Synthesis of Long-Chain Alkanoyl Benzenes by an Aluminum(III) Chloride-Catalyzed Destannylative Acylation Reaction

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Synthesis of Long-Chain Alkanoyl Benzenes by an Aluminum(III)

Chloride-Catalyzed Destannylative Acylation Reaction

Max Roemer,* Sinead T. Keaveney, and Nicholas Proschogo

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ABSTRACT: This paper describes the facile synthesis of haloaryl

compounds with long-chain alkanoyl substituents by the destannylative

acylation of haloaryls bearing tri-n-butyltin (Bu₃Sn) substituents. The

method allows the synthesis of many important synthons for novel

functional materials in a highly eﬃcient manner. The halo-tri-n-butyltin

benzenes are obtained by the lithium−halogen exchange of

commercially available bis-haloarenes and the subsequent reaction

with Bu₃SnCl. Under typical Friedel−Crafts conditions, i.e., the

presence of an acid chloride and AlCl₃, the haloaryls are acylated

through destannylation. The reactions proceed fast (<5 min) at low

temperatures and thus are compatible with aromatic halogen substituents. Furthermore, the method is applicable to para-, meta-, and

ortho-substitution and larger systems, as demonstrated for biphenyls. The generated tin byproducts were eﬃciently removed by

trapping with silica/KF ﬁltration, and most long-chain haloaryls were obtained chromatography-free. Molecular structures of several

products were determined by X-ray single-crystal diﬀraction, and the crystal packing was investigated by mapping Hirshfeld surfaces

onto individual molecules. A feasible reaction mechanism for the destannylative acylation reaction is proposed and supported

through density functional theory (DFT) calculations. DFT results in combination with NMR-scale control experiments

unambiguously demonstrate the importance of the tin substituent as a leaving group, which enables the acylation.

and elevated temperatures are required for the acylation to

proceed. However, these reaction conditions are incompatible

with many haloarenes as they do not withstand the harsh

conditions required. Reactivity versus stability considerations

are of huge importance in the design of synthetic strategies,

with the right balance between these two factors key to the

development of a useful methodology. Aromatic halogens tend

to react in the order I > Br > Cl > F in transition metal-

catalyzed cross-coupling reactions¹⁸therefore, the I and Br

derivatives are in many cases more desirable. However, this

high reactivity makes the I and Br derivatives more diﬃcult

synthetic targets as they are more prone to side reactions.

The steric bulk of the acylium species also inﬂuences the

reaction rate. Hence, acylation reactions involving bulkier or

longer alkyl chains tend to proceed more slowly compared to

those with shorter alkyl chains, thus making them more

diﬃcult synthetic targets. These factors are perhaps the main

reason for the lack of synthetic protocols toward many alkyl-

functionalized haloarenes. Alternatively, a number of function-

INTRODUCTION

■

Functionalized aromatic systems bearing alkyl chains are

important synthons for compounds with applications in

materials science,¹⁻⁴molecular electronics,⁵⁻⁸and catalysis.⁹

The self-assembly of organic or organometallic derivatives on

metal surfaces often utilizes long alkyl chains, which ensure the

alkyl-driven packing of self-assembled monolayers (SAMs).¹⁰

Chain length variation is a well-known approach to tune the

key parameters of physical−organic systems by subtly altering

the molecular packing in SAMs, e.g., to modulate tunneling

barriers in molecular electronic devices,¹¹⁻¹³solubility proper-

ties of organic semiconductors,⁴the hydrophobicity of hole

transport materials,³the intercrystallite ordering in semi-

conducting polymers,¹⁴and the colloidal stability in coated

metallic nanoparticles.¹⁵We recently attached catalytically

active Rh and Ir complexes via alkyl tethers of diﬀerent chain

lengths to carbon surfaces.⁹

The regioselective introduction of functionalized alkanoyl

groups into aromatic systems is a challenging task, which may

be addressed in some instances by Friedel−Crafts acylation

strategies.¹⁶However, the methodology is not entirely

compatible with reactive aromatic halogen substituents.

While electron-rich aromatic compounds can be acylated

using acid chlorides and typical Friedel−Crafts catalysts

easily,¹⁷it is diﬃcult to gain control over the position of the

acylation. Electron-withdrawing halogen substituents signiﬁ-

cantly deactivate aromatic systems; thus, long reaction times

Received: April 28, 2021

Published: June 21, 2021

https://doi.org/10.1021/acs.joc.1c00997

J. Org. Chem. 2021, 86, 9007−9022

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alized haloarenes have been prepared by ring opening reactions

of carbocyclic rings of diﬀerent size through Ir catalysis¹⁹and

light irradiation, with the halogenation of the formed alkyl

chain occurring simultaneously²⁰(Figure 1, top). Direct

reactions are underexplored with respect to the preparation of

long-chain-functionalized haloaromatic compounds.

Herein, we show that a tin-mediated methodology using

stoichiometric aluminum(III) chloride as the catalyst is

applicable for a broad scope of functionalized halobenzenes,

which enables the straightforward preparation of haloarenes

bearing alkanoyl groups of varying chain lengths. We were able

to engineer regioselectivity in the Friedel−Crafts reaction by

preinstalling a tin moiety, which serves as the leaving group.

Our methodology utilizes cheap and readily available

precursors without the use of precious metal catalysts.

RESULTS AND DISCUSSION

■

Syntheses of Tri-n-butyltin Precursors. The lithiation of

dihalobenzenes with n-BuLi and the subsequent in situ

reaction with tri-n-butyltin (Bu₃Sn) chloride aﬀord the

required organotin starting materials for many examples in

good yields (Table 1). Most compounds can be puriﬁed

Table 1. Preparation of Hal-tri-n-butyltin Benzenes by One-

Pot Lithiation/Stannylation

Figure 1. Strategies toward functionalized halobenzenes bearing long

alkyl chains.

transition metal-catalyzed acylation of aryl bromides is another

convenient strategy to access these types of compounds,²¹

which was also recently demonstrated to proceed in

combination with light irradiation.²²Some halobenzoyl

compounds have been prepared by the photochemical

hydroacylation of oleﬁns.²³Furthermore, the blocking of

carbon positions using unreactive methyl substituents allow

acylations to be directed to certain available positions, as

demonstrated for pentamethylbenzene,²⁴tetramethylben-

zene,²⁵and octamethylferrocenes.^26,27

a

Puriﬁed by short-path vacuum distillation unless stated otherwise.

Puriﬁed by column chromatography. This reaction was carried out

b

c

at −110 °C.

However, there are limited examples of the direct long-chain

acylation of haloarenes, as the majority of studies are restricted

to one substrate. The acylation of bromobenzene under

Friedel−Crafts conditions has been reported; however,

bromobenzene was used as solvent, and elevated temperatures

(50 °C) were required.²⁸1′-Functionalized iodoferrocenes

have been prepared by tin-mediated Friedel−Crafts reac-

tions,^29,30and we recently prepared two p-alkanoyl-function-

alized bromobenzenes using a tin-mediated Friedel−Crafts

methodology.⁹These compounds bear 11- and 6-bromoalka-

noyl chains and were intermediates in the synthesis of ligands

used to prepare catalysts, and provided the foundation for the

current study. Alternative routes to alkyl-functionalized

bromoarenes include the reaction of para- and meta-

bromobenzaldehydes with alkyl Grignard reagents and a

further stepwise modiﬁcation³¹and the reaction of bromo-

benzoyl chlorides with alkanyl cadmium compounds, which

proceed in the para-, meta-, and ortho-positions.³²

eﬃciently and in a chromatography-free manner by fractional

short-path vacuum distillation. We used a syringe pump to

control the rate of addition of both n-BuLi and Bu₃SnCl. We

chose para-ﬂuoro- and para-chlorobromobenzene as starting

materials for the ﬂuoro and chloro derivatives, which aﬀorded

the ﬂuorinated product 1a and the chlorinated product 1b in

isolated yields of 51% and 93%, respectively. Dibromo- and

diiodobenzenes aﬀord for the para- and meta-substituted

derivatives (1c−1f) in isolated yields of 43−79%.

The treatment of 1,2-dibromobenzene under the standard

reaction conditions did not result in formation of ortho-bromo-

tri-n-butyltinbenzene (1g) but instead in the formation of a

biphenylbromostannane (1h) in a good yield (Scheme 1). The

formation of 1h likely occurs through aryne generation from

ortho-bromolithiobenzene by the elimination of LiBr and the

reaction of the highly unstable intermediate with remaining the

ortho-bromolithiobenzene and a subsequent reaction with

Bu₃SnCl. Aryne intermediates have been proposed in other

works and applied for the preparation of biphenyl

systems.³⁸⁻⁴⁰For the system under investigation here, we

Tin-mediated reactions involving destannylation in the

presence of aluminum(III) chloride have also been employed

for the synthesis of benzoylic aryls,³³⁻³⁵benzamides,³⁶

cyclopropanes,³⁷and acetyl aryls.³⁵However, tin-mediated

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Destannylative Acylation Reactions. Having a number

of organotin precursors in hand, we tested them for tin-

mediated Friedel−Crafts reactions. Bu₃Sn halobenzenes show

excellent reactivities toward acylation under Friedel−Crafts

type reaction conditions at low temperatures. The Bu₃Sn group

activates the ring carbon position of the aryl to which it is

attached, directing the acylation to this position. The tin group

serves as a very good leaving group, which is removed during

the reaction. Our destannylative acylation procedure is facile at

low temperature (−78 °C) and is applicable for a wide range of

halobenzenes, producing the otherwise diﬃcult to access long-

chain haloaromatic compounds in good yields (Table 2). Our

methodology is compatible with the range of diﬀerent halogens

(e.g., F, Cl, Br, and I), thus overcoming the reactivity problems

of haloaromatic compounds toward acylation. Importantly,

preinstalling the Bu₃Sn group in the para-, meta-, or ortho-

position results in eﬃcient acylation at this position

(compounds 2i−2m). This designation of a speciﬁc carbon

atom also worked in the biphenyl systems (compounds 2n−

2p) for which regioselectivity would be even more diﬃcult to

achieve when using unsubstituted precursors.

Scheme 1. Formation of a Biphenylbromostannane after the

Attempted Lithiation of 1,2-Dibromobenzene

propose a mechanism for the formation of 1h that is analogous

to the previous proposals,^38,41which involves the formation of

(2′-bromo-[1,1′-biphenyl]-2-yl)lithium that then reacts with

Bu₃SnCl (Scheme 2).

Scheme 2. Proposed Mechanism for the Formation of 1h

While a few select examples of the acylation or benzoylation

of bromo- and chlorobenzene in the para-position have been

reported, as discussed in the introduction, it is much more

diﬃcult to direct the acylation to the ortho- and meta-positions.

Further to this, our method is applicable to functionalized

alkanoyl groups bearing the terminal Br, which would not be

compatible with Grignard or alkyl−metal precursors.

It has previously been demonstrated that tin byproducts can

be eﬃciently trapped by KF/silica ﬁltration.^9,30,44−46This

simple ﬁltration step removes the organotin residues to the

extent that they are not detectable by NMR spectroscopy, with

reported values in the parts per million range.^44,45The

procedure was eﬀective for the puriﬁcation of 2a−p, and we

conclude that our protocol is compatible with the very low tin

residues required for biological screening and healthcare

applications.⁴⁴After aqueous workup and the removal of the

tin byproducts, many products can simply be recrystallized.

The recrystallization is particularly important for the iodo- and

bromo derivatives as the products were accompanied by some

dehalogenated and destannylated side products (see additional

details below), accounting for the moderate yields observed in

some cases. These could not be removed by column

chromatography but were easily removed by recrystallization.

In contrast, these impurities were not observed in signiﬁcant

amounts for the biaryl bromides 2n−p, which were successfully

puriﬁed by column chromatography on silica gel. It should be

noted that some mass was also lost during recrystallization;

however, recrystallization was the puriﬁcation technique of

choice as it was simple and eﬀective.

Intrigued by the fast and eﬃcient introduction of the

alkanoyl groups using this method, we tested the functionaliza-

tion in multibatch reactions by pre-preparing the acylium

reagent for several batches of diﬀerent organotin compounds.

Indeed, using one batch of alkanoyl chloride and simply

injecting it into diﬀerent reaction vessels subsequently by

syringe pump led to an optimized work-ﬂow, which allowed

the rapid synthesis of three new compounds (2e, 2f, and 2h),

in less than 6 h.

To further support this hypothesis, we lowered the amount

of Bu₃SnCl from 1.10 equiv to 0.55 equiv. We note that the

yield of the reaction remains unchanged, which suggests that

(2′-bromo-[1,1′-biphenyl]-2-yl)lithium is indeed the inter-

mediate. The formation of 1h in such high yield implies a

signiﬁcant amount of ortho-bromolithiobenzene to be present

either in the reaction mixture or as a transient species over the

course of the reaction. The monolithiation of 1,2-bromoben-

zene has been reported in an excellent yield in THF/ether

(1:1) at −110 °C, and the latter was used for a reaction with a

number of electrophiles.⁴¹In addition, our target compound

1g was previously prepared from the same reagents in THF

using a ﬂow microreactor,^42,43with short residence times that

allowed high yields to be achieved at a temperature of −78 °C.

With these insights in mind, we decreased the addition

amount and reaction time of the n-BuLi with 1,2-

dibromobenzene before the addition of Bu₃SnCl and lowered

the temperature to -110 °C. Indeed, these changes led to a

high yield of 1g (Scheme 3). Therefore, we conclude that 1,2-

bromolithiobenzene is suﬃciently stable in pure THF at −110

°C to be used as a versatile reagent. We are delighted to note

that the procedure also works well in THF on a macroscopic

scale using standard Schlenk techniques in combination with a

syringe pump.

Scheme 3. High-Yield Preparation of ortho-

Bromolithiobenzene at Low Temperature and the

Subsequent Conversion to (2-Bromophenyl)tri-n-

butylstannane (1g)

X-ray Single-Crystal Diﬀraction. To conﬁrm the

regiochemistry and product identity and analyze the crystal

packing, we elucidated molecular structures of four examples

by X-ray single-crystal diﬀraction (Figure 2). The three-

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Table 2. Scope for Destannylative Aluminum(III)-Catalyzed Acylation of Halo-tri-n-butyltin Benzenes

a

b

Isolated yield after recrystallization. Isolated yield after ﬂash chromatography on silica.

dimensional crystal packing is alkyl-dominated for all examples,

with alkyl chains in a straight alignment (Figures S5 and S6).

For the compounds with aromatic Cl, Br, and I atoms,

molecules were arranged head-to-tail in an interdigitated

manner with halogen−halogen interactions present between

the terminal alkyl bromide and the aromatic halide of another

adjacent molecule in the crystal. Comparable packing was

observed in glycolipids bearing 11-carbon alkyl chains.⁴⁸The

bromide−halogen distance Br−X (where Br is the alkyl Br and

X is the aromatic halogen Cl, Br, or I) is near to the sum of the

van der Waals radii of the atoms, i.e., 3.6 Å for Br−Cl, 3.7 Å for

Br−Br, and 3.8 Å for Br−I. The packing is diﬀerent for the

ﬂuorine-containing derivative 2a, as the molecules align head-

to-head in the crystal with two molecules in the asymmetric

unit oriented at diﬀerent angles and F atoms pointing toward

each other.

We have visualized the interactions of the molecules in the

crystals by mapping Hirshfeld surfaces onto molecules of 2a,

2b, 2d, and 2i in the crystal using the CrystalExplorer

program⁴⁹(Figure 3). The Hirshfeld surfaces were constructed

with isovalues of 0.5 e au⁻³and a standard d_evs d_ianalysis (d_e

stands for nearest atoms outside the surface, d_istands for

nearest atoms inside the surface). Contacts that are shorter

than the sum their van der Waals radii are shown in red

intensities, while longer contacts are shown in blue

intensities.^50,51All molecules exhibit weak intramolecular

hydrogen bonding interactions between the CO group and

alkyl H atoms of a neighboring molecule, which manifest in the

observed red intensities in the proximity of the CO groups.

Furthermore, 2a shows intramolecular H bonding between the

F atom and an aromatic H atom of another molecule, with two

molecules aligned pairwise (Figure 3). The Br derivative 2i

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exhibits weak intermolecular interactions between the aromatic

Br and the terminal Br of another molecule, while 2b does not

show red intensities involving the Cl atom. In contrast, the I

derivative 2d shows a more pronounced intermolecular

interaction between the aromatic I and the terminal Br.

Mechanistic and Theoretical Studies. To further

highlight the key role that the SnBu₃group plays in achieving

eﬃcient acylation, we conducted density functional theory

(DFT) calculations, NMR-scale acylation experiments involv-

ing several organostannanes, and NMR-scale control experi-

ments involving conventional halobenzenes. To gain insight

into the origin of the high reactivity observed for the tin-

mediated Friedel−Crafts acylation reaction, DFT calculations

were performed at the CPCM (DCM) M06L/def2TZVP//

ωB97X-D/6-311+G(d,p)+LanL2DZ level of theory, which is

similar to those used in previous studies on Friedel−Crafts

acylation.^52,53AlCl₃is known to readily form dimeric Al₂Cl₆in

solution, and it has been shown that acylium ion generation is

more favorable for Al₂Cl₆than AlCl₃.^54,55Hence, Al₂Cl₆was

used in our DFT studies. To probe how the organotin group

aﬀects the reactivity, we chose to examine the reaction of acetyl

chloride, Al₂Cl₆, and either ﬂuorobenzene or (4-ﬂuorophenyl)-

trimethylstannane in dichloromethane using the established

Friedel−Crafts acylation mechanism,⁵³which involves the

generation of acylium^56,57and Wheland^17,58intermediates. It

should be noted that acetyl chloride and the Me₃Sn group were

chosen to reduce the number of possible conformers compared

to the long-chain alkanoyl chlorides and the Bu₃Sn group that

were used experimentally.

Figure 2. Molecular structures of the halobenzenes 2a, 2b, 2d, and 2i

as determined by X-ray single-crystal diﬀraction. Ellipsoids are shown

at a 50% probability level. H atoms have been omitted for clarity.

Molecular graphics were generated using the OLEX2⁴⁷software.

Larger thermal ellipsoids plots are also included in the Supporting

Information (Figures S1 −4).

The ﬁrst step of the reaction is the generation of the acylium

ion through Al₂Cl₆-assisted Cl abstraction from acetyl chloride.

The calculated reaction pathways for ﬂuorobenzene (Figure

4a) and (4-ﬂuorophenyl)trimethylstannane (Figure 4b) show

that the Gibbs free energy of activation for acylium ion

formation is the same (TS1, 17.9 kcal mol⁻¹) for both, with

concerted Al−Cl bond formation and Al−O bond cleavage

occurring. The generated acylium ion (Int1) is stabilized by

Al₂Cl₇through C−Cl interactions (∼3 Å). It should be noted

that in our experiments the acylium species is ﬁrst generated in

DCM and then added to a solution containing the haloarene.

As such, the energy for acylium ion formation is not relevant

when considering the reactivity diﬀerences between ﬂuoro-

benzene and (4-ﬂuorophenyl)trimethylstannane and was

simply included for completeness. The electrophillic addition

of the acylium ion to ﬂuorobenzene (TS2-H) then occurs with

a Gibbs free energy of activation of 11.7 kcal mol⁻¹, which is

higher than the 8.3 kcal mol⁻¹barrier observed for electro-

phillic addition to (4-ﬂuorophenyl)trimethylstannane (TS2-

SnMe₃).

From this point, the reaction pathways diverge. For

ﬂuorobenzene, the expected Wheland intermediate forms

(Int2-H), followed by Al₂Cl₇-mediated hydrogen atom

abstraction (TS3-H) and a subsequent rearrangement to

generate the Al-coordinated product (−15.3 kcal mol⁻¹) as

anticipated. Interestingly, the expected Wheland intermediate

was unable to be located for (4-ﬂuorophenyl)trimethyl-

stannane. Tracing the intrinsic reaction coordinate indicated

that concerted electrophilic addition and SnMe₃abstraction

occur and lead to Int4-SnMe₃(−26.5 kcal mol⁻¹), which

features a C−Sn interaction of 3.08 Å. The combination of the

low Gibbs free energy of activation (8.3 kcal mol⁻¹) and the

signiﬁcant thermodynamic driving force for Int4-SnMe₃

formation makes SnMe₃is an excellent leaving group. The

Figure 3. Calculated Hirshfeld surfaces for 2a, 2b, 2d, and 2i from

data obtained from X-ray single-crystal diﬀraction. The Hirshfeld

surfaces were generated using the CrystalExplorer⁴⁹software.

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Figure 4. DFT computed energy proﬁles of two model reactions. (a) Friedel−Crafts acylation of ﬂuorobenzene. (b) Tin-mediated acylation of

trimethyl(4-ﬂuorophenyl)stannane. Gibbs free energies are reported in kilocalories per mole.

interaction between Sn and Al₂Cl₇(Sn−Cl length of 2.64 Å)

results in a more stable intermediate (Int3-SnMe₃, −33.1 kcal

mol⁻¹), and subsequent Sn−Cl bond formation leads to the

very stable Al-coordinated product (−52.9 kcal mol⁻¹). Both

Int3 and the product were substantially more stable for the tin-

mediated pathway, suggesting that Sn−Cl bond formation is

highly favorable.

Overall, our DFT studies suggest that there are two factors

that contribute to the tin-mediated reaction being highly

eﬃcient. First, the organotin substituent is an excellent leaving

group, resulting in concerted electrophillic addition and SnMe₃

abstraction that are kinetically favored over the stepwise

mechanism observed for ﬂuorobenzene. Second, Sn−C bond

breaking and Sn−Cl bond formation are highly favorable,

resulting in a substantial thermodynamic driving force that is

exempliﬁed by the marked diﬀerence in product stabilities, i.e.,

−15.3 kcal mol⁻¹when HCl is present and −52.9 kcal mol⁻¹

when Me₃SnCl is present.

NMR-Scale Control Experiments. To gain further insight

into the reaction mechanism and potential byproduct

formation, we examined the reaction between 11-bromounde-

canoic acid chloride and a variety of organostannanes (p-

XPhSnBu₃, where X = F (1a), Cl (1b), Br (1c), and I (1d)) in

CD₂Cl₂using NMR spectroscopy. Analogous to the prepara-

tive scale reactions, we prepared the acylium species from the

acid chloride and AlCl₃in CD₂Cl₂and added it slowly to a

solution of p-XPhSnBu₃in CD₂Cl₂. Without exposing it to air

and without aqueous workup, we analyzed the crude reaction

1

mixtures using H and ¹³C NMR spectroscopy; ¹⁹F NMR

spectroscopy was used for the example with 1a as the starting

material. In all cases, the p-XPhSnBu₃starting material was

completely consumed after 5 min, and the air-sensitive p-

XPhCOR−AlCl₃complex was the major species present. A

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stoichiometric amount of Bu₃SnCl, which was identiﬁed

carbonyl oxygen until aqueous workup, at which point the

aluminum complex is hydrolyzed and the products 2 are

generated. However, the reaction can also proceed via pathway

b, resulting only in destannylation. As mentioned above, the

experiments on the NMR scale show that the amount of

halobenzene side products formed increases in the order F <

Cl < Br, I. This is in agreement with the electronic eﬀects of

the halogen substituents, i.e., the more electron-withdrawing

the substituent is, the less reactive the starting material is to

acylation and thus also destannylation. It should be noted that

while all reactions were performed using anhydrous CD₂Cl₂

and under an inert atmosphere, the anhydrous AlCl₃was used

as received without further puriﬁcation. The purity of

anhydrous AlCl₃is variable, and it may contain trace impurities

such as bound water,¹⁶which could be the source of the

proton required for the generation of the halobenzenes.

Alternatively, the CD₂Cl₂solvent may contain traces of acidic

species such as HCl, which could also be the origin of the

proton required.

1

unambiguously by H and ¹³C NMR spectroscopy, was also

present as expected. The NMR experiments also show that

destannylation, without acylation, occurs as side reaction,

aﬀording the halobenzenes, i.e., XPh (X = F, Cl, Br, and I) as

byproducts (Figures S7 and S8). This product ratio was

dependent on the rate at which the acylium species was added

to the tin precursors (see the Experimental Section). The

obtained ratios between the desired p-XPhCOR−AlCl₃

complexes and the halobenzene byproduct are shown in

Figure 5. The data show that destannylation without product

Noteably, Al coordination results in 0.2−0.4 ppm downﬁeld

1

shifts of the aromatic resonances in the H NMR spectra

compared to those of the pure products after aqueous workup

(Table 3). The ipso-carbons in the ¹³C NMR spectra are

1

Table 3. Selected H, ¹³C, and ¹⁹F NMR Chemical Shifts

(ppm) of the AlCl₃Complex Intermediates 2−AlCl₃and

Products 2 in Dichloromethane-d

Figure 5. Product ratios of the reactions involving tin precursors 1a−

d with undecanoic acid chloride and AlCl₃as determined by the

integration of aromatic resonances in the H NMR spectra. The blue

1

bars represent the yield of product intermediates 2a−d−AlCl₃and the

orange bars the yield of the halobenzenes. The reactions involving the

bromo and iodo derivatives produced small amounts of dehalo-

genated material as well.

compound

δ H_2/6

δ H_3/5

δ C₁

δ C₄

δ C₇

δ F

2a−AlCl₃

2a

2b−AlCl₃

2b

2c−AlCl₃

2c

2d−AlCl₃

2d

8.4

8.0

8.3

7.9

8.1

7.8

8.1

7.8

7.4

7.1

7.7

7.5

7.8

7.6

7.9

7.7

171

166

149

139

128

113

101

129

134

130

136

132

136

132

137

218

200

219

199

220

200

220

200

−89

−107

formation occurs in the order F < Cl < Br, I. As such, there are

the folowing two competing pathways: (a) destannylative

acylation, which results in the generation of the desired

products, and (b) destannylation, which leads to halobenzene

formation (Scheme 4).

For pathway a, we propose a mechanism analogous to the

well-known Friedel−Crafts mechanism,¹⁶as described above

in the DFT section. The AlCl₃remains coordinated to the

Scheme 4. Proposed Mechanism for (a) the Destannylative

shifted downﬁeld by 4−11 ppm, and the carbonyl carbon atom

is shifted by 20−21 ppm. Regarding product 2a, the singlet in

the ¹⁹F NMR spectrum is shifted downﬁeld by 28 ppm.

Selected NMR chemical shifts for the in situ characterized p-

XPhCOR−AlCl₃complex intermediates are reported in Table

3.

Acylation of Tri-n-butyltin Aryl Compounds and (b) the

a

Competing Pathway of Destannylation without Acylation

Lastly, an examination of the Friedel−Crafts acylation

reactions of ﬂuorobenzene and bromobenzene as control

experiments (page S7 in the Supporting Information) showed

that the acylation reaction proceeded poorly even when using

higher temperatures (rt) and extended reaction times (24 h),

with only 38% (2a−AlCl₃) and 5% (2c−AlCl₃) conversions

observed for the ﬂuoro- and bromo- derivatives, respectively,

compared to full consumption of the organostannanes and

higher yields of 88% (2a−AlCl₃) and 54% (2c−AlCl₃) that

were observed immediately after the addition of the acylium.

Overall, this experimental data, in combination with our DFT

studies, clearly demonstrate the central role that the SnBu₃

group plays in achieving the eﬃcient and selective acylation of

haloarenes.

a

In the mechanisms, AlCl₃is used for simplicity instead of dimeric

Al₂Cl₃.

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CONCLUSIONS

■

The tin-mediated Friedel−Crafts reaction is a versatile method

to obtain many alkanoyl-functionalized halobenzenes. We

show that the preparation of the organotin precursors is

straightforward, occuring by lithium−halogen exchange and

the reaction with the Bu₃SnCl electrophile. The destannylative

acylation reaction proceeds fast (<5 min) under mild

conditions (−78 °C), allowing the eﬃcient preparation of

ﬂuoro-, chloro, bromo-, and iodo-functionalized alkanoyl

arenes. We demonstrate that highly regioselective acylation

can be achieved at the para-, meta-, and ortho positions using

the organotin directing group. The methodology is independ-

ent from the alkyl chain length; thus, is highly versatile and

allows access to a diverse range of haloarenes with alkanoyl

substituents. DFT studies show that the high eﬃciency of our

methodology is due to the organotin species being an excellent

leaving group, resulting in concerted electrophilic addition and

SnR₃abstraction. Additionally, Sn−C bond breaking and Sn−

Cl bond formation are highly thermodynamically favorable.

general procedure described above. 1-Bromo-4-ﬂuorobenzene (3.0 g,

17.1 mmol) in THF (120 mL) gave a colorless oil after lithiation with

n-BuLi (11.3 mL, 18.0 mmol), a subsequent reaction with tri-n-

butyltin chloride (6.1 g, 18.9 mmol), and workup. Fractional vacuum

distillation (bp = 105−107 °C and 4.6−4.9 × 10⁻¹mbar) aﬀorded the

product as a colorless oil (3.35 g, 8.7 mmol, 51%) after the

1

redistillation of the main fraction. H NMR (400 MHz, CDCl₃): δ

7.50 (m, 2H), 7.10 (m, 2H), 1.64 (m, 6H), 1.42 (m, 6H), 1.15 (m,

6H), 0.98 (t, J_H−H= 7 Hz, 9H) ppm. ¹³C{¹H} (101 MHz, CDCl₃): δ

163.5 (d, J_C−F= 246 Hz, d, J_C−Sn= 5 Hz), 138.0 (d, J_C−F= 6 Hz, J_C−Sn

= 18 Hz), 136.8 (d, J_C−F= 4 Hz, J_C−Sn= 184 Hz, J_C−Sn= 192 Hz),

115.3 (J_C−F= 19 Hz, J_C−Sn= 22 Hz), 29.3 (J_C−Sn= 10 Hz), 27.5 (J_C−Sn

= 28 Hz), 13.8, 9.8 (J_C−Sn= 164 Hz, J_C−Sn= 171 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃): δ −113.6 (J_F−Sn= 8 Hz) ppm. ¹¹⁹Sn{¹H}

NMR (149 MHz, CDCl₃): δ −39.1 (d, J_Sn−F= 8 Hz) ppm.

Tri-n-butyl(4-chlorophenyl)stannane (1b). The title compound⁶³

was prepared from 1-bromo-4-chlorobenzene by the general

procedure described above. 1-Bromo-4-chlorobenzene (3.50 g, 18.2

mmol) in THF (120 mL) gave the crude product after lithiation with

n-BuLi (12.0 mL, 19.1 mmol), a subsequent reaction with tri-n-

butyltin chloride (6.56 g, 20.1 mmol), and workup. Fractional vacuum

distillation (bp = 128−132 °C and 3.8 × 10⁻¹mbar) aﬀorded the

EXPERIMENTAL SECTION

■

General. Reactions were conducted under argon atmospheres

using standard Schlenk techniques unless otherwise stated. Starting

materials and solvents were purchased from Sigma-Aldrich, AK

Scientiﬁc, Honeywell, and Merck. THF and dichloromethane were

puriﬁed using an LC Technology Solution Inc. solvent puriﬁcation

system and further dried by storage over 4 Å molecular sieves.

Dichloromethane-d was dried over 4 Å molecular sieves. NMR spectra

were recorded on Bruker AV NEO 300 and AVIIIHD 400 MHz

spectrometers. ¹³C NMR, ¹⁹F, and ¹¹⁹Sn NMR spectra were recorded

¹H-decoupled. NMR spectra were referenced to residual solvent

1

product (6.83 g, 17.0 mmol, 93%) as a colorless oil. H NMR (400

MHz, CDCl₃): δ 7.53−7.50 (m, 2H), 7.43−7.40 (m, 2H), 1.69 (m,

6H), 1.48 (m, 6H), 1.21 (m, 6H), 1.02 (t,J_H−H= 7 Hz, 9H) ppm.

¹³C{¹H} (75 MHz, CDCl₃): δ140.1 (J_C−Sn= 179 Hz, J_C−Sn= 187 Hz),

137.7 (J_C−Sn= 17 Hz), 134.5 (J_C−Sn= 7 Hz), 128.3 (J_C−Sn= 21 Hz),

29.2 (J_C−Sn= 11 Hz), 27.5 (J_C−Sn= 28 Hz), 13.8, 9.8 (J_C−Sn= 163 Hz,

signals for the ¹H and ¹³C spectra⁵⁹or to external to TMS for the ¹⁹

F

and ¹¹⁹Sn NMR spectra. Mass spectra were acquired on a Bruker

amaZon SL ion trap mass spectrometer with an atmospheric solid

analysis probe that was heated to 400 °C into an atmospheric pressure

chemical ionization source that was run in the positive ion mode

(APCI low resolution) and a Bruker Solarix 2xR 7T Fourier

Transform Ion Cyclotron Resonance mass spectrometer with an

atmospheric solid analysis probe that was heated to 400 °C into an

atmospheric pressure chemical ionization source that was run in the

positive ion mode (APCI high resolution). Melting points were

determined using a Mettler Toledo MP50 melting point system.

Injections with a syringe pump were performed with a New Era NE-

1000 syringe pump using grease- and rubber-free plastic syringes

(HENKE-JECT 2, 5, 10, 20, or 50 mL) equipped with 0.8 × 120 mm

needles (Braun). Silica gel used for ﬂash chromatography and

ﬁltrations was purchased from Merck (0.040−0.063 mm or 230−400

mesh).

J

_C−Sn= 171 Hz) ppm. ¹¹⁹Sn{¹H} NMR (149 MHz, CDCl₃): δ −38.7

ppm.

(4-Bromophenyl)tri-n-butylstannane (1c). The title compound

was prepared from 1,4-dibromobenzene^9,63by the general procedure

described above. 1,4-Dibromobenzene (7.00 g, 29.7 mmol) in THF

(300 mL) gave the crude product after lithiation with n-BuLi (19.4

mL, 11.1 mmol), a subsequent reaction with tri-n-butyltin chloride

(10.6 g, 32.6 mmol), and workup. Fractional vacuum distillation (bp

= 148−151 °C and 2.2−2.4 × 10⁻¹mbar) aﬀorded the product (9.81

g, 22.0 mmol, 74%) as a colorless oil. We previously reported the

analytical data.⁹

General Procedure for Preparation of the Tin Precursors.

The halobenzene (14.8 mmol) was dissolved in THF (150 mL) in a

Schlenk ﬂask, and the mixture was cooled to −78 °C. n-Butyllithium

(9.7 mL, 15.6 mmol, 1.05 equiv) was added slowly over 30 min under

stirring using a syringe pump. Stirring was continued for another 30

min before tri-n-butyltin chloride (5.32 g, 16.3 mmol) was added over

30 min using a syringe pump. The cooling bath was removed, and the

mixture was allowed to warm to room temperature. Water (150 mL)

was added to the mixture, and the mixture was transferred into a

separatory funnel. The mixture was extracted with hexane (3 × 200

mL). The combined organic layers were dried over MgSO₄, and

solvent evaporation aﬀorded a colorless oil that was subjected to

fractional short-way vacuum distillation. The slight excess of tri-n-

butyltin chloride was removed with the ﬁrst fraction, followed by the

collection of the product fraction. Alternatively, some of the tin

compounds were puriﬁed by chromatography on silica using hexane

as the eluent.

Tri-n-butyl(4-iodophenyl)stannane (1d). The title compound^63,64

was prepared from 1,4-diiodobenzene by the general procedure

described above. 1,4-Diiodobenzene (3.5 g, 10.6 mol) in THF (70

mL) gave the crude product after lithiation with n-BuLi (7 mL, 11.1

mmol), a subsequent reaction with tri-n-butyltin chloride (3.8 g, 11.8

mmol), and workup. Fractional vacuum distillation (bp = 148−151

°C and 2.2−2.4 × 10⁻¹mbar) aﬀorded the product (2.23 g, 3.4 mmol,

1

43%) as a colorless oil. H NMR (400 MHz, CDCl₃): δ 7.69 (dm,

J_H−H= 8 Hz, 2H), 7.23 (dm, J_H−H= 8 Hz, 2H), 1.58 (m, 6H), 1.38

(m, 6H), 1.10 (m, 6H), 0.93 (t, J_H−H= 7 Hz, 9H). ¹³C{¹H} NMR

(101 MHz, CDCl₃): δ 141.4 (J_C−Sn= 176 and 184 Hz), 138.2 (J_C−Sn

= 16 Hz), 137.0 (J_C−Sn= 20 Hz), 94.9 (J_C−Sn= 6 Hz), 29.2 (J_C−Sn

=

Tri-n-butyl(4-ﬂuorophenyl)stannane (1a). The title com-

10 Hz), 27.5 (J_C−Sn= 29 Hz), 13.8, 9.8 (J_C−Sn= 163 Hz, 171 Hz)

pound⁶⁰⁻⁶³was prepared from 1-bromo-4-ﬂuorobenzene by the

ppm. ¹¹⁹Sn{¹H} NMR (149 MHz, CDCl₃): δ −37.7 ppm.

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MHz, CDCl₃): δ 7.60−7.58 (m, 1HH), 7.46−7.43 (m, 1H), 7.34−

7.30 (m, 1H), 7.24−7.19 (m, 1H), 1.71 (m, 6H), 1.49 (m, 6H), 1.30

(m, 6H), 1.02 (t, J_H−H= 7 Hz, 9H) ppm. ¹³C{¹H} NMR (101 MHz,

CDCl₃): δ 146.7 (J_C−Sn= 173 and 181 Hz), 138.1 (J_C−Sn= 14 Hz),

133.5 (J_C−Sn= 7 Hz), 131.8 (J_C−Sn= 11 Hz), 130.0 (J_C−Sn= 4 Hz),

126.3 (J_C−Sn= 16 Hz), 29.0 (J_C−Sn= 10 Hz), 27.4 (J_C−Sn= 30 Hz),

13.7, 10.9 (J_C−Sn= 167 Hz, 175 Hz) ppm. ¹¹⁹Sn{¹H} NMR (149

MHz, CDCl₃): δ −25.8 ppm.

(3-Bromophenyl)tri-n-butylstannane (1e). The title compound⁶³

was prepared from 1,3-dibromobenzene by the general procedure

described above. 1,3-Dibromobenzene (3.5 g, 14.8 mol) in THF (70

mL) gave the crude product after lithiation with n-BuLi (9.7 mL, 15.6

mmol), a subsequent reaction with tri-n-butyltin chloride (5.3 g, 16.3

mmol), and workup. Fractional vacuum distillation (bp = 142 °C and

2.4 × 10⁻¹mbar) aﬀorded the product (5.25 g, 11.8 mmol, 79%) as a

colorless oil after the redistillation of the main fraction. ¹H NMR (300

MHz, CDCl₃): δ 7.57 (m, 1H), 7.43 (m, 1H), 7.38 (m, 1H), 7.20 (m,

1H), 1.54 (m, 6H), 1.35 (m, 6H), 1.08 (m, 6H), 0.90 (t, J_H−H= 7 Hz,

9H) ppm. ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 145.4 (J_C−Sn= 168

Hz, J_C−Sn= 176 Hz), 138.7 (J_C−Sn= 16 Hz), 134.8 (J_C−Sn= 14 Hz),

131.0 (J_C−Sn= 5 Hz), 129.7 (J_C−Sn= 21 Hz), 123.4 (J_C−Sn= 24 Hz),

29.1 (J_C−Sn= 10 Hz), 27.5 (J_C−Sn= 29 Hz), 13.8, 9.8 (J_C−Sn= 163 Hz,

(2′-Bromo-[1,1′-biphenyl]-2-yl)tri-n-butylstannane (1h). The title

compound was prepared from 1,2-diiodobenzene by a modiﬁed

general procedure. 1,2-Diiodobenzene (3.5 g, 14.8 mol) in THF (75

mL) gave the crude product after lithiation with n-BuLi (10 mL, 15.6

mmol), a subsequent reaction with tri-n-butyltin chloride (2.65 g, 8.2

mmol), and workup, which was subject to fractional vacuum

distillation. The main fraction (bp = 162−165 °C and 4.7−4.5 ×

10⁻¹mbar) contained the product, which was further puriﬁed by ﬂash

chromatography on silica using hexane as the eluent. The remaining

residue from the distillation was as well-puriﬁed by ﬂash

chromatography on silica using hexane as the eluent, aﬀording the

product as a colorless oil (combined yield of 2.57 g, 4.9 mmol, 66%).

¹H NMR (400 MHz, CDCl₃): δ 7.69−7.67 (m), 7.62- 7.57 (m),

7.39−7.34 (m), 7.31−7.20 (m), 1.45−1.22 (m), 0.91−0.56 (m),

J

_C−Sn= 171 Hz) ppm. ¹¹⁹Sn{¹H} NMR (149 MHz, CDCl₃): δ −40.8

ppm.

Tri-n-butyl(3-iodophenyl)stannane (1f). The title compound⁶³

was prepared from 1,3-diiodobenzene by the general procedure

described above. 1,3-Diiodobenzene (3.00 g, 9.1 mol) in THF (60

mL) gave the crude product after lithiation with n-BuLi (6 mL, 9.5

mmol), a subsequent reaction with tri-n-butyltin chloride (3.26 g, 10.0

mmol), and workup. The crude product was puriﬁed ﬁrst by fractional

vacuum distillation (bp = 148−149 °C and 4.4−2.3 × 10⁻¹mbar) and

then by ﬂash ﬁltration through a plug of KF/silica, eluting with

dichloromethane, to remove a small contamination in the product

fraction of tin residues, which had presumably formed from the

thermal decomposition of the product during the distillation

procedure. Solvent evaporation and drying under high vacuum

aﬀorded the product (2.57 g, 5.4 mmol, 57%) as a colorless oil. We

0.80−0.74 (m). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 149.2 (J_C−Sn

=

13 Hz), 145.6 (J_C−Sn= 8 Hz), 142.4, 136.9 (J_C−Sn= 15 Hz), 132.8,

131.4, 129.6 (J_C−Sn= 16 Hz), 128.9, 127.6 (J_C−Sn= 5 Hz), 127.1,

126.9 (J_C−Sn= 20 Hz), 124.1, 29.1 (J_C−Sn= 10 Hz), 27.5 (J_C−Sn= 30

Hz), 13.8, 10.3 (J_C−Sn= 163 and 170 Hz) ppm. ¹¹⁹Sn{¹H} NMR (149

MHz, CDCl₃): δ −37.8 ppm. MS (APCI) m/z: 465 [M − Bu + H]⁺

(100%). HRMS (APCI) m/z: [M − Bu + H]⁺Calcd for C₂₀H₂₆BrSn

465.0234, found 465.0235.

1

note that a small impurity was still visible in the ¹¹⁹Sn spectrum. H

NMR (300 MHz, CDCl₃): δ 7.67 (m, 1H), 7.49 (m, 1H), 7.29 (m,

1H), 6.91 (m, 1H), 1.44 (m, 6H), 1.24 (m, 6H), 0.97 (m, 6H), 0.79

(t, J_H−H= 7 Hz, 9H) ppm. ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 145.7

(J_C−Sn= 167 Hz, 175 Hz), 144.7 (J_C−Sn= 16 Hz), 136.9 (J_C−Sn= 5

Hz), 135.2 (J_C−Sn= 14 Hz), 130.0 (J_C−Sn= 14 Hz), 96.5 (J_C−Sn= 22

Hz), 29.1 (J_C−Sn= 5 Hz), 27.5 (J_C−Sn= 28 Hz), 13.8, 9.9 (J_C−Sn= 162

Hz, 170 Hz) ppm. ¹¹⁹Sn{¹H} NMR (149 MHz, CDCl₃): δ −39.2

ppm.

(4′-Bromo-[1,1′-biphenyl]-4-yl)tri-n-butylstannane (1i). The title

compound was prepared from 4,4′-dibromobiphenyl by the method

described above. 4,4′-Dibromobiphenyl (2.0 g, 6.4 mol) was reacted

with n-BuLi (4.2 mL, 6.7 mmol), followed by a reaction with tri-n-

butyltin chloride (2.20 g, 6.7 mmol). The crude oil was subject to

ﬂash chromatography on silica using hexane as the eluent, aﬀording

the product as a colorless oil (1.92 g, 3.7 mmol, 57%). ¹H NMR (400

MHz, CDCl₃): δ 7.70−7.61 (m, 6H), 7.56 (dm, J_H−H= 9 Hz), 1.72

(m, 6H), 1.51(m, 6H), 1.25 (m, 6H), 1.05 (t, J_H−H= 7 Hz, 9H) ppm.

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 141.6, 140.3, 139.6 (J_C−Sn= 5

Hz), 137.2 (J_C−Sn= 16 Hz), 132.0, 128.8, 126.5 (J_C−Sn= 21 Hz),

(2-Bromophenyl)tri-n-butylstannane (1g). The title compound⁴³

was prepared from 1,2-dibromobenzene by the following procedure. A

Schlenk ﬂask equipped with rubber septum and a magnetic stirring

bar was charged with 1,2-bromobenzene (1.17 g, 5.0 mol) and THF

(50 mL). The solution was cooled to −110 °C using an ethanol/

liquid N₂cooling bath. The solution was maintained at that

temperature for 5 min before n-BuLi (3.3 mL, 5.2 mmol) was

injected under vigorous stirring over 3 min using a syringe pump.

Stirring was continued for 5 min before a solution of tri-n-butyltin

chloride (2.59 g, 7.9 mmol) in THF (4 mL) was added over 3 min

using a syringe pump. Stirring was continued at −110 °C for 10 min.

Then, the cooling bath was removed, and the mixture was allowed to

warm to room temperature. Water (30 mL) was added, and the

mixture was extracted with hexane (3 × 100 mL), dried over

magnesium sulfate, and concentrated to dryness using a rotatory

evaporator. Flash chromatography over silica, using hexane as eluent,

aﬀorded the product as a colorless oil after solvent evaporation and

121.6, 29.3 (J_C−Sn= 10 Hz), 27.6 (J_C−Sn= 29 Hz), 13.9, 9.8 (J_C−Sn

=

163 and 170 Hz) ppm. ¹¹⁹Sn{¹H} NMR (149 MHz, CDCl₃): δ −40.9

ppm. MS (APCI) m/z: 465 [M − Bu + H]⁺. HRMS (APCI) m/z: [M

− Bu+ H]⁺Calcd for C₂₀H₂₆BrSn 465.0234, found 465.0235.

General Procedure for the Tin-Mediated Friedel−Crafts

Reactions. A Schlenk ﬂask was charged with the carboxylic acid (5.7

mmol) and dichloromethane (20 mL). Oxalyldichloride (1.45 mL, 17

mmol) was added while stirring at room temperature, followed by the

addition of two drops of DMF. The mixture was stirred for 45 min,

after which the gas evolution had ceased. The solvents and the excess

oxalyldichloride were removed under high vacuum, and the colorless

oily solids were redissolved in dichloromethane (50 mL), followed by

the addition of aluminum(III) chloride (0.776 g, 5.7 mmol). The

mixture was stirred for 10 min at room temperature. A second

Schlenk ﬂask was charged with the tin precursor (5.7 mmol) and

dichloromethane (50 mL), and the mixture was cooled to −78 °C

using a dry ice acetone bath. The acylium mixture was taken up with a

1

drying under high vacuum (2.06 g, 3.9 mmol, 78%). H NMR (400

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syringe and added slowly over 1 h under stirring to the solution using

a syringe pump. After the addition was complete, the cooling bath was

removed, and the mixture was allowed to warm to room temperature,

at which point water (100 mL) was added mixture. The workup was

conducted on air. Phases were separated, and the aqueous layer was

extracted twice with dichloromethane (100 mL). The combined

organic extracts were dried over MgSO₄and concentrated to dryness

using a rotary evaporator. The crude mixture was ﬂash-ﬁltered

through a short column (12 cm × 3 cm) ﬁlled with silica/KF (1:1/

vol) in the upper half and pure silica in the lower half using

dichloromethane as the eluent, which eﬃciently removed the tin

byproducts.^45,46The colorless elute was tested by TLC for completed

product elution. Solvent evaporation using a rotary evaporator gave a

colorless oil, which was recrystallized from pentane or pentane/DCM

to aﬀord the product as a white crystalline solid for most examples.

Alternatively, the obtained colorless oil was puriﬁed by column

chromatography on silica gel using hexane/ethyl acetate (9:1).

solution of the acid chloride in dichloromethane (25 mL) and

aluminum(III) chloride (415 mg, 3.1 mmol) was added to 1a (1.2 g,

3.1 mmol) in dichloromethane (50 mL) using a syringe pump.

Aqueous workup and ﬂash ﬁltration through KF/silica gave the crude

product as an oil. Solvent evaporation gave a white solid, which was

recrystallized from DCM/pentane to aﬀord the product as a white

crystalline powder (640 mg, 1.3 mmol, 44%). mp 98−99 °C. ¹H

NMR (400 MHz, CD₂Cl₂): δ 7.84 (dm, J_H−H= 9 Hz, 2H), 7.66 (dm,

J_H−H= 9 Hz, 2H), 3.42 (t, J_H−H= 7 Hz, 2H), 2.91 (t, J_H−H= 7 Hz,

2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.44−1.30 (brm, 12H) ppm.

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 199.9, 138.3, 136.9, 129.8,

100.8, 38.9, 34.6, 33.3, 29.81, 29.78, 29.65, 29.1, 28.6, 24.2 ppm. MS

(APCI) m/z: 453 [M + H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺

Calcd for C₁₇H₂₅BrIO 451.0128, found 451.0128.

Preparation of a Stock Solution for the Synthesis of Compounds

2e, 2f, and 2h. 16-Bromohexadecanoic acid (1.306 g, 3.9 mmol) was

converted to the corresponding acid chloride in dichloromethane (17

mL) using oxalyl dichloride (1.0 mL, 11.7 mmol) as described by the

general procedure above. A solution of the acid chloride in

dichloromethane (33 mL) and aluminum(III) chloride (519 mg,

3.9 mmol) was prepared and drawn up in a 50 mL syringe. The

solution was used for three diﬀerent batches for the preparation of 2e,

2f, and 2h; 11 mL of the solution was for each reaction. Between each

addition, the syringe pump was simply stopped and the new ﬂask was

added, allowing all three compounds to be readily synthesized.

11-Bromo-1-(4-ﬂuorophenyl)undecan-1-one (2a). 11-Bromoun-

decanoic acid (826 mg, 3.1 mmol) was converted to the

corresponding acid chloride in dichloromethane (10 mL) using

oxalyl dichloride (0.8 mL, 9.3 mmol) as described by the general

procedure above. A solution of the acid chloride in dichloromethane

(25 mL) and aluminum(III) chloride (415 mg, 3.1 mmol) was added

to 1a (1.20 g, 3.1 mmol) in dichloromethane (50 mL) using a syringe

pump. Aqueous workup and ﬂash ﬁltration through KF/silica gave the

crude product as an oil. Solvent evaporation gave a white solid, which

was recrystallized from DCM/pentane to aﬀord the product as a

white crystalline powder (678 mg, 2.0 mmol, 63%). mp 59−60 °C. ¹H

NMR (400 MHz, CD₂Cl₂): δ 7.98 (m, 2H), 7.14 (dm, 2H), 3.42 (t,

J

_H−H= 7 Hz, 2H), 2.93 (t, J_H−H= 7 Hz, 2H), 1.85 (m, 2H), 1.70 (m,

16-Fluoro-1-(4-chlorophenyl)-hexadecan-1-one (2e). The solu-

tion of 16-bromohexadecanoyl chloride and AlCl₃described above

(11 mL) was added to a solution of compound 1a (500 mg, 1.3

mmol) in dichloromethane (11 mL) using a syringe pump. Aqueous

workup and ﬂash ﬁltration through KF/silica gave the crude product

as an oil. Solvent evaporation gave a white solid, which was

recrystallized from DCM/pentane to aﬀord the product as a white

crystalline powder (333 mg, 0.8 mmol, 62%). mp 54−55 °C. ¹H

NMR (300 MHz, CDCl₃): δ 7.98 (m, 2H), 7.12 (m, 2H), 3.40 (t,

J_H−H= 7 Hz, 2H), 2.93 (t, J_H−H= 7.2 Hz, 2H), 1.85 (m, 2H), 1.72

(m, 2H), 1.44−1.26 (brm, 22H) ppm. ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 198.8, 165.6 (d, J_C−F= 254 Hz), 133.6 (d, J_C−F= 3 Hz),

130.7 (d, J_C−F= 9 Hz), 115.6 (d, J_C−F= 22 Hz), 38.6, 34.0, 32.9,

29.69, 29.67, 29.6, 29.55, 29.50, 29.4, 28.8, 28.2 ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃): δ −105.8 (s, 1F) ppm. MS (APCI) m/z: 415 [M

+ H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺Calcd for

C₂₂H₃₅BrFO 413.1850, found 413.1849.

2H), 1.44−1.31 (brm, 12H) ppm. ¹³C{¹H} NMR (101 MHz,

CD₂Cl₂): δ 199.0, 166.0 (d, J_C−F= 253 Hz), 134.2 (d, J_C−F= 3 Hz),

131.0 (d, J_C−F= 9 Hz), 115.9 (d, J_C−F= 22 Hz), 38.9, 34.6, 33.3.

29.84. 29.80, 29.7, 29.2, 28.6, 24.7 ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃): δ −109.9 (s, 1F) ppm. MS (APCI) m/z: 345 [M + H]⁺

(100%). HRMS (APCI) m/z: [M + H]⁺Calcd for C₁₇H₂₅BrFO

343.1067, found 343.1068.

11-Bromo-1-(4-chlorophenyl)undecan-1-one (2b). 11-Bromoun-

decanoic acid (826 mg, 3.1 mmol) was converted to the

corresponding acid chloride in dichloromethane (10 mL) using

oxalyl dichloride (0.8 mL, 9.3 mmol) as described by the general

procedure above. A solution of the acid chloride in dichloromethane

(25 mL) and aluminum(III) chloride (415 mg, 3.1 mmol) was added

to 1b (1.25 g, 3.1 mmol) in dichloromethane (50 mL) using a syringe

pump. Aqueous workup and ﬂash ﬁltration through KF/silica gave the

crude product as an oil. Solvent evaporation gave a white solid, which

was recrystallized from DCM/pentane to aﬀord the product⁶⁵as a

white crystalline powder (842 mg, 2.3 mmol, 75%). mp 61−62 °C. ¹H

NMR (400 MHz, CD₂Cl₂): δ 7.89 (dm, J_H−H= 8 Hz, 2H), 7.45 (dm,

J_H−H= 8 Hz, 2H), 3.42 (t, J_H−H= 7 Hz, 2H), 2.93 (t, J_H−H= 7 Hz,

2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.43−1.30 (brm, 12H) ppm.

¹³C{¹H} NMR (101 MHz, CD₂Cl₂): δ 199.4, 139.4, 136.1, 129.9,

129.2, 39.0, 34.6, 33.3, 29.83, 29.79, 29.7, 29.2, 28.6, 28.3, 24.6 ppm.

MS (APCI) m/z: 361 [M + H]⁺(100%). HRMS (APCI) m/z: [M +

H]⁺Calcd for C₁₇H₂₅BrClO 359.0772, found 359.0773.

16-Bromo-1-(4-chlorophenyl)-hexadecan-1-one (2f). The solu-

tion of 16-bromohexadecanoyl chloride and AlCl₃described above

(11 mL) was added to a solution of compound 1b (521 mg, 1.3

mmol) in dichloromethane (11 mL) using a syringe pump. Aqueous

workup and ﬂash ﬁltration through KF/silica gave the crude product

as an oil. Solvent evaporation gave a white solid, which was

recrystallized from DCM/pentane to aﬀord the product as a white

crystalline powder (390 mg, 0.9 mmol, 70%). mp 65−67 °C. ¹H

NMR (300 MHz, CDCl₃): δ 7.89 (dm, J_H−H= 9 Hz, 2H), 7.43 (dm,

11-Bromo-1-(4-iodophenyl)undecan-1-one (2d). 11-Bromounde-

canoic acid (826 mg, 3.1 mmol) was converted to the corresponding

acid chloride in dichloromethane (10 mL) using oxalyl dichloride (0.8

mL, 9.3 mmol) as described by the general procedure above. A

J_H−H= 9 Hz, 2H), 3.40 (t, J_H−H= 7 Hz, 2H), 2.92 (t, J_H−H= 7.2 Hz,

2H), 1.85 (m, 2H), 1.72 (m, 2H), 1.44−1.26 (brm, 22H)

ppm.¹³C{¹H} NMR (75 MHz, CDCl₃): δ 199.2, 139.3, 135.4,

129.5, 128.9, 38.6, 34.0, 32.9, 29.69, 29.67, 29.6, 29.53, 29.50, 29.4,

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28.8, 28.2, 24.3 ppm. MS (APCI) m/z: 431 [M + H]⁺(100%).

HRMS (APCI) m/z: [M + H]⁺Calcd for C₂₂H₃₅BrClO 429.1554,

found 429.1554.

(100%). HRMS (APCI) m/z: [M + H]⁺Calcd for C₁₇H₂₅Br₂O

403.0267, found 403.0268.

16-Bromo-1-(4-bromophenyl)-hexadecan-1-one (2g). 16-Bromo-

hexadecanoic acid (2.0 g, 6.0 mmol) was converted to the

corresponding acid chloride in dichloromethane (20 mL) using

oxalyl dichloride (1.5 mL, 18.0 mmol) as described by the general

procedure above. A solution of the acid chloride in dichloromethane

(50 mL) and aluminum(III) chloride (795 mg, 5.9 mmol) was added

to 1c (2.7 g, 5.9 mmol) in dichloromethane (50 mL) using a syringe

pump. Aqueous workup and ﬂash ﬁltration through KF/silica gave the

crude product as an oil. Solvent evaporation gave a white solid, which

was recrystallized from DCM/pentane to aﬀord the product as a

white crystalline powder (1.862 g, 3.9 mmol, 66%). mp 71−72 °C. ¹H

NMR (300 MHz, CDCl₃): δ 7.82 (dm, J_H−H= 9 Hz, 2H), 7.60 (dm,

J_H−H= 9 Hz, 2H), 3.40 (t, J_H−H= 7 Hz, 2H), 2.91 (t, J_H−H= 8 Hz,

2H), 1.85 (m, 2H), 1.72 (m, 2H), 1.44−1.26 (brm, 22H) ppm.

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 199.8, 137.9, 136.4, 129.6, 100.8,

38.6, 34.1, 32.9, 29.5, 29.44, 29.42, 29.36, 28.8, 28.2, 24.3 ppm. MS

(APCI) m/z: 475 [M + H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺

Calcd for C₂₂H₃₅Br₂O 473.1049, found 473.1050.

11-Bromo-1-(3-iodophenyl)undecan-1-one (2j). 11-Bromounde-

canoic acid (269 mg, 1.0 mmol) was converted to the corresponding

acid chloride in dichloromethane (3 mL) using oxalyl dichloride (0.3

mL, 3.0 mmol) as described by the general procedure above. After

isolation, the acid chloride was redissolved in dichloromethane (8

mL), and to the mixture was added aluminum(III) chloride (135 mg,

1.0 mmol). The obtained solution was added to 1f (500 mg, 1.0

mmol) in dichloromethane (8 mL) using a syringe pump. Aqueous

workup and ﬂash ﬁltration through KF/silica gave the crude product

as a colorless oil. Puriﬁcation was achieved by recrystallization from

pentane. For this, a solution in approximately 5 mL of pentane was

brieﬂy cooled with the aid of a dry ice/acetone bath in a round-

bottom ﬂask. Within a few seconds, the product started to crystallize

on the glass wall. Upon warming, the solution was quickly removed

using a pipet. This procedure was repeated twice to aﬀord the product

as a white crystalline material (232 mg, 0.5 mmol, 51%). mp 55−56

°C.¹H NMR (300 MHz, CDCl₃): δ 8.27 (m, 1H), 7.89 (m, 2H), 7.20

(m, 1H), 3.40 (t, J_H−H= 7 Hz, 2H), 2.91 (t, J_H−H= 7 Hz, 2H), 1.85

(m, 2H), 1.72 (m, 2H), 1.44−1.30 (brm, 12H) ppm. ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 199.0, 141.6, 138.9, 137.1, 130.3, 127.2, 94.5,

38.6, 34.0, 32.8, 29.4, 29.3, 29.2, 28.7, 28.2, 24.1 ppm. MS (APCI) m/

z: 453 [M + H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺Calcd for

C₁₇H₂₅BrIO 451.0128, found 451.0128.

16-Bromo-1-(4-iodophenyl)hexadecan-1-one (2h). The solution

of 16-bromohexadecanoyl chloride and AlCl₃described above (11

mL) was added to a solution of compound 1d (640 mg, 1.3 mmol) in

dichloromethane (11 mL) using a syringe pump. Aqueous workup

and ﬂash ﬁltration through KF/silica gave the crude product as an oil.

Solvent evaporation gave a white solid, which was recrystallized from

DCM/pentane to aﬀord the product as a white crystalline powder

16-Bromo-1-(3-bromophenyl)hexadecan-1-one (2k). 16-Bromo-

hexadecanoic acid (872 mg, 2.6 mmol) was converted to the

corresponding acid chloride in dichloromethane (11 mL) using oxalyl

dichloride (0.7 mL, 7.8 mmol) as described by the general procedure

above. A solution of the acid chloride in dichloromethane (22 mL)

and aluminum(III) chloride (347 mg, 2.6 mmol) was prepared and

drawn up in a syringe. The solution was used for two diﬀerent batches

for preparation of 2k and 2l; 11 mL of the solution was used for each

reaction. Compound 1e (579 mg, 1.3 mmol) in dichloromethane (11

mL) was reacted with the above-made solution (11 mL). Aqueous

workup and ﬂash ﬁltration through KF/silica gave the crude product

as an oil. Solvent evaporation gave a white solid, which was

recrystallized from DCM/pentane to aﬀord the product as a white

crystalline powder (353 mg, 0.7 mmol, 57%). mp 53−54 °C. ¹H

NMR (300 MHz, CDCl₃): δ 8.08 (m, 1H), 7.87 (m, 1H), 7.68 (m,

1H), 7.34 (m, 1H), 3.40 (t, J_H−H= 6.9 Hz, 2H), 2.93 (t, J_H−H= 7.3

Hz, 2H), 1.85 (m, 2H), 1.72 (m, 2H), 1.44−1.26 (brm, 22H) ppm.

¹³C{¹H} NMR (101 MHz, CDCl₃): δ 199.0, 138.9, 135.7, 131.2,

130.2, 126.6, 123.0, 38.7, 34.1, 32.9, 29.70, 29.67, 29.61, 29.55, 29.51,

29.3, 28.8, 28.3, 24.2 ppm. MS (APCI) m/z: 475 [M + H]⁺(100%).

HRMS (APCI) m/z: [M + H]⁺Calcd for C₂₂H₃₅Br₂O 473.1049,

found 473.1050.

1

(513 mg, 1.0 mmol, 76%). mp 83−84 °C. H NMR (300 MHz,

CDCl₃): δ 7.82 (dm, J_H−H= 9 Hz, 2H), 7.66 (dm, J_H−H= 9 Hz, 2H),

3.40 (t, J_H−H= 7 Hz, 2H), 2.91 (t, J_H−H= 8 Hz, 2H), 1.85 (m, 2H),

1.71 (m, 2H), 1.44−1.26 (brm, 22H) ppm. ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 199.9, 138.0, 136.4, 129.6, 100.8, 38.6, 34.2, 33.0, 29.73,

29.71, 29.65, 29.58, 29.56, 29.4, 28.9, 28.3, 24.4 ppm. MS (APCI) m/

z: 431 [M + H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺Calcd for

C₂₂H₃₅BrIO 521.0911, found 521.0910.

11-Bromo-1-(3-bromophenyl)undecan-1-one (2i). 11-Bromoun-

decanoic acid (1.51 g, 5.7 mmol) was converted to the corresponding

acid chloride in dichloromethane (20 mL) using oxalyl dichloride

(1.45 mL, 17 mmol) as described by the general procedure above.

The solution of acid chloride in dichloromethane (50 mL) and

aluminum(III) chloride (0.776 g, 5.7 mmol) was added to 1e (2.550

g, 5.7 mmol) in dichloromethane (50 mL) using a syringe pump.

Aqueous work-up and ﬂash ﬁltration trough KF/silica gave the

product as colorless oil, which was recrystallized from pentane at −20

°C aﬀording the product as a white crystalline powder (1.643 g, 4.1

mmol, 71%). mp 48−50 °C. ¹H NMR (300 MHz, CDCl₃): δ 8.07 (m,

1H), 7.87 (m, 1H), 7.67 (m, 1H), 7.34 (m, 1H), 3.40 (t, J_H−H= 6.9

Hz, 2H), 2.93 (t, J_H−H= 7.3 Hz, 2H), 1.85 (m, 2H), 1.72 (m, 2H),

1.44−1.30 (brm, 12H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ

198.9, 138.9, 135.7, 131.1, 130.2, 126.6, 123.0, 38.7, 34.0, 32.9, 29.4,

29.4, 29.4, 29.3, 28.8, 28.2, 24.2 ppm. MS (APCI) m/z: 405 [M + H]⁺

16-Bromo-1-(3-iodophenyl)hexadecan-1-one (2l). Compound 1f

(641 mg, 1.3 mmol) in dichloromethane (11 mL) was reacted with

the above-made solution (11 mL) as described for 2m. Aqueous

workup and ﬂash ﬁltration through KF/silica gave the crude product

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as an oil. Solvent evaporation gave a white solid, which was

recrystallized from DCM/pentane to aﬀord the product as a white

crystalline powder (321 mg, 0.6 mmol, 47%). mp 53−54 °C. ¹H

NMR (300 MHz, CDCl₃): δ 8.27 (m, 1H), 7.89 (m, 2H), 7.20 (m,

1H), 3.41 (t, J_H−H= 7 Hz, 2H), 2.91 (t, J_H−H= 7 Hz, 2H), 1.85 (m,

2H), 1.72 (m, 2H), 1.44−1.26 (brm, 22H) ppm. ¹³C{¹H} NMR (75

MHz, CDCl₃): δ 199.2, 141.7, 139.0, 137.2, 130.4, 127.3, 94.6, 38.7,

34.2, 33.0, 29.74, 29.72, 29.70, 29.59, 29.56, 29.4, 28.9, 28.3, 24.3

ppm. MS (APCI) m/z: 431 [M + H]⁺(100%). HRMS (APCI) m/z:

[M + H]⁺Calcd for C₂₂H₃₅BrIO 521.0911, found 521.0910.

mL, 6.9 mmol) as described by the general procedure above. A

solution of the acid chloride in dichloromethane (20 mL) and

aluminum(III) chloride (306 mg, 2.3 mmol) was added to 1h (1.2 g,

2.3 mmol) in dichloromethane (20 mL) using a syringe pump.

Aqueous workup and ﬂash ﬁltration through KF/silica gave the crude

product as an oil. Puriﬁcation was achieved by ﬂash chromatography

on silica using hexane/ethyl acetate (9:1) as the eluent to aﬀord the

1

product as a colorless oil (0.773 g, 1.9 mmol, 84%). H NMR (300

MHz, CDCl₃): δ 7.67−7.63 (m, 2H), 7.55−7.43 (m, 2H), 7.37−7.20

(m, 4H), 2.48 (m, 2H), 1.49 (m, 2H), 1.23−1.16 (brm, 14H), 0.88 (t,

11-Bromo-1-(2-bromophenyl)undecan-1-one (2m). 11-Bro-

moundecanoic acid (1.19 g, 4.5 mmol) was converted to the

corresponding acid chloride in dichloromethane (10 mL) using oxalyl

dichloride (1.1 mL, 13.5 mmol) as described by the general procedure

above. A solution of the acid chloride in dichloromethane (40 mL)

and aluminum(III) chloride (598 mg, 4.5 mmol) was added to 1g

(2.00 g, 4.5 mmol) in dichloromethane (40 mL) using a syringe

pump. Aqueous workup, ﬂash ﬁltration through KF/silica and solvent

evaporation gave the crude product as an oil, which was recrystallized

from pentane with the aid of an acetone/dry ice cooling bath. The

compound was dissolved in pentane (∼50 mL) in a round-bottom

ﬂask equipped with rubber septum and a canula with ﬁtted ﬁlter

paper, then placed into the cooling bath the ﬂask was gently shaken.

This quickly led to the formation of a white precipitate. The cold

pentane solution was removed through the canula by applying N₂

pressure. The obtained solids were redissolved in pentane, and the

procedure was repeated twice. The product was obtained crystalline

solid, which melted to a colorless oil at room temperature (882 mg,

2.2 mmol, 49%). ¹H NMR (300 MHz, CDCl₃): δ 7.61−7.58 (m, 1H),

7.36−7.34 (m, 2H), 7.30−7.24 (m, 1H), 3.40 (t, J_H−H= 7 Hz, 2H),

2.90 (t, J_H−H= 7 Hz, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.44−1.29

(brm, 12H) ppm. ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 204.3, 142.0,

133.5, 131.3, 128.2, 127.3, 118.5, 42.7, 34.0, 32.8, 29.29, 29.27, 29.25,

29.0, 28.7, 28.1, 24.0 ppm. MS (APCI) m/z: 405 [M + H]⁺(100%).

HRMS (APCI) m/z: [M + H]⁺Calcd for C₁₇H₂₅Br₂O 403.0267,

found 403.0267.

J

_H−H= 7 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 204.8, 142.1,

140.0, 139.7, 132.8, 131.3, 131.2, 130.6, 129.2, 128.1, 128.0, 127.4,

123.0, 41.7, 32.0, 29.7, 29.6, 29.4, 29.2, 24.3, 22.8, 14.2 ppm. MS

(APCI) m/z: 403 [M + H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺

Calcd for C₂₃H₃₀BrO 401.1475, found 401.1475.

11-Bromo-1-(4′-bromo-[1,1′-biphenyl]-4-yl)undecan-1-one (2p).

11-Bromoundecanoic acid (508 mg, 1.9 mmol) was converted to the

corresponding acid chloride in dichloromethane (8 mL) using oxalyl

dichloride (0.5 mL, 5.7 mmol) as described by the general procedure

above. A solution of the acid chloride in dichloromethane (17 mL)

and aluminum(III) chloride (255 mg, 1.9 mmol) was added to 1i (1.0

g, 1.9 mmol) in dichloromethane (17 mL) using a syringe pump.

Aqueous workup and ﬂash ﬁltration through KF/silica gave the crude

product as an oil. Solvent evaporation gave a white crystalline solid,

which was recrystallized from DCM/pentane to aﬀord the product as

a white crystalline powder (497 mg, 1.0 mmol, 54%). mp 115−116

1

°C. H NMR (300 MHz, CDCl₃): δ 8.02 (dm, J_H−H= 9 Hz, 2H),

7.63 (dm, J_H−H= 9 Hz, 2H), 7.59 (dm, J_H−H= 9 Hz, 2H), 7.48 (dm,

J_H−H= 9 Hz, 2H), 3.40 (t, J_H−H= 7 Hz, 2H), 2.98 (t, J_H−H= 7 Hz,

2H), 1.85 (m, 2H), 1.75 (m, 2H), 1.44−1.30 (brm, 12H) ppm.

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 200.2, 144.4, 138.9, 136.2, 132.2,

128.9, 128.9, 127.1, 122.7, 38.8, 34.2, 32.9, 29.6, 29.50, 29.486,

29.470, 28.9, 28.3, 24.5 ppm. MS (APCI) m/z: 481 [M + H]⁺

(100%). HRMS (APCI) m/z: [M + H]⁺Calcd for C₂₃H₂₉Br₂O

479.0580, found 479.0582.

11-Bromo-1-(2′-bromo-[1,1′-biphenyl]-2-yl)undecan-1-one (2n).

11-Bromoundecanoic acid (762 mg, 2.9 mmol) was converted to the

corresponding acid chloride in dichloromethane (10 mL) using oxalyl

dichloride (0.7 mL, 8.6 mmol) as described by the general procedure

above. A solution of the acid chloride in dichloromethane (25 mL)

and aluminum(III) chloride (383 mg, 2.9 mmol) was added to 1h

(1.5 g, 2.9 mmol) in dichloromethane (25 mL) using a syringe pump.

Aqueous workup and ﬂash ﬁltration through KF/silica gave the crude

product as an oil. Puriﬁcation was achieved by ﬂash chromatography

on silica using hexane/ethyl acetate (9:1) as the eluent, aﬀording the

NMR Scale Reactions. 11-Bromoundecanoic acid (1.0 g, 5.4

mmol) was converted to the corresponding acid chloride in

dichloromethane (10 mL) using oxalyl dichloride (1.4 mL, 16.1

mmol) as described by the general procedure above. The acid

chloride was dried under high vacuum, kept under Ar, and used for all

NMR-scale test reactions. On a small scale (0.8 mL) for an NMR

experiment, a slow addition (1h) of acylium surprisingly resulted in

the formation of substantially more halobenzene compared to a fast

addition (5 min) and a slow addition on a preparative scale (50 mL).

When the addition was performed over 1 h, the ratio of 2a−AlCl₃/

ﬂuorobenzene was 35:65 based on the integrations of the aromatic ¹H

NMR resonances. The amount of the desired product 2a−AlCl₃

substantially increased when the addition was conducted over only 5

min, giving a ratio of 88:11. Similar results were observed for the

chloro derivative 2b−AlCl₃, with the ratio of 2b−AlCl₃to

chlorobenzene being 13:87 when the acylium species was added

over 1 h and increasing to 72:28 when the addition was conducted

over 5 min. Based on these observations, the acylium species was

added over 5 min for all NMR-scale reactions. The discrepancies of

the product distribution are most likely attributed to the

concentration of acylium in the reaction vessel and the drop size.

For all additions, we used needles of the same gauge size. Thus, when

1

product as a colorless oil (1.226 g, 2.6 mmol, 86%). H NMR (400

MHz, CDCl₃): δ 7.67−7.61 (m, 2H), 7.50−7.40 (m, 2H), 7.34−7.30

(m, 1H), 7.25−7.18 (m, 3H), 3.37 (t, J_H−H= 7 Hz, 2H), 2.51 (m,

2H), 1.82 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H), 1.24−1.17 (brm,

10H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 204.0, 141.8, 139.6,

139.4, 132.5, 131.0, 130.9, 130.4, 128.9, 127.9, 127.7, 127.1, 122.7,

41.3, 33.8, 32.7, 29.2, 29.13, 29.09, 28.9, 28.6, 28.0, 24.0 ppm. MS

(APCI) m/z: 481 [M + H]⁺(100%). HRMS (APCI) m/z: [M + H]⁺

Calcd for C₂₃H₂₉Br₂O 479.0580, found 479.0582.

1-(2′-Bromo-[1,1′-biphenyl]-2-yl)undecan-1-one (2o). Undeca-

noic acid (428 mg, 2.3 mmol) was converted to the corresponding

acid chloride in dichloromethane (8 mL) using oxalyl dichloride (0.6

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adding the acylium dropwise for the smaller scale reaction, the

concentration [RCO]⁺[AlCl₄]⁻is higher at the point the drop enters

the solution of the organostannane compared to the larger batches.

Furthermore, the aluminum catalyst is deactivated in the destannly-

lative acylation pathway as it coordinates to the CO group after

completed reaction. However, no CO group is formed in pathway b;

therefore, the catalyst is regenerated and becomes available for

subsequent reactions. These facts likely lead to more side product

formation when the reaction is carried out on a small scale.

Nevertheless, it is possible to suppress side product formation by

adding the acylium quickly.

NMR-Scale Control Reactions. The control reactions were

conducted analogously to the NMR-scale reactions described above

using ﬂuorobenzene and bromobenzene instead of the organotin

precursors 1a and 1c. Selected ranges of the H NMR spectra are

shown in Figures S9 and S10.

1

2a−AlCl₃. 11-Bromoundecanoic acid chloride (27 mg, 0.09 mmol)

and aluminum(III) chloride (13 mg, 0.09 mmol) in dichloromethane-

d (0.4 mL) were added to ﬂuorobenzene (9 mg, 0.09 mmol). The

1

mixture was analyzed by H and ¹⁹F NMR spectroscopy at diﬀerent

time points (Table S2). Yield (determined by ¹H NMR spectroscopy

after 24 h): 38%.

2c−AlCl₃. 11-Bromoundecanoic acid chloride (27 mg, 0.09 mmol)

and aluminum(III) chloride (13 mg, 0.09 mmol) in dichloromethane-

d (0.4 mL) were added to bromobenzene (15 mg, 0.09 mmol). The

mixture was analyzed by ¹H NMR spectroscopy at diﬀerent time

points (Table S2). Yield (determined by ¹H NMR spectroscopy after

24 h): 5%.

2a−AlCl₃. A 4 mL Schlenk tube equipped with a Young PTFE

stopcock and a magnetic stirring bar was charged with 11-

bromoundecanoic acid chloride (27 mg, 0.09 mmol) and dichloro-

methane-d (0.4 mL). To the mixture was added aluminum(III)

chloride (13 mg, 0.09 mmol), and the mixture was stirred for 5 min.

Another 4 mL Schlenk tube equipped with rubber septum and

magnetic stirring bar was charged with dichloromethane-d (0.4 mL)

and 1a (36 mg, 0.09 mmol). The solution was cooled to −78 °C, and

the acylium species in dichloromethane-d was added dropwise over 5

min. Stirring was continued for another 5 min before the mixture was

allowed to warm room temperature. Once warmed, the mixture in the

Schlenk tube was opened under a continues ﬂow of Ar. A syringe

equipped with a PTFE syringe ﬁlter was ﬂushed several times with Ar.

The mixture was drawn up and carefully added to an NMR tube

under an Ar atmosphere, and the tube was sealed. The mixture was

Preparative-Scale Reaction Using Bromobenzene as a

Starting Material. A Schlenk ﬂask was charged with 11-

bromocundecanoic acid (500 mg, 1.9 mmol) and dichloromethane

(15 mL). Oxalyldichloride (0.5 mL, 5.6 mmol) was added while

stirring at room temperature, followed by the addition of two drops of

DMF. The mixture was stirred for 45 min, after which the gas

evolution had ceased. The solvents and the excess oxalyldichloride

were removed under high vacuum, and the colorless oily solids were

redissolved in dichloromethane (15 mL), followed by addition of

aluminum(III) chloride (251 mg, 1.9 mmol). The mixture was stirred

for 10 min at room temperature. A second Schlenk ﬂask was charged

with bromobenzene (281 mg, 1.8 mmol) and dichloromethane (15

mL) and cooled to −40 °C. The acylium mixture was added to the

solution of bromobenzene slowly over 1 h under stirring using a

dropping funnel. After the addition was complete, the cooling bath

was removed. The mixture was allowed to warm to room temperature

and stirred for 48 h hours. Water (20 mL) was added to the mixture,

and the workup was conducted under air. Phases were separated, and

the aqueous layer was extracted twice with dichloromethane (20 mL).

The combined organic extracts were dried over Na₂SO₄and

concentrated to dryness using a rotary evaporator. The crude mixture

was puriﬁed by column chromatography on silica gel. Unreacted

bromobenzene was removed by eluting with hexane. The product was

subsequently eluted with hexane/ethyl acetate (95:5). The solvents

were removed using a rotary evaporator, giving 117 mg of a white

crystalline solid that contained mainly 2c. The product was

accompanied by impurities in the aromatic region, which presumably

originated from dehalogenation and 11-bromocarboxylic acid. The

integration of ¹H NMR resonances gave a yield of approximately 11%.

Computational Details. All calculations were performed using

Gaussian 16 software⁶⁶at the Australian National Computational

Infrastructure, with access provided through the Macquarie University

Partner Scheme (project ID xn11). All images of the calculated

structures were generated using CYLView.⁶⁷The frequency

calculations and structure optimizations were performed in the gas

phase at 25 °C using ωB97XD with the 6-311+g(d,p) basis set for C,

H, O, Al, Cl, and F and LanL2DZ ECP for Sn. Single point energy

calculations were performed using the M06L method and the

def2TZVP basis set, and the CPCM solvation model was used to

incorporate the solvent eﬀects of dichloromethane. Frequency

calculations were performed to conﬁrm whether the calculated

structure was a local minimum or a transition state. For transition

state structures, intrinsic reaction coordinate (IRC) calculations were

performed to conﬁrm whether the located transition state connected

the correct minima.

1

analyzed by H, ¹³C, and ¹⁹F NMR spectroscopy. Yield (determined

1

by H NMR spectroscopy): 88%.

2b−AlCl₃. The compound was prepared analogously from 1b (38

1

mg, 0.09 mmol) and characterized as a mixture by H and ¹³C NMR

1

spectroscopy. Yield (determined by H NMR spectroscopy): 72%.

2c−AlCl₃. The compound was prepared analogously from 1b (42

1

mg, 0.09 mmol) and characterized as a mixture by H and ¹³C NMR

1

spectroscopy. Yield (determined by H NMR spectroscopy): 54%.

2d−AlCl₃. The compound was prepared analogously from 1b (47

1

mg, 0.09 mmol) and characterized as mixture by H and ¹³C NMR

1

spectroscopy. Yield (determined by H NMR spectroscopy): 58%.

1

Figure S7 shows the aromatic regions of the H NMR spectra of

the diﬀerent aluminum complexes. We note that after prolonged

standing at room temperature (18 h), the composition of the mixtures

changed slightly toward to the products, most likely due to the

acylation of in situ-generated halobenzenes by unreacted acylium

1

present in the mixture. The full H and ¹³C NMR spectra shown in

the appendix were recorded after 18 h of standing, and the spectra

shown in Figures S7 and 8 are the same samples measured directly

after the reaction.

Control Reactions. We probed the reactivity of two haloben-

zenes, ﬂuorobenzene and bromobenzene, in the aluminum(III)

chloride-catalyzed Friedel−Crafts reaction with stoichiometric

amounts of AlCl₃and 11-bromoundecanoic acid chloride as control

reactions. We monitored the acylation over time by ¹H NMR

spectroscopy using NMR-scale reactions in DCM-d and also carried

out the reaction involving bromobenzene on a preparative scale. All

the reactions show that the acylation reaction proceeds very slowly

compared to the reaction of the organotin derivatives at room

temperature under the applied conditions. The ratios of the starting

material to the formed AlCl₃intermediates 2a−AlCl₃and 2c−AlCl₃

after >1 h of reaction time were approximately 84:14 and 98:1,

respectively. Fluorobenzene tended to react somewhat faster than

bromobenzene, and side products formed for both reactions.

Bromobenzene undergoes dehalogenation to a small extent, and

both reactions also generate other side products in small quantities.

We further investigated preparative-scale reactions involving bromo-

benzene and note that even after a reaction time of 2 days the reaction

did not go to completion, with a substantial amount of unreacted

bromobenzene visible by TLC. From this reaction, we were able to

isolate compound 2c in a yield of ∼10%. However, the compound was

always accompanied by impurities, which we could not separate by

column chromatography.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00997.

■

sı

Spectral and crystallographic data, Cartesian coordi-

nates, and energies of calculated structures (PDF)

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J. Org. Chem. 2021, 86, 9007−9022

The Journal of Organic Chemistry

pubs.acs.org/joc

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Accession Codes

CCDC 2079952−2079955 contain the supplementary crys-

tallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

Corresponding Author

■

Max Roemer − School of Chemistry, The University of Sydney,

Sydney, NSW 2006, Australia; orcid.org/0000-0003-

4876-8011; Email: max.roemer@sydney.edu.au

Authors

Sinead T. Keaveney − Department of Molecular Sciences,

Macquarie University, Sydney, NSW 2109, Australia;

orcid.org/0000-0002-7613-7383

Nicholas Proschogo − School of Chemistry, The University of

Sydney, Sydney, NSW 2006, Australia

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layers of Ferrocenyl Terminated n Alkanethiolates on Gold Surfaces.

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Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00997

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

M.R. acknowledges ﬁnancial support from the School of

Chemistry at The University of Sydney. S.T.K. acknowledges

the ﬁnancial support of Macquarie University through the

receipt of a Macquarie University Research Fellowship

(MQRF). We acknowledge the scientiﬁc and technical

assistance of the NMR and chemical analysis facilities at

Sydney Analytical at the University of Sydney. We thank Dr.

Ian Luck for scientiﬁc and technical assistance with NMR

spectroscopy experiments. We thank Dr. William Lewis for

scientiﬁc and technical assistance with X-ray single-crystal

diﬀraction experiments and data analysis. We thank Prof

Barbara A. Messerle for providing some of the chemicals and

equipment used for this research. We thank Prof Stephen

Moggach (UWA) for scientiﬁc discussions. This project was

undertaken with the assistance of resources and services from

the National Computational Infrastructure (NCI), which is

supported by the Australian Government.

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https://doi.org/10.1021/acs.joc.1c00997

J. Org. Chem. 2021, 86, 9007−9022

Article Doi

Synthesis of Long-Chain Alkanoyl Benzenes by an Aluminum(III) Chloride-Catalyzed Destannylative Acylation Reaction

DOI: 10.1021/acs.joc.1c00997

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Full text of DOI:10.1021/acs.joc.1c00997

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