid electron transfer is crucial for the catalytic process. In the review by Coroş et al. [10], graphene’s electrical conductivity was highlighted as a key factor in enhancing the analytical performance of electrochemical sensors and biosensors.

Another notable property of graphene is its large surface area, which provides ample active sites for catalysis. The specific surface area of graphene is commonly reported as approximately 2630 m²/g [28,29,30]. This is particularly beneficial for the adsorption of small molecules, thereby increasing the sensitivity of detection in electrocatalytic applications. The high surface area of graphene, often coupled with its modifiability, allows for a higher loading of catalytic materials, as demonstrated in the detection of hydrazine [31], cholesterol [32], paracetamol [33], DA [34], and other small molecules [35].

Graphene’s mechanical strength and chemical stability are also advantageous in electrocatalytic applications, especially under harsh environmental conditions. Its robust structure ensures durability and long-term stability, which are essential for practical applications [36]. However, it is important to note that while graphene is chemically stable, it often requires functionalization to improve its catalytic activity, as pristine graphene can be relatively inert electrochemically [37]. This necessity for functionalization or doping introduces a layer of complexity in utilizing graphene, as the choice of dopants and the method of doping significantly impact its electrocatalytic performance.

Moreover, the zero-bandgap nature of graphene, while beneficial for conductivity, can be a limitation in specific electrocatalytic applications that require a semiconducting behavior [38]. This has led to a growing interest in graphene derivatives, such as graphene oxide (GO) and reduced graphene oxide (RGO), which exhibit a bandgap and can be more effective in certain electrocatalytic reactions [39,40]. These derivatives demonstrate how the modification of graphene’s inherent properties can expand its applicability in electrocatalysis.

In the realm of electrocatalysis, graphene’s properties are not universally advantageous, leading to critical assessments of its application. For instance, the challenge of achieving uniformity in graphene-based materials raises questions about the reproducibility and scalability of graphene-based electrocatalytic systems [41]. This aspect is crucial for transitioning laboratory-scale discoveries to real-world applications, a gap that is yet to be fully bridged in the case of graphene-based electrocatalysts. Therefore, while graphene’s properties, such as high electrical conductivity, large surface area, mechanical strength, and chemical stability, make it a promising material for electrocatalysis, its practical application is nuanced. The necessity for functionalization, challenges in reproducibility, and the quest for suitable dopants are critical considerations that continue to drive research in this field. Future advancements in graphene-based electrocatalysis hinge on addressing these challenges and leveraging graphene’s properties to their fullest potential.

2.2. Limitations of Undoped Graphene in Electrocatalysis

Undoped graphene, despite its remarkable electrical conductivity and high surface area, exhibits inherent limitations as an electrocatalyst due to its chemically inert nature. This inactivity stems from the lack of functional groups or active sites on its surface, which are essential for catalyzing electrochemical reactions [42]. The electrochemical reactivity of undoped graphene is limited, impacting its efficiency in specific electrocatalytic processes. For instance, in biosensing applications, the lack of specificity in undoped graphene can lead to inadequate selectivity and sensitivity for the detection of certain biomolecules [43]. This limitation is evident when comparing the performance of undoped graphene with doped or functionalized graphene derivatives [44], which show enhanced reactivity due to the introduction of heteroatoms that provide active sites and modify the electronic structure of graphene. For example, Chen et al. [45] focused on the development and characterization of nitrogen-doped holey graphene (N-HG) for use as an electrochemical sensor in detecting methyl parathion (MP), a commonly used organophosphorus pesticide. The study investigated the effects of various nitrogen configurations on the electron transfer kinetics and sensing performance of N-HG. Nitrogen doping in HG significantly increases the number of electroactive sites. This enhances the electrocatalytic activity of the material, making it more efficient in detecting target molecules like MP. The presence of nitrogen, especially pyrrolic N, in the graphene structure enhances the electron transfer rate. In CV experiments, the N-HG-modified electrodes showed notable differences compared to unmodified or differently modified electrodes (Figure 2A). The N-HG-modified electrodes exhibited higher peak currents, indicating better electrocatalytic activity. For MP detection, there was a shift in reduction peaks towards lower potentials, demonstrating the enhanced electrocatalytic activity due to nitrogen doping. Cao et al. [46] provided a comprehensive study on the role of nitrogen doping, particularly graphitic N, in enhancing the electrochemical sensing capabilities of N-doped graphene for acetaminophen detection. The study successfully synthesized graphitic N-rich N-doped graphene (NGE-A) and demonstrated its superior electrocatalytic activity for the redox of acetaminophen compared to graphitic N-free N-doped graphene (NGE-U). The presence of graphitic N in NGE-A plays a pivotal role in the improved electrocatalysis observed. It facilitates electron transport through the carbon materials and enhances the interaction between NGE and H⁺ ions. This leads to a more efficient detection of acetaminophen with a lower detection limit and improved catalytic activity. Figure 2B presents CV showing the electrochemical response of acetaminophen on NGE-A, NGE-U, and CRGE (chemically RGO without N doping)-modified electrodes. It illustrates that NGE-A exhibits much higher current responses than NGE-U and CRGE, indicating the enhanced electrocatalytic properties of NGE-A. The difference in peak potentials between NGE-A and NGE-U points out the significant contribution of graphitic N in NGE-A towards its superior sensing performance.

The application scope of undoped graphene in various electrochemical domains is constrained by its limited interaction with different analytes and reactants. For instance, in the detection of heavy metal ions, undoped graphene’s lack of specific interaction sites can lead to poor selectivity, a critical factor for environmental monitoring applications [47]. A good example has been demonstrated by Thiruppathi et al. [48]. They reported on the facile one-pot synthesis of fluorinated GO (FGO) for the electrochemical sensing of heavy metal ions. The doping of GO with F leads to the formation of semi-ionic C-F bonds, which significantly increase the capacitance of FGO compared to undoped GO. This is crucial for electrochemical applications, as higher capacitance can lead to better sensing capabilities. The introduction of F into the GO matrix provides specific sites for the binding of heavy metal ions, which is essential for high-sensitivity detection. The FGO demonstrated superior performance in the simultaneous detection of heavy metal ions like Cd²⁺, Pb²⁺, Cu²⁺, and Hg²⁺ using square-wave anodic stripping voltammetry, with significant improvement over GO (Figure 3A). This indicates that F doping creates more effective binding sites for these ions, enhancing the sensitivity and selectivity of the sensor. The F doping alters the electronic structure of graphene, adding dual characteristics—electron withdrawal due to fluorine’s strong electronegativity and electron donating from the lone-pair electrons. These alterations can be instrumental in changing the interaction dynamics between the sensor and the heavy metal ions, thereby affecting the sensing performance. A similar investigation has been conducted by Lin et al. [49] as well. They focused on developing a N-doped graphene sensor for detecting heavy metal ions with high sensitivity. The N-doped laser-engraved graphene (N@LEG) was synthesized using polyaniline (PANI) and polyvinylpyrrolidone (PVP) as N dopants. The presence of nitrogen atoms in the graphene structure introduced potential active sites, thereby ameliorating the electrochemical activities of the nanomaterial. The introduction of nitrogen atoms to the graphene lattice created more binding sites for heavy metal ions, facilitating their accumulation on the sensor surface. This enhancement was crucial for detecting lower concentrations of heavy metals with higher sensitivity. The sensor was particularly effective in the simultaneous determination of Cd²⁺ and Pb²⁺ (Figure 3B), showing wide linear ranges and low detection limits, much lower than the guideline values set by the WHO for these heavy metals in drinking water.

The process of doping or functionalizing graphene to overcome its inherent limitations presents its own set of challenges. Achieving a balance between maintaining graphene’s intrinsic properties and introducing functional groups or dopants requires precise control over the doping process. This is crucial to ensure that the modified graphene retains its desirable properties, such as high surface area and electrical conductivity, while gaining enhanced catalytic activity and specificity. However, this balance is challenging to achieve and often requires sophisticated techniques and careful optimization.

2.3. Comparative Analysis with Other Catalytic Materials

Unlike metal catalysts, graphene’s high surface area and superior conductivity enable faster electron transfer, enhancing reaction rates. For example, in hydrogen evolution reactions, graphene-based catalysts have shown promise, offering an alternative to costly platinum-based catalysts [50]. However, metal catalysts often exhibit higher catalytic activity due to their well-defined active sites, a property where graphene falls short unless appropriately functionalized or doped. In many cases, metals are often used to support the surface of graphene to improve the performance of electrocatalytic sensing [51,52]. For example, in a study conducted by Wang and colleagues [53], a novel electrochemical sensor was developed for the simultaneous detection of DA and uric acid (UA). This sensor was based on a glassy carbon electrode modified with cubic Pd and RGO. The research demonstrated that the Pd/RGO/GCE sensor exhibited superior electrochemical activity compared to sensors modified with either Pd/GCE or RGO/GCE alone. Specifically, the sensor showed a clear separation of the oxidation peak potentials of DA and UA, with a peak potential difference of 145 mV, highlighting its ability to distinctly detect both molecules. The study revealed linear calibration curves for DA and UA over concentration ranges of 0.45–421 μM and 6–469.5 μM, respectively, with detection limits of 0.18 μM for DA and 1.6 μM for UA. Since this strategy is not the focus of this review, it will not be detailed.

MOFs, known for their high porosity and tunable structures, offer unique advantages in catalysis, particularly in terms of selectivity and structural diversity [54]. In applications like electrochemical sensing, graphene-modified electrodes have better electrochemical detection results than MOF-modified electrodes alone. Their composite electrodes, in general, show better results. For example, Li et al. [55] described the electrochemical behaviors of hydroquinone (HQ) and catechol (CT) on different modified electrodes. In Figure 4A, the study evaluated the oxidation peak currents of 1.0 × 10⁻⁴ M HQ in a PBS solution (pH 7) at a rate of 100 mV/s on bare GCE, Cu–MOF/GCE, GN/GCE, and Cu–MOF–GN/GCE. It was observed that at the bare electrode, the oxidation peak current of HQ was only 49 μA. This current increased significantly upon introducing GN (graphene) or Cu–MOF (copper-based metal–organic framework). Notably, the peak current reached a maximum of 98 μA when the electrode was modified with the Cu–MOF–GN composite, demonstrating the effectiveness of this composite in enhancing the electrochemical detection of HQ. Figure 4B shows similar trends for CT, where the oxidation peak current on the Cu–MOF–GN/GCE was considerably higher than on other modified electrodes, indicating that Cu–MOF–GN has strong catalytic properties for CT as well. In Figure 4C, the simultaneous detection of HQ and CT using Cu–MOF–GN/GCE is examined. The results showed that the oxidation peak currents for a mixture of HQ and CT detected by Cu–MOF–GN/GCE were significantly higher than those on other modified electrodes. This indicates that the Cu–MOF–GN composite effectively enables the simultaneous determination of HQ and CT, despite their similar structures and properties, which make them difficult to separate and determine simultaneously. In other reports, graphene-modified electrodes are not as good as MOF-modified electrodes alone. For example, Habibi and co-workers [56] developed an electrochemical sensor for determining sertraline hydrochloride (STLHC), an antidepressant drug, using a Cu–MOF on S and F co-doped graphene (SNDGr) layered over a pencil graphite electrode (PGE). Figure 4D compares the electrochemical oxidation of STLHC at various electrode configurations using CV. At the bare PGE, no detectable electrochemical signal related to the electrooxidation of STLHC was observed, indicating that no redox reaction takes place. This serves as a baseline or control, showing the ineffectiveness of the bare electrode in facilitating the reaction. A weak irreversible oxidation peak is observed at a potential of 0.91 V for SNDGr/PGE, with a current of 1.5 μA. This indicates that while SNDGr/PGE shows some activity towards STLHC electrooxidation, it is still relatively poor. Cu-MOF/GPE showed a notable improvement with the Cu-MOF modification. A higher anodic current (3.4 μA) is observed at a slightly more positive potential (0.93 V). This implies that Cu-MOF enhances the electrooxidation of STLHC. Cu-MOF/SNDGr/PGE showed a significant enhancement with the combination of Cu-MOF and SNDGr. The current doubles to 7.2 μA at a less positive potential (0.85 V). This suggests a strong synergistic effect between Cu-MOF and SNDGr, improving the electrooxidation efficiency of STLHC. The combination of Cu-MOF and SNDGr enhances electrical conductivity and catalytic performance, leading to improved electrooxidation of STLHC. The large surface area and enhanced electron transfer processes in this nanocomposite contribute significantly to its effectiveness.

Graphene’s unique electronic properties also place it in contrast with semiconductor catalysts. For instance, in photocatalytic applications, graphene can enhance light absorption and charge carrier mobility, outperforming some semiconductor materials [57]. However, semiconductors like TiO₂ still hold the upper hand in specific reactions due to their inherent bandgap, which graphene lacks. This bandgap facilitates effective charge separation, a critical aspect in photocatalysis. While graphene can be combined with semiconductors to form hybrid materials, overcoming this limitation, it often requires precise engineering [58,59]. For example, Azis et al. [60] successfully synthesized composites of RGO modified with ZnO (RGO–ZnO) from cocoa shells. The study’s central focus was on evaluating the photoelectrocatalytic performance of these composites. Results indicated that the RGO–ZnO electrodes showed significant efficiency in detecting methylene blue compounds, following Faraday’s law. The precision of these electrodes in detecting methylene blue was notable, highlighting their potential application in environmental monitoring and water quality assessment. Yan et al. [61] developed a photoelectrochemical (PEC) sensor for the ultrasensitive detection of DA, leveraging the synergistic effects of graphene quantum dots (GQDs) and TiO₂ nanoparticles. These nanocomposites demonstrated a substantial enhancement in the photoelectrochemical signal under visible light irradiation compared to individual GQDs or TiO₂ nanoparticles. The photocurrent of the GQDs–TiO₂/GCE exhibited a remarkable 30-fold and 12-fold increase compared to GQDs/GCE and TiO₂/GCE, respectively (Figure 4E). This enhancement was attributed to the effective synergistic amplification between TiO₂ nanoparticles and GQDs. The study revealed that the photocurrent of GQD–TiO₂ nanocomposites was sensitized by the presence of DA, increasing proportionally with DA concentration. This led to the development of a new methodology for DA detection, showcasing a linearly enhanced photocurrent over a broad concentration range from 0.02 to 105 μM. The detection limit for DA was identified as 6.7 nM under optimized conditions.

Both graphene and CNTs are allotropes of carbon with exceptional mechanical and electrical properties. While CNTs have been used extensively in catalysis due to their unique tubular structure providing distinct reactive sites, graphene’s planar structure offers a larger surface area, potentially exposing more catalytic sites [62]. However, the reactivity of these sites in graphene is generally lower than the highly curved surfaces of CNTs [63]. In applications like electrocatalysis, the choice between graphene and CNTs often depends on the balance between surface area and inherent reactivity of the material. Some work shows that combining CNTs with graphene will show better electrocatalytic sensing properties. For example, Woo et al. [64] synthesized a composite material combining graphene with multiwalled carbon nanotubes (MWCNTs). The resultant material demonstrated an enhanced electrochemical surface area and rapid electron transfer capabilities. The key focus of the research was on the composite’s application in electrochemical sensing, particularly for H₂O₂ detection. The study revealed that electrodes modified with the graphene–MWCNT composite exhibited superior performance in electrocatalytic reduction of H₂O₂, showcasing a good linear dependence on H₂O₂ concentration ranging from 2 × 10⁻⁵ to 2.1 × 10⁻³ mol/L, with a detection limit estimated at 9.4 × 10⁻⁶ mol/L (Figure 4F). The graphene–MWCNT composite’s superior performance is attributed to its increased surface area, improved electrical conductivity, structural stability, enhanced electrocatalytic properties, and the synergistic effects arising from the combination of graphene and MWCNTs. These characteristics make it an excellent material for sensitive and efficient electrochemical sensing applications.

While graphene exhibits certain advantages like high surface area, conductivity, and stability, its catalytic performance is often outshone by materials with inherent active sites and specificity, such as metal catalysts and MOFs. The future of graphene in catalysis lies in its functionalization and combination with other materials, leveraging its stability and conductivity while overcoming its intrinsic limitations.

Figure 4. CVs of (A) 1.0 × 10⁻⁴ M of HQ, (B) 1.0 × 10⁻⁴ M CT and (C) a mixture of 1.0 × 10⁻⁴ M HQ and 1.0 × 10⁻⁴ M CT at GCE, GN/GCE, Cu−MOF/GCE and Cu−MOF-GN/GCE [55]. (D) CVs of the bare PGE (a), SNDGr/PGE (b), Cu−MOF/PGE (c) and Cu-MOF/SNDGr/PGE (d) toward 11.8 µM STLHC [56]. (E) Photocurrent responses of GQDs (a), GQD−TiO₂ nanocomposites (b) and TiO₂ NPs (c) [61]. (F) Current response curves at GC, M/GC, G/GC, and G−M/GC electrodes with addition of increasing concentration of H₂O₂ [64].

Figure 4. CVs of (A) 1.0 × 10⁻⁴ M of HQ, (B) 1.0 × 10⁻⁴ M CT and (C) a mixture of 1.0 × 10⁻⁴ M HQ and 1.0 × 10⁻⁴ M CT at GCE, GN/GCE, Cu−MOF/GCE and Cu−MOF-GN/GCE [55]. (D) CVs of the bare PGE (a), SNDGr/PGE (b), Cu−MOF/PGE (c) and Cu-MOF/SNDGr/PGE (d) toward 11.8 µM STLHC [56]. (E) Photocurrent responses of GQDs (a), GQD−TiO₂ nanocomposites (b) and TiO₂ NPs (c) [61]. (F) Current response curves at GC, M/GC, G/GC, and G−M/GC electrodes with addition of increasing concentration of H₂O₂ [64].

3. Dopants in Graphene and Mechanisms of Electrocatalysis

3.1. Methods of Graphene Doping

3.1.1. Substitutional Doping

Substitutional doping in graphene involves replacing carbon atoms in the graphene lattice with other atoms, typically nitrogen or boron. This type of doping alters the electronic properties of graphene, making it suitable for various applications, from sensors to energy storage devices.

Nitrogen is a popular choice for substitutional doping due to its ability to impart n-type characteristics to graphene. Techniques such as chemical vapor deposition (CVD) are often used for nitrogen doping [65]. For instance, ammonia and pyridine are commonly employed as nitrogen sources for the doping process [66]. That study revealed that using pyridine, both as a carbon and nitrogen source, resulted in more effective nitrogen doping in terms of content and homogeneity compared to ammonia. For the synthesis of N-doped single-layer graphene, the combination of pyridine and a small amount of methane proved most effective. This method significantly reduced the sheet resistance of the graphene film. Raman spectroscopy indicated a red shift in G peak and 2D peaks for N-doped graphene compared to pristine graphene, signifying successful doping (Figure 5A). The SEM-EDS results showed the presence of nitrogen in the doped graphene, with an approximate nitrogen content of 1–2%. The study also observed a decrease in optical transmission with increased doping. Specifically, nitrogen doping using the N₂–NH₃ mixture resulted in around 93% transmission at 633 nm wavelength, while doping with only C₅H₅N lowered it to 83%. The sheet resistance of the graphene films was significantly reduced through doping, with the lowest values achieved using only C₅H₅N, demonstrating a balancing act between electrical conductivity and optical properties. In a study conducted by Zhang et al. [67], the researchers successfully synthesized N-doped graphene films using CVD employing urea as the nitrogen source and methane as the carbon source. This approach was favored for its simplicity, low cost, and ability to produce large-scale, uniform N-doped graphene films. A notable achievement was the attainment of a N-doping level of 3.72 at.%, predominantly in a pyrrolic nitrogen configuration. The N-doped graphene exhibited n-type doping behavior and demonstrated a significantly high carrier mobility of about 74.1 cm²/Vs.

Boron doping introduces p-type characteristics to graphene. It is typically achieved through methods like CVD, where diborane (B₂H₆) can be used as a boron source [68]. Boron atoms replace carbon atoms in the graphene lattice, creating p-type doping effects. This type of doping has been shown to enhance the electronic and optical properties of graphene, useful in electronics and photovoltaic applications. In a study conducted by Wang et al. [69], a method for synthesizing B-doped graphene monolayers was developed, using phenylboronic acid as the sole solid feedstock in a CVD process. This approach successfully produced large homogeneous B-doped graphene monolayers, marking a significant advancement in the field. The researchers demonstrated that the synthesized graphene exhibited p-type transport behavior, a desirable characteristic for various applications. Notably, the carrier mobility of the B-doped graphene was measured to be approximately 800 cm²V⁻¹s⁻¹ at room temperature, a considerably high value indicating excellent electronic properties. The boron content in the graphene was estimated to be around 1.5 at.%, and the material displayed a uniform thickness of about 0.86 nm, consistent with monolayer graphene. Raman spectra confirm the successful doping (Figure 5B). Gebhardt et al. [70] investigated the detail growth and electronic structure of B-doped graphene. The research revealed that doping graphene with boron caused significant shifts in the graphene bands towards lower binding energies, observable up to 1.2 eV, depending on the boron concentration. These shifts were consistent across experimental observations and density-functional theory (DFT) calculations. The doping process maintained the overall band structure of the graphene, while the boron atoms incorporated into the graphene led to a preferential adsorption in the top-fcc geometry due to their affinity for fcc-hollow sites in the substrate. Additionally, a smaller bonding distance of boron atoms within graphene compared to carbon atoms resulted in a bending of the graphene layer near the boron atoms. This bending was more pronounced at lower boron concentrations. High concentrations of boron doping led to the formation of a Dirac point above the Fermi level, while the adsorption of graphene on Ni(111) typically shifted the bands to higher binding energies. The combined effects of adsorption and boron doping resulted in bands located above most of the substrate bands around the K-point, creating a Dirac point estimated to be 0.7 eV above the Fermi level with a 0.3 eV band gap. The boron doping offers a feasible method for tuning the electronic properties of graphene.

While substitutional doping can significantly enhance the properties of graphene, it also presents challenges. The introduction of foreign atoms can disrupt the sp² bonding in graphene, potentially affecting its structural integrity and electronic properties. Moreover, controlling the concentration and distribution of dopants remains a challenge that impacts the consistency and reliability of the doped graphene.

Figure 5. (A) Raman spectra of pristine and nitrogen−doped graphene with C₅H₅N and CH₄ [66]. (B) Raman spectra of the boron-doped (red) and intrinsic (black) graphene transferred on SiO₂/Si substrate [69].

Figure 5. (A) Raman spectra of pristine and nitrogen−doped graphene with C₅H₅N and CH₄ [66]. (B) Raman spectra of the boron-doped (red) and intrinsic (black) graphene transferred on SiO₂/Si substrate [69].

3.1.2. Adsorption-Based Doping

Adsorption-based doping in graphene involves the addition of foreign atoms or molecules onto its surface without altering the lattice structure. This method is less disruptive than substitutional doping and allows for the preservation of graphene’s intrinsic properties. The adsorption of metal ions onto graphene is a common method to alter its electronic properties. For example, Fe³⁺ and Zn²⁺ ions can be adsorbed onto graphene to enhance its conductivity and chemical reactivity [71]. Güneş et al. [72] introduced a method of layer-by-layer (LbL) adsorption doping of thin graphene films using AuCl₃. They synthesized monolayer graphene on Cu foil using the CVD method and transferred each layer onto a polyethylene terephthalate substrate. They then applied a salt-solution casting technique and repeated the process several times to create the LbL-doped thin layers (Figure 6). The LbL-doped graphene exhibited superior environmental stability compared to samples fabricated by topmost layer doping, making it an attractive option for applications that require both high conductivity and stability. This type of doping is beneficial in applications like sensors and catalysis [73,74], where the interaction between graphene and adsorbed metal ions plays a crucial role.

Organic molecules can also be adsorbed onto graphene to modify its properties. Molecules like tetrafluorotetracyanoquinodimethane (F4-TCNQ) are used to p-dope graphene [75], while molecules like benzyl viologen (BV) can introduce n-type characteristics [69]. The choice of organic adsorbates depends on the desired application and the specific properties required for the graphene. In a study conducted by Wang et al. [76], the electronic properties of F4-TCNQ on graphene were explored using local density function theory. Their findings revealed a charge transfer of 0.3 holes per molecule from graphene to F4-TCNQ, effectively resulting in p-type doping of graphene. The deposition of F4-TCNQ on graphene not only increased the work function but also indicated a significant binding energy of 1.26 eV, suggesting thermal stability at room temperature. Additionally, the research discussed the implications of this molecular interaction on the carrier mobility of graphene. They concluded that the presence of F4-TCNQ could potentially reduce graphene’s mobility due to additional Coulomb scattering, similar to the effect observed with metallic clusters. In the study conducted by Wang et al. [69], the focus was on the use of BV molecular doping to modulate the displacement field in bilayer graphene transistors. This doping allowed for the opening of a transport band gap and increased the on/off ratio in these transistors. A key finding was that the amount of BV doping could be precisely controlled to adjust the Fermi energy level within the opened gap, enabling the creation of bilayer graphene transistors with tunable Dirac points. They demonstrated that BV doping shifted the threshold voltage (Dirac point) from a positive to a negative regime, enhancing the on/off ratio with increased doping. This effect was explained through the concept of displacement fields, where the doping introduced an additional offset voltage that influenced these fields and consequently the band gap. The study found that before doping, oxygen doping produced a positive displacement field, which shifted to negative with increased BV doping. This shift allowed for the tuning of the band gap based on the amount of displacement field.

3.2. Dynamic Doping Modulation Using External Stimuli

3.2.1. Light-Mediated Doping Modulation

Light-mediated doping modulation in graphene leverages the interaction between light and graphene to dynamically adjust its electronic properties [77]. This method is particularly attractive due to its noninvasive nature and the potential for precise spatial and temporal control. Light can alter the electronic structure of graphene by inducing charge-transfer processes or by affecting adsorbed species on its surface. This process is reversible, allowing for the dynamic tuning of graphene’s doping levels. For instance, UV light can desorb oxygen molecules adsorbed on graphene, thereby reducing p-type doping [78]. In the study by Luo et al. [79], they found UV irradiation was distinct in its minimal impact on charge mobility, a common issue with other doping methods. They employed a shadow mask technique for electrode definition on graphene grown by CVD, thereby avoiding harmful chemicals typically used in lithography. The key findings were that UV irradiation led to a saturation change in charge concentration at approximately 2 × 10¹² cm⁻¹, with a quantum yield of about 10⁻⁵ e/photon upon initial exposure. This method showed a distinct advantage in that it did not significantly alter the electronic properties of graphene other than carrier concentration. Remarkably, the UV doping effect was stable under vacuum conditions, slowly reversed when exposed to ambient, and quickly reversed at elevated temperatures in ambient conditions. The mobility of electrons remained unchanged or even increased slightly, while the hole mobility decreased marginally (by no more than 5%). This minimal variation in carrier mobility during the doping and de-doping process was a significant observation (Figure 7A). The reversible nature of the doping, demonstrated by the ability to return to the original state after annealing, suggested a novel mechanism different from conventional chemical doping, which typically modifies the graphene structure more significantly.

Light-mediated doping is advantageous for its reversibility and the ability to control doping levels without physical contact. It is useful in developing smart materials and devices, such as photodetectors and light-responsive sensors [80]. For instance, graphene field-effect transistors (FETs) can be tuned using UV light to modulate their conductive states, making them suitable for applications in optoelectronics and flexible electronics.

Organic chromophores like azobenzenes and spiropyrans (SP), which change their electronic properties upon light illumination, can be used for doping modulation. These molecules can adsorb onto graphene and undergo structural changes when exposed to light, resulting in a reversible alteration in the doping state of graphene. For example, the study conducted by Döbbelin et al. [81] explored the enhancement of liquid-phase exfoliation (LPE) of graphite into graphene and the photo-modulation of current in graphene–azobenzene composites. The researchers demonstrated that the use of alkyl-substituted azobenzenes, specifically 4-(decyloxy)azobenzene, as dispersion-stabilizing agents significantly improved the efficiency of graphene’s LPE. This improvement was attributed to the large conformational change accompanying the trans-cis photochemical isomerization of these azobenzenes. The study demonstrated reversible photo-modulated current in devices made from the graphene–azobenzene composites. This tunable electrical characteristic was ascribed to the intercalation of azobenzene between adjacent graphene layers, which led to an increase in interlayer distance when switching from the linear trans form to the bulky cis form of the photochromes (Figure 7B). The researchers observed that under UV light, the conductivity of the hybrid films decreased, whereas it was restored under visible light due to the reversible isomerization of the azobenzene molecules. In the study conducted by Wang et al. [82], graphene was innovatively functionalized with SP. This functionalization was achieved through noncovalent bonding, specifically π–π interactions, between pyrene-modified SP and graphene. The FET device, which incorporated SP-functionalized graphene, demonstrated notable n-doping effects and intriguing optoelectronic behaviors. The Dirac point of graphene within the FET could be reversibly controlled through light modulation. This modulation occurred as the spiropyran switched between two different conformations—a neutral form (colorless SP) and a charge-separated form (purple merocyanine, MC)—under the influence of UV and visible light irradiation. Significantly, the researchers observed a shift in the Dirac point of graphene towards negative gate voltage during UV light irradiation, which induced the transformation to the MC form. Conversely, the shift moved towards positive gate voltage under visible light irradiation or in darkness, reverting to the SP form. This alteration in the Dirac point was reproducible upon repeated exposure to UV and visible light. Furthermore, SP molecules enhanced the conductance change in the FET device, signifying an improved performance. The utilization of noncovalent bonding for functionalization presents an advantage over traditional methods, as it avoids defect generation in graphene, thus preserving its intrinsic properties.

3.2.2. Chemical Cue-Responsive Doping Modulation

Chemical cue-responsive doping modulation in graphene is a technique where the doping level of graphene can be dynamically controlled in response to specific chemical stimuli [83]. This approach is highly valuable in sensor technology and smart-material applications. This method relies on the sensitivity of graphene to its chemical environment. The doping level of graphene can change in response to the presence of certain chemical cues, such as pH changes or specific molecules. This change can be detected as a variation in the electrical properties of graphene, making it an effective sensing material.

An example of chemical cue-responsive doping is the use of pH-sensitive molecules. Proteins, for instance, can exhibit different charges at various pH levels, thereby serving as electron acceptors or donors to graphene. Jang et al. [84] developed a method for doping graphene using denatured bovine serum albumin (BSA) to create tunable p- and n-type doping, which is essential for the practical application of graphene in electronic devices. The process involved using BSA as a dopant, which—depending on the pH—either donates or accepts electrons, thus modulating the charge of graphene. This was achieved by layering graphene with denatured BSA through π-stacking interactions, enabling pH-dependent charge modulation. The carrier concentration in graphene could be controlled by the concentration and pH-dependent net charge of the protein molecules. This approach did not lead to any significant degradation in the mobility of the graphene transistors, indicating that the electrical performance of graphene was modulated without compromising its inherent properties. The results demonstrated that this protein-mediated charge-transfer doping could effectively modulate graphene properties in terms of doping type and carrier concentration.

Chemical cue-responsive doping is not limited to pH changes. Specific chemical compounds can also modulate the doping state of graphene. For instance, Hess et al. [85] developed an approach for biosensing applications using graphene transistors modified with multifunctional polymer brushes. This method significantly enhanced the sensitivity and specificity of biosensors. The team utilized CVD-grown graphene functionalized with polymer brushes, which effectively integrated functional groups without introducing additional defects. Enzyme acetylcholinesterase and a transducing pH-sensitive group were incorporated into these brushes, enabling the detection of the neurotransmitter acetylcholine. The study demonstrated that the modified graphene transistors could detect acetylcholine concentrations as low as 0.5 µM. This was achieved by exploiting the enzymatic reaction of acetylcholinesterase, which produced hydronium ions, leading to a local pH change. This change was detected by the transistor, indicating the presence of the neurotransmitter.

3.3. Influence of Dopant Type and Concentration on Electrocatalytic Activity

The type of dopant used in graphene significantly influences its electrocatalytic activity. Metallic dopants are known to enhance electrocatalytic processes by introducing new active sites and improving electron transfer rates [86]. On the other hand, nonmetallic dopants such as nitrogen, boron, and sulfur modify the electronic properties of graphene by altering its charge carrier concentration and creating defect sites, which can be beneficial for specific types of electrocatalytic reactions [87]. Among them, N-doped graphene is the most widely studied and is also considered to have excellent properties for electrocatalytic detection of small molecules. Table 1 shows common graphene dopants and their record of being used to electrocatalytic detect different small molecules.

The concentration of dopants in graphene is another critical factor that determines its electrocatalytic performance. While an optimal level of doping can significantly enhance the material’s catalytic activity, over-doping can lead to aggregation of dopants, increased scattering of charge carriers, and a decrease in the overall performance. For instance, Megawati et al. [88] investigated the impact of varying nitrogen doping levels in graphene on its electrochemical sensing capabilities. The study focused on N-doped graphene materials synthesized through hydrothermal synthesis using different GO precursors. These precursors include Staudenmaier, Hummers, Hofmann, and Brodie methods, producing ST-GO, HU-GO, HO-GO, and BR-GO respectively. The research found that the nitrogen content in these graphene oxides increased in the order of ST-GO < BR-GO < HO-GO < HU-GO, with a corresponding increase in the pyridinic form of nitrogen. This trend also influenced the electrocatalytic effect of N-doped graphene. These N-doped materials showed enhanced sensitivity over bare GCE in detecting biomolecules like ascorbic acid (AA), UA, and DA. The study concluded that nitrogen doping, particularly with higher pyridinic nitrogen content, significantly enhances the electrochemical sensing properties of graphene, making it a promising material for biosensing applications.

Incorporating multiple types of dopants in graphene can create synergistic effects that enhance its electrocatalytic activity beyond that which can be achieved with single dopants. For example, Yuan et al. [89] developed an advanced electrochemical sensor for nitrite detection using a novel graphene film doped with nitrogen and oxygen. The study’s innovation lies in its use of a facile and quick laser processing technique to create N–O co-doped porous graphene. The sensing sensitivity was enhanced by the co-doping of nitrogen and oxygen, as these dopants introduced functional groups that improved the graphene’s electrocatalytic properties. As shown in Figure 8A, when the commercial polyimide (PI) film is exposed to ultraviolet laser irradiation, a significant deoxidation reaction occurs. This process generates various gaseous products, including water molecules, carbohydrates, and oxynitrides. The intense reaction breaks C = O and C-N bonds in the polyimide’s amide groups, leading to the formation of functional groups like pyrrole nitrogen and carboxyl. Additionally, the replacement of carbon atoms with nitrogen in the benzene rings results in the creation of pyridine nitrogen. This transformation alters the chemical structure of the original polyimide, turning it into a porous, co-doped graphene structure with embedded nitrogen and oxygen atoms. The functional groups in the laser-induced graphene (LIG) play a crucial role in its sensitivity to nitrite ions. The LIG contains active sites, particularly pyridine nitrogen, which has a propensity to adsorb nitrite ions. At an optimal pH (around 4), the pyridine group becomes positively charged and can attract nitrite ions through electrostatic forces. However, at higher pH levels, the nitrite ions and carboxyl groups on the LIG surface become negatively charged, leading to repulsion and decreased adsorption of nitrite ions. This pH-dependent behavior is crucial for the sensor’s selective and sensitive detection of nitrite.

Zhao and colleagues [90] developed a type of multiple-heteroatom co-doped graphene fiber (GF), specifically focusing on N and B co-doped GF (NBGF), as a flexible and biocompatible microelectrode for electrochemical detection in biological samples. The research aimed to enhance the electrocatalytic activity of graphene fibers by co-doping with heteroatoms like nitrogen and B. The microelectrode showcased remarkable performance in the sensitive detection of H₂O₂, with a high sensitivity of 431.37 μA cm²/mM and a low detection limit of 350 nM. The NBGF microelectrode’s effectiveness was further validated in practical applications, where it successfully tracked H₂O₂ released from different human colorectal cancer cells (Figure 8B), distinguishing between cancer cell types and assessing the efficacy of chemotherapy drugs (Figure 8C). Additionally, its application extended to in situ detection of H₂O₂ in tumor tissues from mice, showcasing its potential in clinical diagnosis and cancer treatment evaluation. The study concluded that the co-doping of heteroatoms in graphene fibers significantly improves their electrochemical sensing capabilities, making them promising for future applications in implantable sensor devices for clinical purposes.

While doping has been shown to enhance the electrocatalytic properties of graphene, the field faces challenges in controlling dopant distribution, concentration, and the introduction of unintended impurities. The current debate centers on optimizing doping strategies to maximize electrocatalytic efficiency without compromising graphene’s inherent properties. Future research should focus on developing precise doping methods that allow for control over dopant type and concentration and understanding the underlying mechanisms of how these factors influence graphene’s electrocatalytic activity. This understanding is vital for the advancement of graphene-based materials in applications such as sensors, energy conversion, and environmental monitoring.

Table 1. Common graphene dopants and their record of being used to electrocatalytic detect different small molecules.

Dopants	Doping Method	Analyte
N	CVD	DA [91,92], AA, UA, glucose [92].
	Thermally annealing	DA [93,94,95], AA [93,94], UA [93,94], hydroquinone [96], o-dihydroxybenzene [96].
	Microwave synthesis	Acetaminophen [43], glucose [97].
	Hydrothermal synthesis	H2O2 [98], glucose [97], salbutamol [99], parathion [45], adrenaline [100], nitrite [101], glycated hemoglobin [102], DA [103,104,105], AA [103], UA [103], daunorubicin [106], cholesterol [107], doxorubicin [108], rutin [109], chloramphenicol [110], diethylstilbestrol [110].
	Wet chemical synthesis	Pb2+ [111], Cu2+ [111], Ha2+ [112],chloramphenicol [113], TNT [114], paraquat [115], bisphenol A [116], nicotine [117], AA [118], UA [118], DA [118,119], melatonin [119], tryptophan [119], glucose [120,121], 4-nitrophenol [122], amaranth [123], hydroquinone [124,125], catechol [124,125], acetaminophen [46].
	Electrochemical exfoliation	Acetaminophen [126].
B	Atmospheric pressure carbothermal reaction	H2O2 [127].
	Bubbling method	Pb2+ [128].
	Hydrothermal synthesis	Hydroquinone [129], catechol [129], HMX [130].
S	Thermally annealing	Hg2+ [131].
	Solvothermal synthesis	H2O2 [132], nilutamide [133].
	Wet chemical synthesis	8-hydroxy-2′-deoxyguanosine [134], Ha2+ [135].
F	Modified Hummers’ method	Caffeic acid [136], Cd2 + [48], Pb2 + [48], Cu2 + [48], vanillin [137].
P	Hydrothermal synthesis	Acetaminophen [138], DA [139], H2O2 [140].
Cl	Wet chemical synthesis	Chloramphenicol [141].
I	Wet chemical synthesis	Bisphenol A [142].
Ag	Wet chemical synthesis	H2O2 [143], Hg2+ [144].

Table 1. Common graphene dopants and their record of being used to electrocatalytic detect different small molecules.

Dopants	Doping Method	Analyte
N	CVD	DA [91,92], AA, UA, glucose [92].
	Thermally annealing	DA [93,94,95], AA [93,94], UA [93,94], hydroquinone [96], o-dihydroxybenzene [96].
	Microwave synthesis	Acetaminophen [43], glucose [97].
	Hydrothermal synthesis	H2O2 [98], glucose [97], salbutamol [99], parathion [45], adrenaline [100], nitrite [101], glycated hemoglobin [102], DA [103,104,105], AA [103], UA [103], daunorubicin [106], cholesterol [107], doxorubicin [108], rutin [109], chloramphenicol [110], diethylstilbestrol [110].
	Wet chemical synthesis	Pb2+ [111], Cu2+ [111], Ha2+ [112],chloramphenicol [113], TNT [114], paraquat [115], bisphenol A [116], nicotine [117], AA [118], UA [118], DA [118,119], melatonin [119], tryptophan [119], glucose [120,121], 4-nitrophenol [122], amaranth [123], hydroquinone [124,125], catechol [124,125], acetaminophen [46].
	Electrochemical exfoliation	Acetaminophen [126].
B	Atmospheric pressure carbothermal reaction	H2O2 [127].
	Bubbling method	Pb2+ [128].
	Hydrothermal synthesis	Hydroquinone [129], catechol [129], HMX [130].
S	Thermally annealing	Hg2+ [131].
	Solvothermal synthesis	H2O2 [132], nilutamide [133].
	Wet chemical synthesis	8-hydroxy-2′-deoxyguanosine [134], Ha2+ [135].
F	Modified Hummers’ method	Caffeic acid [136], Cd2 + [48], Pb2 + [48], Cu2 + [48], vanillin [137].
P	Hydrothermal synthesis	Acetaminophen [138], DA [139], H2O2 [140].
Cl	Wet chemical synthesis	Chloramphenicol [141].
I	Wet chemical synthesis	Bisphenol A [142].
Ag	Wet chemical synthesis	H2O2 [143], Hg2+ [144].

4. Direct Electrocatalytic Quantification of Small Molecules

4.1. Importance of Detection of Small Molecules via Electrocatalytic Sensors

Electrochemical sensors are highly effective in the direct detection of small molecules in analytical chemistry due to several key features. They exhibit high sensitivity and specificity, crucial for accurately identifying specific small molecules. Their ability to provide rapid response times enables real-time monitoring of changes in small-molecule concentrations, essential in fields like environmental monitoring and clinical diagnostics. Additionally, these sensors are cost-effective and portable, making them suitable for a wide range of applications, including on-site testing where complex laboratory facilities are not available. The simplicity of the sample preparation process further enhances their applicability in various settings.

In terms of specific small molecules commonly targeted by electrochemical sensors, glucose detection in diabetes management is a prime example [145]. These sensors are also used for detecting neurotransmitters like DA and serotonin, aiding in neurological research and treatment [146]. In environmental and biomedical research, the detection of molecules such as nitric oxide and various heavy metals like Pb, Hg, and Cd is crucial [147]. Additionally, the measurement of dissolved oxygen levels with electrochemical sensors is vital in assessing water quality [148]. These examples underscore the versatility and effectiveness of electrochemical sensors in the direct detection of small molecules across diverse fields. The quantification of such molecules using doped graphene-based sensors offers heightened sensitivity and specificity, providing a reliable method for continuous monitoring and early detection of these conditions.

On the other hand, these molecules are not only vital analytes in practical electrochemical detection applications but also serve as benchmarks for assessing the performance of electrochemical sensors. These molecules are often employed to differentiate between various electrode test materials, highlighting disparities in their electrochemical detection capabilities. This usage underscores the importance of these molecules in both practical and experimental settings, providing a standard measure for sensor efficiency and effectiveness. Their role extends beyond mere detection, contributing significantly to the advancement and refinement of electrochemical sensing technologies.

While doped graphene shows promise in the detection of small molecules, further research is needed to fully understand the interaction mechanisms between the doped graphene and the target analytes. Questions remain about the long-term stability and reproducibility of these sensors in real-world applications. Future research should focus on developing scalable production methods for doped graphene sensors and rigorous testing in clinical settings to ensure reliability and accuracy. Additionally, there is a need to explore the environmental impact of these sensors, ensuring that their use is sustainable and safe. The optimization of doping strategies and a deeper understanding of the interaction between doped graphene and small molecules will be crucial for the advancement of this technology.

4.2. Techniques for Quantitative Analysis

Electrochemical methods are at the forefront of quantitative analysis using doped graphene. These techniques, including amperometry, linear sweep voltammetry (LSV) and differential pulse voltammetry (DPV), rely on the electrocatalytic properties of graphene enhanced by doping. For instance, Sha et al. [149] focused on creating N-doped graphene-like mesoporous nanosheets (N-GMNs) for detecting vitamin C. The core of the study was the construction of a nonenzymatic amperometric biosensor using these N-GMNs (Figure 9A). The researchers modified a GCE with the synthesized N-GMNs and compared its performance with both a traditional GCE and one modified with carbon nanotubes (CNTs–GCE). Performance-wise, the N-GMNs–GCE demonstrated remarkable results. It exhibited a higher sensitivity (144.65 μA mM/cm²), a wider linear range (10–5640 μM), and a lower detection limit (0.51 μM) in comparison to the other electrodes. Zhang et al. [108] developed an electrochemical sensor for detecting doxorubicin (DOX) utilizing N-doped graphene quantum dots (NGQDs) confined within silica nanochannels on an indium tin oxide (ITO) electrode. The vertically ordered mesoporous silica films (VMSFs) provided a solid template for NGQDs, capitalizing on their electrostatic preconcentration effects and the π–π interaction, crucial for attracting DOX to the electrode surface. The NGQDs@VMSF/ITO sensor showed remarkable performance, with LSV revealing a significant increase in cathodic peak current in the presence of DOX (Figure 9B), indicating effective electrochemical reduction. The sensor demonstrated a broad linear range for DOX detection, from 5 nM to 1 μM, and a low detection limit of 0.5 nM. Chen et al. [45] developed an electrochemical sensor using N-HG for detecting MP. The core of the study centered on the use of DPV as the analytical technique, offering a robust and accurate method for analyzing MP. In terms of specific performance, the N-HG sensor, particularly the variant with a high pyrrolic N content, showcased an ultralow detection limit of 3.5 pg/mL and a wide linear range from 1 ng/mL to 150 μg/mL (Figure 9C).

FET-based biosensors using doped graphene represent a promising avenue for the quantification of small molecules. The doping alters the graphene’s charge carrier concentration, making it highly sensitive to changes in the local electric field caused by the binding of analyte molecules. Such sensors have shown high sensitivity and selectivity for gas molecule detection. Niu et al. [150] synthesized P-doped graphene nanosheets (P-GNSs) using high-temperature annealing of GO and triphenylphosphine. The primary focus was to explore the application of these nanosheets in room temperature NH₃ sensing. The P-GNSs demonstrated remarkable NH₃ sensing capabilities due to their p-type semiconducting behavior, where phosphorus atoms served as active sites for NH₃ adsorption. The P-GNSs were prepared at different annealing temperatures (400, 500, 600, and 800 °C) and their NH₃ sensing performance was evaluated. Specifically, P-GNS-400 showed a high response value of 5.4 ± 0.2% for 100 ppm NH₃, with a response time of 134 s and a recovery time of 816 s. Jaiswal et al. [151] recently utilized I-doped multilayer graphene (I-MLG) in the development of a NO₂ gas sensor operating at room temperature. The I-MLG demonstrated a significant sensing response of 69% for 100 ppm of NO₂ gas within a remarkably swift 16 s. However, the recovery from NO₂ exposure initially took a prolonged duration of 1380 s. To address this, the team introduced an electric field-assisted sensor element, which remarkably reduced the recovery time to just 156 s when a negative gate voltage of −15 V was applied.

4.3. Case Studies from Current Research

The direct electrochemical detection of glucose remains a crucial topic in electrochemical sensor research, primarily due to the widespread prevalence of diabetes, a condition marked by high blood glucose levels [145]. This necessitates frequent monitoring for effective management. Electrochemical glucose sensors offer a convenient, rapid, and noninvasive method for this purpose. Additionally, advancements in this field can lead to more sensitive, selective, and cost-effective sensors, benefiting a large population globally. Moreover, these sensors have potential applications in various industries, including food and beverage quality control and bioprocessing, making their development and improvement a focus in both medical and industrial sectors. Doped graphene is also widely used in electrode materials for the electrochemical detection of glucose. Enzymes can be used directly to doping graphene. The study conducted by Niu et al. [152] focused on enhancing the performance of biosensors using enzyme-doped graphene nanosheets for glucose detection. The researchers chemically synthesized graphene nanosheets and then covalently conjugated them with glucose oxidase (GOD), an enzyme model. This conjugation was achieved through the reactive functionalities present on graphene, such as ketonic, quinonoid, and carboxylic functional groups, which strongly bind with the free amine terminals of GOD, forming a robust covalent amide linkage. The GCE modified with polypyrrole (Ppy) was then immobilized with the conjugated graphene–GOD for glucose detection (Figure 10A). The results indicated that electrodes with graphene–GOD exhibited significantly better sensitivity and response time compared to those immobilized with graphene alone. This improvement was attributed to the two-dimensional (2D) structure of graphene, which proved to be an excellent platform for enzyme conjugation, and the entrapment of graphene–GOD within the porous structure of Ppy, which maintained the original structure and functionality of the enzymes. Enzyme-free strategies are more widely welcomed. For example, Reynoso-Soto et al. [121] synthesized NG through a solvothermal method, aiming to enhance electrochemical glucose detection. The key finding was that NG exhibited superior conductivity compared to GO and RGO, a result of the nitrogen-doping process. The study demonstrated that NG’s enhanced electrocatalytic activity was largely attributed to the presence of pyridinic nitrogen groups, which outnumbered pyrrolyic, graphitic, and oxide nitrogen in the NG. These nitrogen groups were instrumental in improving the charge carrier density due to the significant electronegativity difference between nitrogen and carbon atoms, thereby boosting the electrocatalytic activity of NG. Specifically, the NG sheets showed a sensitivity of 1.3767 µA/µM for glucose detection within a range of 0 to 100 µM at pH 7, which was significantly higher than that of RGO and GO. This sensitivity enabled the NG to function effectively as a nonenzymatic sensor for glucose, demonstrating a promising application for third-generation glucose sensors.

AA (vitamin C), UA, and DA are often simultaneously detected using electrochemical sensors due to their significant biochemical roles and co-presence in bodily fluids [153]. AA is vital for tissue repair and enzyme function, UA is a product of purine metabolism, and DA is a key neurotransmitter. Monitoring these compounds is crucial for diagnosing and managing various health conditions, including metabolic disorders and neurological diseases. Simultaneous detection of these molecules provides comprehensive data, crucial for accurate health assessments [154]. When these compounds are detected together, it challenges the sensor’s ability to distinguish between similar electrochemical behaviors, leading to advancements in electrode design and surface modification [155]. In a study conducted by Sheng and colleagues [93], NG was synthesized through thermal annealing of GO and melamine. This research was primarily focused on developing an electrochemical sensor utilizing NG for the simultaneous detection of AA, DA, and UA. The study found that NG-based sensors demonstrated a wide linear response and low detection limits for AA, DA, and UA, making them suitable for sensitive detection of these biomolecules. Specifically, the detection limits were 2.2 × 10⁻⁶ M for AA, 2.5 × 10⁻⁷ M for DA, and 4.5 × 10⁻⁸ M for UA (Figure 10B). Furthermore, the study observed that the electrochemical behavior of these biomolecules on NG-modified electrodes exhibited well-defined oxidation peaks with considerable separation, highlighting the potential of NG for sensitive and selective simultaneous determination of AA, DA, and UA.

Doped graphene is also widely used in the electrochemical detection of heavy metal ions. Guo et al. [156] developed three-dimensional graphene aerogels (3DGAs) doped with pyrrole for enhanced electrochemical sensing of Cd(II). The team synthesized the aerogels through a hydrothermal reaction, ingeniously utilizing pyrrole not only as a nitrogen source but also as a reductant and structural regulator. This dual role of pyrrole significantly influenced the electrochemical properties of the aerogels. The aerogels exhibited a wide linear range and a notably low detection limit for Cd(II) (Figure 10C). The optimal balance in the composition and structure was achieved with a specific pyrrole-to-GO ratio. In another similar work [49], a 3D porous N-doped laser-engraved graphene (N@LEG) demonstrated excellent sensitivity and selectivity for detecting Cd(II) and Pb(II). The study revealed that the N@LEG/GCE sensor exhibited extremely wide linear detection ranges from 5 to 380 μg/L for Cd(II), and 0.5 to 380 μg/L for Pb(II), respectively. The detection limits were impressively low: 1.08 μg/L for Cd(II) and 0.16 μg/L for Pb(II).

Figure 10. (A) Representation of graphene-GOD entrapped within a porous Ppy matrix [152]. (B) DPV profiles at NG/GCE in 0.1 M PBS containing different concentrations of AA, DA and UA [93]. (C) Pyrrole-doped 3DGA for electrochemical sensing Cd(II) [156].

Figure 10. (A) Representation of graphene-GOD entrapped within a porous Ppy matrix [152]. (B) DPV profiles at NG/GCE in 0.1 M PBS containing different concentrations of AA, DA and UA [93]. (C) Pyrrole-doped 3DGA for electrochemical sensing Cd(II) [156].

In addition to N-doped graphene, B-doped graphene is a candidate that is often studied. Ghanbari et al. [157] developed a sensor for detecting flunitrazepam (commonly known as Rohypnol). This sensor was crafted by integrating electropolymerized β-cyclodextrin (Eβ-CD) with B-doped RGO (B-RGO) and applied onto a GCE. The incorporation of boron into GO notably enhanced the material’s electrochemical properties, making it a highly efficient supporting structure for the nanocomposite. This boron doping contributed to increased electron transport speed and improved conductivity, crucial for the sensor’s heightened sensitivity and selectivity. The study examined the sensor’s performance, emphasizing its ability to detect flunitrazepam with remarkable sensitivity and selectivity. Two linear ranges were established for flunitrazepam determination: 2.0 nM to 0.5 μM and 0.5 μM to 20.0 μM. The detection limit was impressively low, at 0.6 nM. The unique combination of B-RGO and Eβ-CD in the nanocomposite was pivotal. While B-RGO improved the electron transfer properties, Eβ-CD contributed to the sensor’s supramolecular recognition capabilities, enabling the selective detection of flunitrazepam. Boron and nitrogen dopants in graphene may have opposite effects on the electrochemical detection. Rohaizad et al. [158]. investigated the effects of doping graphene with boron and nitrogen. They discovered that N-doped graphene significantly enhanced the electrochemical signal for TNT detection compared to pristine graphene, whereas B-doped graphene showed inferior performance. This contrast in performance effectively debunked previous claims in literature that any form of doping would invariably enhance the electrochemistry of graphene.

A recent application of S-doped graphene in the detection of (R)-(+)-limonene illustrates the versatility of doped graphene [159]. The research highlighted the enhanced electrochemical properties of S-doped graphene, which played a crucial role in the sensors’ heightened sensitivity and efficiency. These sensors, utilizing DPV for analysis, demonstrated remarkable detection capabilities, with a lower detection limit of 3 × 10⁻⁶ M and a quantification limit of 1 × 10⁻⁵ M. The study’s results indicated that these sensors could accurately measure R-limonene within a wide concentration range, spanning from 1 × 10⁻⁵ to 6 × 10⁻⁴ M for the TPP/AuNPs-S-Gr sensor, and from 1 × 10⁻⁵ to 1 × 10⁻³ M for the Fe(TPFPP)Cl/AuNPs-S-Gr sensor. The research underscored the advantages of using S-doped graphene in electrochemical sensors, namely, its impact on improving conductivity and enhancing the sensor’s overall responsiveness. This advancement in sensor technology is particularly beneficial for the food industry, offering a cost-effective, less labor-intensive alternative to traditional methods for quality control and safety assurance in beverage production. Sharma and Hwa [133] focused on developing an electrochemical sensor for the detection of the antiandrogen drug nilutamide. Utilizing a novel nanocomposite material, which combined copper vanadate nanoparticles (Cu₂V₂O₇) and S-RGO, they aimed to enhance the sensor’s sensitivity and performance. The doping of sulfur into the RGO played a crucial role. It contributed to creating mixed-valence oxidative states and forming Cu-O bonds, which were pivotal for the sensor’s enhanced performance. The main achievement of the study was the development of an electrochemical sensor using this nanocomposite, which displayed remarkable sensitivity and a wide working range for nilutamide detection. Specifically, the sensor exhibited a detection range of 0.001–15 µM and an impressively low detection limit of 0.00459 nM.

P doping is an alternative way. For example, Tamilarasi et al. [160] recently developed a high-performance nonenzymatic glucose sensor by creating a nanocomposite material composed of P-doped graphene (PG) and a NiO₂ nanostructure. The primary goal was to enhance the electrochemical detection of glucose in human blood serum. P doping was utilized to improve the graphene’s electrochemical properties, contributing significantly to the sensor’s efficiency. The synthesized NiO₂@PG nanocomposite showed a broad dynamic detection range for glucose concentration (10–170 μM). Notably, the sensor demonstrated a LOD of 7.83 μM, highlighting its capability to detect very low glucose concentrations. This sensitivity was further complemented by a rapid response time of just 1.07 s. The research underscored the importance of using phosphorus doping in graphene for enhancing electrochemical sensors. The presence of phosphorus not only prevented the restacking of graphene oxide sheets but also played a crucial role in forming a strong bond with the NiO₂, thereby improving the overall structural integrity and functional performance of the nanocomposite.

5. Computational Approaches

Computational methods, including DFT and molecular dynamic (MD) simulations, play a crucial role in predicting the outcomes of graphene doping. These techniques help in understanding the electronic structure, stability, and reactivity of doped graphene at an atomic level. For example, DFT simulations have been used for understanding and predicting the atomic-level interactions and properties of chemically doped graphene used in HER catalysts [161]. DFT calculations are used to analyze the electronic structure and charge distribution of the graphene edges, particularly when doped with nitrogen and phosphorus [162]. These calculations help in identifying the most energetically favorable positions for dopants and in understanding how these dopants alter the electronic properties of graphene. The use of DFT in that study led to several improvements in the performance of the catalysts. Firstly, it helped in pinpointing the catalytically active sites, especially highlighting the role of pyridinic nitrogen atoms. This insight is vital for designing more efficient catalysts [163]. Secondly, DFT calculations show how phosphorus dopants enhance the charge accumulation on nitrogen atoms, thereby increasing the catalytic activity for the hydrogen evolution reaction [164]. Finally, by analyzing the charge distribution and Gibbs free energy changes, DFT provides a deeper understanding of how the edge structure of graphene and the presence of dopants synergistically improve the overall HER performance. This computational approach thus not only guides the experimental design of better catalysts but also offers a theoretical foundation for why certain configurations of atoms and dopants enhance catalytic activity. Lu et al. [165] conducted a comprehensive study on sulfur-doped graphene (SGV), exploring its potential as a metal-free electrocatalyst for ORR based on dispersion-corrected DFT (DFT-D) calculations. They revealed that SGV was notably stable, positioning it as a promising candidate for electrocatalysis. The study found that SGV facilitated the ORR through two primary pathways: the dissociation of OOH and the hydrogenation of OOH. These pathways had rate-determining steps with activation energies of 0.75 eV and 0.62 eV, respectively. Moreover, the research demonstrated that the hydrogenation of HOOH was the most favorable pathway, even at a high potential of 0.86 V. This was a significant finding, as it highlighted the efficiency of SGV in ORR processes, suggesting that it could serve as an effective alternative to traditional platinum-based catalysts. Sun et al. [166] investigated the ORR mechanism on Sn-doped graphene. Utilizing DFT, the researchers explored the ORR mechanism on Sn-doped divacancy graphene (Sn–Gra). They discovered that Sn and the adjacent four carbon atoms formed the primary catalytic sites. The study showed that the ORR on Sn–Gra likely follows a four-electron process, with the most favorable pathway being the hydrogenation of the O₂ molecule. A key finding was that the rate-determining step in this process is the hydrogenation of the OOH intermediate to form water and oxygen, with an energy barrier slightly lower (0.75 eV) than that of platinum (0.80 eV), suggesting that Sn–Gra could be a potential alternative to more expensive platinum-based catalysts.

DFT has also been used for studying the specific interactions between doped graphene with analyte. Srivastava and Srivastava [167] explored the use of boron- and nitrogen-doped graphene sheets as potential detectors for Pb in water, employing DFT for their analysis. The study’s primary objective was to understand how B and N doping in graphene sheets could enhance Pb detection sensitivity. The researchers modeled the electronic and transport properties of these doped graphene sheets both in isolation and upon adsorption of Pb atoms. They used a DFT-based ab initio approach, an effective method for calculating electronic properties in systems with fewer than 100 atoms and spatial periodicity. Through their analysis, they discovered that N-doped graphene demonstrated a particularly high sensitivity to Pb presence, significantly more than B-doped graphene. Notably, N–graphene exhibited a sensitivity of approximately 67% at a bias voltage of 16 mV (Figure 11A), highlighting its potential for detecting Pb at lower bias voltages. This finding is significant, as it implies that N–graphene can function effectively as a Pb detector in water at relatively low power inputs. Furthermore, the study revealed that N–graphene’s detection capabilities are notably efficient, with a fast recovery time of 22 s, making it a promising candidate for real-time monitoring applications. In contrast, while B–graphene also showed potential for Pb detection, its sensitivity and recovery times were less favorable than N–graphene. The effectiveness of these graphene-based sensors was also evaluated under different environmental conditions, including the presence of water molecules, to mimic real-world scenarios. The results indicated that the presence of water influenced the adsorption characteristics and the sensitivity of the graphene sheets to Pb. Interestingly, the sensitivity of N–graphene increased to about 329% at a lower bias voltage in an aqueous environment, further affirming its superior performance as a Pb detector. Khodadadi [168] explored the efficacy of graphene, specifically transition metal-doped and metal-decorated graphene nanosheets, in adsorbing H₂S gas. Utilizing the principles of DFT, the investigation was guided by the hypothesis that graphene’s inherent properties could be enhanced for better H₂S gas adsorption, crucial for industrial waste stream purification and sensor applications. The research primarily focused on graphene doped with transition metals like Ni, Cu, and Zn, as well as graphene sheets decorated with these metals. Significant findings emerged from the study: metal-doped graphene, especially with Cu, demonstrated a high adsorption energy, indicating a stronger affinity for H₂S molecules. The most stable adsorption configuration was observed when two hydrogen atoms of the H₂S molecule were directed towards the metal-doped graphene surface. In contrast, metal-decorated graphene sheets showed varying levels of adsorption efficiencies, with Ni-decorated graphene standing out due to its large adsorption energy and shorter binding distance, making it particularly suitable for chemisorption. This highlighted the role of unfilled d-shells in these nanosheets, which were instrumental in enhancing reactivity.

Metal doping in graphene is not particularly easy to achieve experimentally, but there has been a lot of theoretical research on it. The theoretical approach was pivotal in analyzing how doping graphene with metals, specifically copper and platinum, influences its sensitivity to hydrogen gas sensing. The research found that doping—and more notably, co-doping—graphene with these metals significantly enhances its interaction with hydrogen molecules. The study primarily focused on four types of graphene structures: pristine graphene (PG), Cu-doped graphene (Cu-G), Pt-doped graphene (Pt-G), and Pt-Cu co-doped graphene (CG). Each structure was examined for its hydrogen adsorption energy, electronic properties, and charge distribution changes upon interaction with hydrogen molecules. The results indicated that both Cu-G and Pt-G exhibited superior hydrogen sensing abilities compared to PG, but the most remarkable improvement was observed in CG, where the combined effect of both Cu and Pt doping led to a more than fourfold increase in adsorption energy. Furthermore, the study delved into the electronic properties of these graphene structures. It was observed that the bandgap, a critical parameter in sensing applications, showed notable changes upon hydrogen adsorption, especially in the doped graphene structures. The decrease in bandgap in doped graphene pointed towards increased electrical conductivity, a desirable trait for gas sensing materials. Additionally, the electric dipole moment, a measure of polarity induced upon hydrogen adsorption, also saw significant changes, further affirming the improved sensing performance of doped graphene.

In a study conducted by Salih and Ayesh [169], a gas sensor based on copper and zinc co-doped zigzag graphene nanoribbons (Cu/Zn–ZGNRs) was studied for the detection of H₂S gas using DFT. The study revealed that co-doping ZGNRs with Cu and Zn significantly improved their gas sensing capabilities. Specifically, the adsorption energy of H₂S on the Cu/Zn–ZGNRs was found to be −7.043 eV, a substantial increase compared to −2.237 eV for H₂S/Zn–ZGNR and −1.129 eV for H₂S/Cu–ZGNR systems. This enhancement indicated a stronger interaction between the gas molecules and the sensor surface, leading to higher sensitivity. The charge transfer to the H₂S/Cu/Zn–ZGNR system was measured at −0.311 e, far surpassing the charge transfer rates in other systems like ZGNR, Zn–ZGNR, and Cu–ZGNR. This result suggested a more effective electron exchange process during gas adsorption, crucial for detecting gas presence. Additionally, the adsorption distance between H₂S and Cu/Zn–ZGNRs decreased significantly to 2.23 Å, further evidencing a stronger molecular interaction. The formation of an S–Cu bond upon H₂S adsorption on Cu/Zn–ZGNRs was a notable finding, suggesting a chemical interaction that enhances the sensor’s efficiency. The study also investigated the electronic properties and electron transport properties of the developed sensors. Significant changes were observed in the band structure and density of states of Cu/Zn–ZGNRs upon H₂S adsorption (Figure 11B), indicating alterations in the electronic characteristics due to the gas interaction. These changes were pivotal in confirming the successful adsorption of H₂S and the sensor’s ability to detect its presence.

MD simulation in this field is not as widely used as DFT. Yang and colleagues [170] explored the adsorption–activation characteristics of two active molecules, H₂O₂ and peroxymonosulfate (PMS), on graphene and its heteroatom-doped variants using MD simulations. One of the critical findings was that heteroatom doping, particularly with boron and nitrogen, significantly enhances the adsorption and activation properties of graphene. The research revealed that B-doped graphene (BGR) exhibited superior catalytic activation performance for H₂O₂, while N-doped graphene (NGR) showed better activation properties for PMS. The study employed MD simulations to analyze the distribution of H₂O₂ and PMS on the surface of both graphene and heteroatom-doped graphene. This approach allowed the team to ascertain the stability and efficiency of these interactions. For instance, the equilibrium structure analysis of H₂O₂ on the surface of these materials demonstrated that BGR offers the most stable adsorption system. Similarly, in the case of PMS, NGR provided a more stable adsorption environment. These findings were further substantiated by the calculated interaction energies, which indicated that BGR and NGR had stronger interactions with H₂O₂ and PMS, respectively.

Currently, in the quantification of small molecules, the optimization of graphene dopants involves a substantial amount of experimental and theoretical computation work, but these methods are largely conducted independently. If more research could integrate computational and experimental approaches, it would significantly enhance our ability to efficiently design graphene-based sensors tailored for specific small molecules. This integrated approach would not only improve the efficiency and sensitivity of the sensors but also better bridge the gap between theoretical predictions and practical applications.

6. Challenges and Future Directions

A primary challenge in the application of doped graphene is the scalability of the doping process. While laboratory experiments have demonstrated the efficacy of doped graphene, replicating these results on an industrial scale remains problematic. This issue is compounded by difficulties in maintaining consistency and reproducibility in the doping process. Variables such as dopant concentration, distribution, and the precise control of doping conditions often vary, leading to inconsistencies in sensor performances. Addressing these challenges requires the development of standardized and robust doping methodologies that can be reliably scaled up.

The long-term stability of doped graphene sensors in real-world applications is another significant challenge. Factors such as environmental conditions, operational wear, and the potential for dopant leaching or degradation can impact sensor longevity and reliability. Furthermore, there are environmental concerns regarding the synthesis and disposal of doped graphene materials. The use of toxic chemicals in doping processes and the potential ecological impact of graphene waste are issues that need urgent attention. Research focused on developing eco-friendly doping processes and biodegradable graphene materials could be a viable solution.

The future of graphene doping in electrocatalysis is likely to witness several emerging trends. One promising area is the exploration of new dopants and doping combinations that could offer enhanced or novel electrocatalytic properties. The integration of artificial intelligence and machine learning in the doping process could lead to more precise and optimized doping configurations. Another trend is the focus on multifunctional doped graphene materials that can perform a range of tasks, from sensing to energy storage, thereby increasing their applicability in various fields.

Future research should prioritize the development of a deeper understanding of the interaction mechanisms between doped graphene and target analytes. This understanding is key to enhancing selectivity and sensitivity in sensors. Strategic development in the field should also include a focus on the commercialization and practical application of these sensors, ensuring that they are not only effective in a laboratory setting but also viable in real-world scenarios. Collaborations between academia, industry, and regulatory bodies will be crucial in addressing these challenges and steering the research towards practical and sustainable solutions.

Computational methods like DFT and MD simulations continue to hold significant importance. Addressing the scalability issues in doped graphene production and application requires not just experimental advancements but also computational insights. Advanced simulations can aid in predicting the outcomes of large-scale doping processes and in understanding the complexities involved in maintaining consistency and reproducibility. Furthermore, computational models can be pivotal in evaluating the long-term stability and environmental impacts of doped graphene materials, thus guiding the development of more sustainable and robust doping methodologies. As we move towards integrating artificial intelligence and machine learning with these computational techniques, there is potential for more precise, efficient, and innovative approaches in overcoming the current challenges and in exploring new directions in the field of graphene doping.

7. Conclusions

In conclusion, the optimization of graphene dopants for the electrocatalytic quantification of small molecules and ions marks a significant stride in both the scientific and technological realms. The unique properties of graphene, such as high electrical conductivity, extensive surface area, and remarkable mechanical strength, are enhanced through various doping techniques, broadening its applications in electrocatalysis. While nitrogen, boron, sulfur, and metallic dopants have been shown to improve graphene’s sensitivity and specificity in detecting small molecules, challenges like scalability, reproducibility, and long-term stability persist. Computational methods like DFT and MD simulations play a crucial role in understanding the doping mechanisms and predicting outcomes. Looking ahead, the integration of artificial intelligence and machine learning with experimental and computational approaches promises more precise and efficient doping strategies. As research continues to evolve, the future of doped graphene in electrocatalysis is poised to bridge the gap between laboratory research and practical applications, with a focus on sustainable and eco-friendly practices.