Introduction

The hydrochlorination of alkenes dates back to its discovery by Markovnikov in 1869, who formulated the "Markovnikov rule" as follows: "Experience shows that the halide adds to the least hydrogenated carbon, that is, to the one most susceptible to the influence of other carbon units” . In the 1960s and 1970s, various research groups conducted detailed investigations into the kinetics and stereochemistry of hydrochlorination reactions. However, both aspects are highly dependent on the reaction conditions and substrates, and no general conclusions could be drawn . Research activity in this field remained relatively dormant until the early 1990s when Kropp's pivotal paper on the surface-mediated hydrochlorination of unactivated alkenes reignited interest . Since then, continuous efforts have been made to enhance the generality, efficiency, and functional group tolerance of hydrochlorination reactions. Recently, several groups reported on metal-catalyzed radical hydrochlorinations and anti-Markovnikov hydrochlorination reactions, highlighting the ongoing challenges in achieving a simple addition of HCl across a simple double bond. During our literature review for this article, we identified two other significant reviews focusing on hydrochlorination reactions. Firstly, an outstanding overview, including extensive research from the former Soviet Union, was reported in 1982 by Sergeev and co-workers . Secondly, the chapter on “Addition of H-X Reagents to Alkenes and Alkynes” in comprehensive organic synthesis gives a great overview of hydrochlorinations which were reported between 1940–1980 . Thirdly, Yang and co-workers presented a mini-review on recent hydrochlorinations in 2021 . In this review, hydrochlorination reactions from 1990 to 2023 are comprehensively covered, including several earlier reports to provide a better overall understanding.

The hydrochlorination of alkenes can be categorized into three main classes (Scheme 1; only a terminal alkene is shown as a substrate, although polysubstituted and conjugated alkenes can also serve as substrates). 1) Polar reactions: These involve the protonation of the alkene in the first step, providing a carbocation that subsequently reacts with a chloride anion to yield the Markovnikov product. While this ionic mechanism is commonly illustrated in textbooks by showing “naked” cations as intermediates, several recent studies suggest a molecular concerted or simultaneous mechanism . 2) Radical hydrochlorinations: These reactions involve the in situ formation of a carbon-centered radical, which is then trapped by an appropriate chlorine source. 3) anti-Markovnikov products: This category describes a new field in hydrochlorination reactions leading to anti-Markovnikov products via several pathways. We have chosen not to present a fourth class of reactions involving either HCl gas or CuCl2 and a Pd catalyst, as reported by Alper and Sigman , as these reactions are somewhat exotic and are sufficiently discussed in Yang’s review .

Scheme 1: Classes of hydrochlorination reactions discussed in this review.

It is important to note that we are not aware of any catalytic enantioselective hydrochlorination reactions of alkenes. Conjugate additions of HCl to a complex of α,β-unsaturated acids, incorporated in an α-cyclodextrin, which corresponds to a formal hydrochlorination was reported by Tanaka and co-workers . Recently, Jacobsen reported asymmetric Prins cyclizations with HCl solutions . Hence, all the described hydrochlorinations are racemic or diastereoselective reactions.

Review Polar hydrochlorination reactions

To comprehend polar hydrochlorination reactions, a solid understanding of alkene reactivity is essential. Two reactivity scales for alkenes are available in the literature, one considering the reactivity of the alkene itself (Mayr scale) and the other the stability of the corresponding cation after protonation (hydride affinities) . In the polar hydrochlorination reaction, the protonation of the alkene is the rate-determining step. This process can be viewed as the reaction between a nucleophile (alkene) and an electrophile (proton). According to the Mayr–Patz equation log(k) = s(N + E), the second order reaction rate constant k at 20 °C for a reaction is related to the electrophilicity parameter E, the nucleophilicity parameter N, and a nucleophile-dependent slope parameters . The nucleophilicity parameter N, as proposed by Mayr, provides a dependable estimation of the reactivity of a given nucleophile, such as an alkene in our case (Figure 1). Conveniently, these parameters are freely available on Mayr's database of reactivity parameters .

Figure 1: Mayr’s nucleophilicity parameters for several alkenes. References for each compound can be consulted via the database.

On the other hand, one can assess the stability of the in situ-generated cation. The greater its stability, the easier the protonation of the alkene will be, making it more reactive towards hydrochlorination. Thermodynamic and theoretical data provide hydride affinities, which correspond to the negative heat of formation for the combination of a hydride anion with a given cation in the gas phase (Figure 2) .

Figure 2: Hydride affinities relating to the reactivity of the corresponding alkene towards hydrochlorination.

It is noteworthy that, in contrast to the hydride affinity scale, the Mayr scale considers energetic differences among alkenes. As demonstrated in the case of methylcyclopentene (Figure 1), the nucleophilicity of the exo-double bond is higher compared to the internal double bond. The higher energy of exo-alkenes compared to internal alkenes is well known and attributed to a less-effective hyperconjugation of C–H bonds into the alkene π-bond .

Before reviewing polar hydrochlorination reactions in detail, it is worth mentioning several statements which were made in the Sergeev review : a) The activation energy for an anti-Markovnikov addition is at least by 30 kJ mol−1 higher than for normal addition. Therefore, anti-Markovnikov products are generally not observed. b) In contrast to the reactions with HBr (peroxide effect) , the formation of anti-Markovnikov products is low even in the presence of peroxides or photochemical activation. For instance, Whitmore and co-workers observed only 10–25% of the primary chloride for the reaction of tert-butylethylene with HCl in the presence of benzoyl peroxide . c) Several metal halides such as AlCl3, SnCl4, FeCl3, and CuCl exhibit catalytic activities for the hydrochlorination of alkenes. The enthalpy of formation for the hydrogen chloride metal halide complexes are −6 kJ mol−1 for SnCl4, −8 kJ mol−1 for BiCl3, −9 kJ mol−1 for ZnCl2, −15 kJ mol−1 for CdCl2, −16 kJ mol−1 for FeCl3, and −41 kJ mol−1 for AlCl3. d) Addition of chloride-containing salts (e.g., LiCl) accelerate the reaction. e) Traces of water can increase the rate of the reaction.

In light of the numerous research articles on polar hydrochlorination reactions, we have categorized the reports based on the source of HCl (Scheme 2). The first section covers reactions involving HCl gas, typically supplied from an HCl gas cylinder. The second section explores reactions involving the in situ-formation of HCl gas. Lastly, the third section discusses reactions using an aqueous solution of HCl (hydrochloric acid). It is crucial to emphasize the distinction between hydrochloric acid and HCl (gas) or HCl solutions in apolar solvents, as HCl molecules in hydrochloric acid are predominantly dissociated into H3O+ and Cl−. Recent studies by Jacobsen suggest a similar dissociation of HCl for ethereal HCl solutions, which are better described as HEt2O+ and Cl−.

Scheme 2: Distinction of polar hydrochlorination reactions.

Reactions with HCl gas

Hydrochlorination reactions with HCl gas were predominant in the field until the 1990s. Generally, HCl gas was bubbled through neat alkene 1 for several hours, as depicted in Scheme 3A . This example highlights an intriguing regioselectivity that might have been challenging to predict through a simple analysis of the stability of the corresponding cations.

Scheme 3: Reactions of styrenes with HCl gas or HCl solutions.

Alternatively, the HCl gas was bubbled through a solution of the alkene in diethyl ether at 0 °C or rt (Scheme 3B and 3C) . Despite its effective reaction with styrene (3), the reaction displayed sluggish reactivity with 1-propenylbenzene (5). It is noteworthy, that the following HCl solutions are commercially available: 4.0 M in dioxane, 3.0 M in methanol, 3.0 M in 1-butanol, 2.0 M in diethyl ether, 3.0 M in cylopentyl methyl ether, 1.0 M in acetic acid.

Terminal aliphatic alkenes, such as prop-1-ene (7) do not react with HCl gas at rt and pressures of 1 atm or less (Figure 3A) . In contrast, higher pressures and temperatures significantly accelerate the reaction with aliphatic alkenes (Figure 3B) . A detailed mechanistic analysis for the hydrochlorination with (Z)-2-butene (9) was carried out by Dalton and co-workers . The reaction between (Z)-2-butene (9) and hydrogen chloride gas possesses an expected temperature dependence (higher temperature results in higher rates).

Figure 3: Normal temperature dependence for the hydrochlorination of (Z)-but-2-ene.

In 1966, Brown and co-worker reported a specialized apparatus enabling the monitoring and control of HCl gas consumption during the reaction . They observed full conversion of α-methylstyrene (11) within minutes and suggested that the hydrochlorination is operating within the rate of diffusion control (Figure 4). They also noted that the reaction was significantly slower at room temperature when compared to reactions carried out at 0 °C. However, reaction rates were exclusively reported at 0 and −45 °C, indicating an inverse temperature dependence. Brown also explored the influence of solvents (Figure 4). While reactions conducted in neat α-methylstyrene (11) or dichloromethane showed identical kinetics, the reaction was delayed when pentane was employed as a solvent.

Figure 4: Pentane slows down the hydrochlorination of 11.

The method of bubbling HCl gas through neat alkenes or solutions of alkenes remains a commonly employed approach, yielding high yields for styrene derivatives (Scheme 4) . The example by Theato is remarkable (Scheme 4A), who used HCl (gas) bubbled into neat alkene 13 for 5 hours, and obtained a relatively high yield of the monohydrochlorinated product 14 after distillation . Under these conditions, exclusive formation of the bis-hydrochlorinated product (not shown) might have been anticipated.

Scheme 4: Recently reported hydrochlorinations of styrenes with HCl gas or HCl solutions.

Several examples of the hydrochlorination of more complex molecules were reported (Scheme 5). Torii demonstrated the selective formation of chloride 20 when treating enone 19 with HCl/Et2O . This selectivity is notable, especially when compared to reports by other groups indicating the formation of the corresponding phenol derivative under prolonged reaction times (see Scheme 9). Honda reported a quantitative yield in the hydrochlorination of 21 with an ethereal solution of HCl, even in the presence of secondary alcohol and ester functionalities (Scheme 5B) . An application in the synthesis of Δ9-tetrahydrocannabutol, the butyl homologue of Δ9-tetrahydrocannabinol (Δ9-THC), is outlined in Scheme 5C . In this case, ZnCl2 was employed as a catalyst, but unfortunately data in the absence of ZnCl2 was not provided by the authors. ZnCl2 has been previously reported as a catalyst for hydrochlorination reactions, notably in the case of cyclooctene (25) with HCl in benzene (Scheme 5D) . The use of ZnCl2 as a catalyst for hydrochlorinations dates back to a patent by the British Oxygen Cooperation in 1956 . In 2012, Carreira reported the hydrochlorination of alkene 27, yielding racemic (±)- gomerone C (28) .

Scheme 5: Hydrochlorination reactions with di- and trisubstituted alkenes.

Grob observed that the stereochemistry of hydrochlorination reactions can be significantly influenced by the solvent or temperature (Table 1) . Using liquefied HCl gas, he predominantly obtained cis-30 for the hydrochlorination of 1,2-dimethylcyclohexene (29) (Table 1, entry 1), while solutions of HCl gas in ether favored trans-30 (Table 1, entry 2). A similar study, though with lower selectivities, had been conducted by Fahey earlier . In the presence of ammonium salts, a dilute solution of HCl in AcOH resulted in a 7:93 mixture of cis-30 and trans-30 (Table 1, entry 3), whereas an HCl solution in acetyl chloride produced a moderate 73:27 mixture (Table 1, entry 4).

Table 1: Stereoselective hydrochlorination of 1,2-dimethylcyclohexene (29).

Entry Reaction conditions cis-30 trans-30 1 HCl (liquid), −98 °C, 30 min 87 13 2 HCl/Et2O, 0 °C, 30 min 5 95 3 0.14 M HCl/AcOH (1.29 equiv), Me4NCl (16.6 equiv) 7 93 4 HCl/AcCl, 0 °C, 4 h 73 27

Grob also explored other bicyclic substrates such as octahydronaphthalene (31) and hexahydroindene 33 (Table 2 and Table 3). However, in the case of compound 31, the cis-selectivity was relatively low (Table 2, entry 1).

Table 2: Stereoselective hydrochlorination of octahydronaphthalene (31).

Entry Reaction conditions cis-30 trans-30 1 HCl (liquid), −98 °C, 30 min 64 36 2 HCl/Et2O, 0 °C, 30 min 2 98

Table 3: Stereoselective hydrochlorination of hexahydro-1H-indene (33).

Entry Reaction conditions cis-30 trans-30 1 HCl (liquid), −98 °C, 30 min 87 13 2 HCl/Et2O, 0 °C, 30 min 7 93

Recently, Frøyen and Skramstad studied the hydrochlorination of 1,2-disubstituted alkenes with HCl gas (Scheme 6) . Numerous unsuccessful attempts to hydrochlorinate fatty acids, even with the addition of ZnCl2 and LiCl as potential promoters, were reported. Finally, successful reactions conditions were found by using liquefied HCl gas (boiling point of HCl = −85 °C). The researchers concluded that the notable rate acceleration was attributed to the higher concentration of liquid HCl compared to gaseous HCl.

Scheme 6: Hydrochlorination of fatty acids with liquified HCl.

A systematic study of hydrochlorination reactions with concentrated solutions of HCl gas in DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone) was recently disclosed by Hammond and Xu (Scheme 7) . These solutions were prepared by bubbling HCl gas, generated from NaCl and H2SO4, into dry DMPU. This yields a 14 M solution of HCl in DMPU, a concentration significantly higher than HCl solutions in other organic solvents. Further enhancement of the reaction was achieved through the addition of acetic acid.

Scheme 7: Hydrochlorination with HCl/DMPU solutions.

The reaction displays broad generality and tolerates various sensitive functional groups, including aldehyde 45 and nitrile 46. However, electron-poor styrene, resulting in chloride 40, or terminal and 1,2-disubstituted alkenes forming chlorides 41–46 and cyclooctyl chloride (26) necessitated harsher reaction conditions.

As a side note, it should be mentioned that Hutchings and colleagues reported the hydrochlorination of ethylene with Lewis acids on solid supports . However, this work solely focuses on kinetic studies and is therefore not discussed in this report.

Reactions with in situ-generated HCl

HCl gas can be generated in situ through the reaction of "reactive" chlorides with a proton donor. For instance, the reaction of acetyl chloride with ethanol is exothermic, accompanied by vigorous HCl gas evolution. It is crucial to emphasize that HCl solutions in MeOH, produced from AcCl and MeOH, pose potential safety hazards, especially in large-scale reactions . Instead of acetyl chlorides, various other reagents, including pivaloyl chloride, oxalyl chloride, SOCl2, and TMSCl, can be employed to generate HCl. Numerous proton donors, such as water, alcohol, phenol, or acidic C–H groups, have been reported. In surface-mediated reactions, the proton donor is typically Si–OH or Al–OH. For clarity in discussing subsequent reactions, we have separated the in situ HCl gas synthesis from the hydrochlorination. It is important to note that these reactions are one-pot processes rather than two-pot reactions.

Yadav demonstrated that a mixture of 8 equivalents of acetyl chloride with an equimolar amount of ethanol efficiently hydrochlorinates several reactive alkenes (Scheme 8) . Electronic effects are noteworthy; p-methoxy-substituted styrene reacted within only 10 minutes to afford chloride 47, whereas no reaction was observed with p-chloro-substituted styrene (product 52). Geraniol chloride reacted rapidly but only with the more electron-rich double bond (product 49). 1-Methylcyclohex-1-ene was conveniently transformed into chloride 50 within 20 minutes at 0 °C. Limonene was fully hydrochlorinated affording chloride 51 as a mixture of cis- and trans-isomers. The hydrochlorination of 1,2-dimethylcyclohexene (29) resulted in high selectivity for trans-30. The authors also showed that an increase in ethanol to 40 equivalents led to a dramatic drop in yield, likely due to an overall lower concentration of HCl. No reaction was observed for terminal and 1,2-disubstituted alkenes such as cyclooctene (25) and 1-decene (53).

Scheme 8: Hydrochlorination with HCl generated from EtOH and AcCl.

Boudjouk and co-workers examined PCl3, SnCl4, SOCl2, SiCl4, Me2SiCl2, and Me3SiCl as hydrogen chloride sources . They found that PCl3 and SnCl4 gave the desired hydrochlorination products in acceptable yields but that trimethylchlorosilane (TMSCl) was generally the most useful reagent (Scheme 9). The reactions were typically conducted at room temperature, as elevated temperatures led to a decrease in yield, and lower temperatures were prohibited by the freezing temperature of water. Under slightly more forcing conditions (5 equivalents of TMSCl and 5 equivalents of water), even 1-hexene and cyclohexene reacted successfully at room temperature to afford the corresponding products 56 and 57. Interestingly, Δ9,10-octaline gave exclusively the trans-product 32. The reaction with carvone necessitates careful observation of the reaction time. After 20 minutes, the desired product 58 and only traces of 59 were observed, whereas after 3 h of reaction time 59 was the exclusive product . The method was also recently applied for the synthesis of a derivative of the natural product dictyophlebine (60) . Surprisingly, the reported hydrochlorination conditions for the synthesis of 60 differ significantly from the original protocol by Boudjouk (2500 equivalents of H2O instead of 1.5 equiv).

Scheme 9: Hydrochlorination with HCl generated from H2O and TMSCl.

A surface-mediated hydrochlorination reaction was reported by Kropp and co-workers . They observed that silica gel and alumina, when thermally equilibrated (120 °C, 48 h), facilitated efficient hydrochlorinations when treated with HCl or reactive chlorides. A compelling demonstration of the potent role of silica gel is presented in Table 4. In the absence of silica gel, cycloheptene (61), when exposed to a concentrated solution of HCl in dichloromethane, did not show any reaction (Table 4, entry 1). Under the same conditions, in the presence of silica gel, they observed 97% conversion and a GC yield of 62% for chloride 62 (Table 4, entry 2). Further optimization identified thermally treated alumina and SOCl2 (2 equiv) as an ideal HCl precursor, affording the product 62 in a 94% yield with 100% conversion in only 18 minutes of reaction time (Table 4, entry 3).

Table 4: Hydrochlorination of cycloheptene (61).

Entry Conditions GC yield of 62 (%) 1 HCl in CH2Cl2 (sat.), 1 h, −78 °C 0 2 HCl in CH2Cl2 (sat.), SiO2 , 1 h, −78 °C 62 3 SOCl2, Al2O3, rt, 18 min 94

During their investigations, they discovered a correlation between the efficiency of the hydrochlorination reaction and the surface area of the silica gel or alumina. Ethereal solvents were found to yield hydrochlorination reactions only with highly reactive alkenes, such as pinene. Subsequent studies revealed the need to adapt the hydrochlorination procedure for each substrate (e.g., Table 5). For instance, the hydrochlorination of 1-octene (63) required a combination of alumina and oxalyl chloride (Table 5, entry 3). It should be noted that this reaction needs to be carried out under a well-ventilated hood due to the evolution of toxic carbon monoxide.

Table 5: Hydrochlorination of 1-octene (63).

Entry Conditions GC yield of 41 (%) 1 HCl in CH2Cl2 (sat.), 1 h, −78 °C 0 2 HCl in CH2Cl2 (sat.), SiO2, 1 h, −78 °C 47 3 (COCl)2 (2 equiv), Al2O3, rt, 1 h 97

Kropp and co-workers observed that the remaining 2% of the alkene was a mixture of E- and Z-octene (67) (Scheme 10). They also mentioned in a footnote that 2-chlorooctane (41) was contaminated by "some 3-chlorooctane” (68). The formation of regioisomers through hydride or alkyl shifts is a common occurrence in hydrochlorination reactions involving secondary cations (Scheme 10).

Scheme 10: Regioisomeric mixtures of chlorooctanes as a result of hydride shifts.

α-Branched alkenes are particularly prone to alkyl migrations which lead to more stabilized cations (Scheme 11). Thus, the hydrochlorination of tert-butylethylene (70) produces a mixture of 73 and the rearranged product 74. The rearrangement of 70 was previously reported by Stevens and Fahey .

Scheme 11: Regioisomeric mixtures of products as a result of methyl shifts.

Kropp and co-workers also investigated the stereoselectivity for the hydrochlorination of 1,2-dimethylcyclohexene (29) (Scheme 12) . They found a significant dependence of the stereoselectivity on the reaction time. After 1 minute a 88:12 cis-30/trans-30 ratio was observed which, after 2 hours reaction time, changed to the thermodynamic ratio of 23:77 of cis-30/trans-30. The reaction appears to be very robust in terms of scale as illustrated by several examples shown in Scheme 12. More recently, de Mattos applied the Kropp procedure to the delicate monohydrochlorination of limonene on a 50 mmol scale . Little racemization (<7%) of 77 occurred during the reaction. The simplicity of the Kropp protocol resulted in a report in the journal of chemical education .

Scheme 12: Applications of the Kropp procedure on a preparative scale.

Similar work was reported by Delaude and co-workers . They studied a series of zeolites for the hydrochlorination of alkenes with in situ-generated HCl on a solid support. They found that K10 montmorillonite gave good results for the hydrochlorination of 1-methylcyclohexene (78) with SOCl2 as the HCl source (Scheme 13). Surprisingly, they not only obtained the expected product 50 but also the regioisomer 79 (anti-Markovnikov product). One plausible explanation for this intriguing observation is that K10 and other zeolites may function both as Brønsted acids and radical initiators . Consequently, it is likely that both ionic and radical pathways are concurrently in operation.

Scheme 13: Curious example of polar anti-Markovnikov hydrochlorination.

The in situ generation of hydrogen chloride with AlCl3 and subsequent hydrochlorination reactions were reported in two instances as unexpected products. De Paolis observed the hydrochlorination of a terminal alkene 82 upon treatment with AlCl3 (Scheme 14A) . Very likely AlCl3 reacted with the acidic enol and gave in situ HCl gas which is responsible for the hydrochlorination. Tian and co-worker reported in a footnote that eugenol (82) when treated with AlCl3 gives the corresponding hydrochlorination product in a mixture with other products (Scheme 14B) . In this case the reaction of phenol with AlCl3 can be suspected as the source of HCl. Another example which lacks experimental details was reported by Li and co-workers (Scheme 14C) . Very likely this reaction was carried out in the presence of HCl gas as a catalyst loading of 10 mol % is certainly not enough to reach 87% yield.

Scheme 14: Unexpected and expected hydrochlorinations with AlCl3.

HCl gas can also be prepared ex-situ as demonstrated very recently by De Borggraeve and co-workers (Figure 5A) . In a first chamber (A) HCl (gas) was prepared from NaCl and H2SO4 which then was directed towards a second chamber (B) which contains the alkene under solvent-free conditions. The scope of this reaction (Figure 5B) is limited to reactive alkenes but provides very high yields (yields marked with an asterisk are NMR yields). The addition of DCl was also demonstrated by the use of D2SO4 instead of H2SO4.

Figure 5: Ex situ-generated HCl gas and in situ application for the hydrochlorination of activated alkenes (* = NMR yield).

Not surprisingly, as already discussed in section "Reactions with HCl gas", higher pressures of HCl gas gave more efficient reactions with alkene 88 (Table 6).

Table 6: Influence of the HCl gas pressure on the reaction yield.

Entry