A click-based modular approach to introduction of peroxides onto molecules and nanostructures

RSC Advances

View Article Online

View Journal | View Issue

PAPER

A click-based modular approach to introduction of

peroxides onto molecules and nanostructures†

Cite this: RSC Adv., 2020, 10, 44408

*

Alissa Horn and Patrick H. Dussault

Copper-promoted azide/alkyne cycloadditions (CuAAC) are explored as a tool for modular introduction of

peroxides onto molecules and nanomaterials. Dialkyl peroxide-substituted alkynes undergo Cu(^I)-

promoted reaction with azides in either organic or biphasic media to furnish peroxide-substituted 1,2,3-

triazoles. Heterolytic fragmentation of the peroxide to an aldehyde, a side reaction that appears to be

related to the formation of the triazole, can be suppressed by use of excess alkyne, the presence of

triethylsilane, or by use of iodoalkyne substrates. Complementary reactions of simple alkynes with azido-

substituted peroxides are much less eﬃcient. Click reactions of alkynyl peroxyacetals are also reported;

reductive fragmentation can be minimized by increasing the distance between the peroxyacetal and the

alkyne. The strategy enables modular introduction of dialkyl peroxides and peroxyacetals onto gold

nanoparticles, the ﬁrst such process to be reported.

Received 24th October 2020

Accepted 20th November 2020

DOI: 10.1039/d0ra09088c

rsc.li/rsc-advances

now describe explorations of the scope of CuAAC chemistry

reaction in terms of the nature of the peroxide group, whether

Introduction

the peroxide is linked to the alkyne or azide partner, the

distance of the peroxide from the reaction center, and the

inuence of reaction conditions. The fragmentation of the

peroxides observed in some of the click reactions of perox-

yacetals demonstrates a potential for controlled generation of

reactive oxygen species. We also demonstrate successful appli-

cation of these ligations to modular introduction of peroxides

on the surface of functionalized Au nanoparticles (AuNP),

Organic peroxides are capable of a wide range of reaction

pathways,¹and have been applied as oxidants,²radical initia-

tors,³pharmacophores,⁴enzyme inhibitors,⁵and synthons for

electrophilic transfer of alkoxide.⁶Peroxides are also of interest

as intermediates and products of oxidative degradation and

sources of reactive oxygen species.⁷This rich chemistry contrasts

with the limited number of reports describing reactivity or appli-

cation of peroxides at surfaces.⁸This discontinuity cannot be

completely attributed to concerns for stability or safety. Peroxides

are compatible with a surprising variety of synthetic trans-

formations,⁹and many peroxides may be safely employed by

following established precautions.¹⁰A more signicant barrier to

broader use of peroxides is the lack of eﬀective methods for their

modular introduction under mild conditions.

“Click chemistry”, a family of strategies based upon rapid

and specic pairwise reactions of matched functional groups,

has become an indispensable tool for modular approaches to

molecules, supramolecules, and functionalized surfaces and

nanoparticles.¹¹The most widely applied of these trans-

formations, is the copper-assisted azide/alkyne cycloaddition

(CuAAC), now a workhorse reaction for ligation and modica-

tion of molecules and supramolecules.¹²CuAAC chemistry has

been employed to generate derivatives of the peroxide antima-

larial artemisinin,¹³and we became interested in the potential

for modular introduction of peroxides via click reactions. We

Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304,

USA. E-mail: pdussault1@unl.edu

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra

of molecules, as well as ¹H, IR, and XPS characterization of functionalized Au

nanoparticles (100 pages). See DOI: 10.1039/d0ra09088c

Fig. 1 Substrates used for CuAAC chemistry studies.

44408 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

a nanomaterial platform widely applied for sensing, imaging,

and biointeraction applications.¹⁴

Results

Substrates employed in CuAAC chemistry are illustrated in

Fig. 1.

Unfunctionalized peroxyalkynes 1 and 2 were easily assem-

bled (Scheme 1) via Finkelstein exchange on the corresponding

chloroalkyne,¹⁵followed by nucleophilic displacement of the

iodide with tert-butyl hydroperoxide in the presence of CsOH.¹⁶

Iodination of the terminal alkyne furnished the corresponding

iodoalkynes (3 and 4) in good yield.¹⁷

Scheme 1 Synthesis of alkynyl and iodoalkynyl peroxides.

Preparation of alkynyl peroxyacetals was based upon trap-

ping of an ozonolysis-derived carbonyl oxide with an alkynol

(Scheme 2).¹⁸This strategy, although rooted in the successful

preparation of unsaturated hydroperoxyacetals from allyl alco-

hols,¹⁹proved to be strongly dependent upon the structure of the

alkynol. Ozonolysis of 2,3-dimethyl-2-butene in the presence of

propargyl alcohol mainly aﬀorded hydroperoxyperoxide 5a, which

arises through reaction of the desired hydroperoxyacetal (5) with

additional carbonyl oxide. The dimeric product predominates

even in the presence of excess propargyl alcohol, presumably

reecting limited alcohol nucleophilicity.²⁰In contrast, the cor-

responding reactions of 3-butyn-1-ol and 5-hexyn-1-ol gave

moderate and good yields of hydroperoxyacetals 6 and 7, respec-

tively. The hydroperoxyacetals were readily methylated to aﬀord

peroxyacetals 8 and 9.²¹Iodination of the peroxyacetals furnished

iodoalkynyl acetal 10 and 11.

Scheme 2 Synthesis of alkynyl- and iodoalkynyl peroxyacetals.

Preparation of peroxide-substituted azides is summarized in

Scheme 3. Selective nucleophilic substitution of 1-bromo-4-

chlorobutane aﬀorded 1-chloro-4-azidobutane,²²which under-

went CsOH-promoted substitution with tert-butyl hydroperoxide

to generate azidoalkyl peroxide 12. The synthesis of a secondary

peroxide/azide began with conversion of 5-hexene-2-ol to the

corresponding iodide. Nucleophilic displacement with sodium

azide was followed by Mukaiyama peroxidation to generate peroxy

azide 13.²³As 12 and 13 both incorporate two energy-rich groups

within a low molecular weight framework,²⁴initial syntheses were

conducted on modest scales (ꢀ1 mmol). Although both molecules

Scheme 3 Synthesis of peroxy azides.

Table 1 Conditions for click chemistry with peroxy alkynes

Azide

Cu(I) source

Solv.

t (h)

Conv.

Prod. (yield, %)

16

17

CuCl, NEt₃

CuI, NEt₃

THF

3

89%

80%

19 (25%)

20 (37%)

20i (5%)

20 (42%)

17

CuSO₄, Na ascorbate

CH₂Cl₂/H₂O

1.5

85%

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44409

View Article Online

RSC Advances

Paper

2). Ratios of peroxide products (20, 20i) vs. aldehyde (21) were

established by NMR; samples of pure aldehyde were also iso-

lated for characterization. The near absence of aldehyde for

reactions conducted in the presence of excess alkyne (entries 6

and 9) would emerge as an important tool (vide infra).

Resubjecting isolated triazole 20 to either set of reaction

conditions led to formation of aldehyde 21 (eqn (1)); in the

presence of CuSO₄/ascorbate, the aldehyde became the major

product.

(1)

In an eﬀort to better understand the factors leading to

aldehyde formation, we probed the reactivity of triazole 20

towards reaction components (Table 3). No decomposition was

observed in the presence of base or CuSO₄or ascorbate.

However, treatment with CuI, CuI/triethylamine, or CuSO₄/Na

ascorbate generated signicant amounts of aldehyde; the same

was true for reaction with either Cu(^I) source and azide. No

aldehyde was observed in the presence of mixtures containing

added alkyne (entries 5, 6, 11 and 12) which did not result in

aldehyde formation. Interestingly, the 5-iodotriazole (20i) was

unaﬀected by conditions which rapidly degraded 20 (entry 13).

The results in Table 3 suggest that the formation of alde-

hyde may be accelerated in the presence of the neighboring

triazole. Supporting this hypothesis, alkynyl peroxide 1

proved inert towards reaction with copper iodide in THF

(eqn (2)).

Consistent with literature reports,²⁸click reactions pro-

ceeded more rapidly in the presence of tris[(1-benzyl-1H-1,2,3-

triazol-4-yl)methyl]amine (TBTA), a Cu(^I) ligand (Table 4).

However, aldehyde formation continuing to be a problem and

the overall yields of clicked peroxide were no greater, and

sometimes less, than for reactions in the absence of the ligand.

In contrast, performing the CuI or CuSO₄/ascorbate-catalyzed

reactions in the presence of excess alkyne completely sup-

pressed aldehyde formation. This led to the hypothesis that

the lack of byproduct might reect the ability of free alkyne to

protonate the C₅-cuprated triazole intermediate in CuAAC chem-

istry.^12,29We also investigated this reaction in the presence of

a silane, a functionality also known to quench organocopper

species,³⁰and again observed suppression of aldehyde formation.

Finally, replacement of the terminal alkyne with an iodide fur-

nished only the 5-iodoalkyl peroxide; no aldehyde was observed.

These reactions, although allowed to proceed for 18–24 h, were

typically complete (TLC) within 30 minutes.

proved to be stable to at least 100 ^ꢁC (open chamber DSC, range

limited by volatility), subsequent preparations were limited to

#1 g and we avoided exposing either molecule to elevated

temperatures.¹⁰Preparations of 5-hexynyl benzene (15), azi-

doalkylbenzenes 16 and 17, and 6-azido hexanethiol (18) are

detailed in the Experimental section.

Copper(^I) catalyzed click reaction with peroxy alkyne

Reaction of peroxyalkyne 1 with azidoalkylbenzenes 16 or 17

under either homogeneous (CuI and NEt₃, in THF) or biphasic

(CuSO₄, sodium ascorbate, methylene chloride/water) condi-

tions led to the rapid (#15 min) appearance of triazoles 19 or 20

(Table 1);^12,25the presence of a peroxide was evident based upon

a redox-sensitive TLC indicator.²⁶These initial reactions were

stopped aer brief reaction periods (1.5–3 h); longer reaction

times led to consumption of starting material but also contami-

nation with a nearly inseparable byproduct later established to be

the tetrazole aldehyde (21, vide infra). A small amount of the cor-

responding 5-iodotriazole 20i, easily distinguished from 20 by the

¹³C signal for C₅(120.7 ppm for C–H vs. 78.0 ppm for C–I) was

isolated from the reaction employing CuI.²⁷

(2)

Iodoalkynes display enhanced reactivity relative to terminal

alkynes in CuAAC reactions,²⁷and this is also observed in the

reactions of the peroxide-substrates. A competition between

The relationship between reaction time and aldehyde

formation was examined using the reaction of 1 and 17 (Table

(3)

44410 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

Table 2 Inﬂuence of reaction time on byproduct formation

Entry

Catalyst

Solvent

t (h)

21 (yield^a, %)

1

2

CuI/Et₃N

〃

THF

〃

1

3

6%

8%

3

4

〃

8

13%

20%

30%

<2%

20%

38%

57%

5%

18

27

3

4

18

1.5

4

5

〃

6^b

7

CuSO₄/sodium ascorbate

CH₂Cl₂/H₂O

8^c

9

〃

10^b

11^b

22%

a

1

Ratios assessed by H NMR. ^b1.2 equiv. 1. ^c0.4 equiv. Cu(I).

structurally analogous alkyne derivatives led to preferential Cu(^II), the reactions underwent a color change from dark

consumption of the iodoalkynyl peroxide 3.

green to light blue aer 30–60 minutes. The color change could be

temporarily reversed by the addition of more ascorbate but little or

no clicked product was detected. Additionally, minimal progress

was observed with the corresponding iodoalkynyl peroxyacetal (10).

Proximity of peroxide and alkyne

Click reactions of peroxyoctyne 2 and the corresponding

iodoalkyne (4) produced a good yield of peroxy triazoles 22/23

(4)

and iodotetrazoles 22i/23i (Table 5). For reactions employing

In contrast, the longer chain peroxyacetal (9) and the corre-

CuI as the copper source, formation of the aldehyde byprod- sponding iodoalkyne (11) both reacted with azides in the pres-

ucts 24/25 was minimal (2) or did not occur at all (4). In the ence of Cu(^I) to give peroxy triazoles as the only major product

case of reactions using CuSO₄, aldehyde formation was (Table 6). Once again, no reaction was observed in the presence

signicant for reactions involving alkyne 2 and minimal for of a promoter derived from CuSO₄/ascorbate.

iodoalkyne 4.

A separate control experiment (eqn (5)) made obvious the

stability of the alkynyl peroxyacetals towards Cu(^I) in the

absence of other reaction components.

Alkynyl peroxyacetals

Cu(^I)-promoted reaction of the butynyl peroxyacetal (8) with

azides 16 or 17 gave poor results (eqn (4)). In some cases, we

observed successful click reaction to form inseparable

mixtures of the desired peroxyacetal and the acetate ester

derived from peroxyacetal fragmentation. No improvement

(5)

CuAAC reactions of peroxyalkyl azides

was observed based upon the presence of excess alkyne, TBTA, Reactions of simple alkynes with peroxide-containing azide 12

or triethylsilane. In the presence of promoters derived from proceeded in modest yield using CuI/Et₃N (Table 7); the

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44411

View Article Online

RSC Advances

Paper

Table 3 Stability of peroxide tetrazoles to reaction components

Entry

S. mat

Reagents

Azide (equiv.)

Alkyne (equiv.)

21 (yield^a, %)

1

2

3

4

5

6

7

8

20

20i

Et₃N

CuI

CuI, Et₃N

〃

—

1.0

—

1.0

—

Nr

95%

70%

50%

0%

43%

0%

61%

0%

〃

Na ascorbate

CuSO₄, Na ascorbate

CuSO₄

CuSO₄, Na ascorbate

CuI, Et₃N

9

—

1.0

10

11

12

13

—

1.0

—

a

NMR yields; isolated yield in parentheses.

Table 4 Inﬂuence of additives

t

Alkyne

Azide

Cond.

Additive (equiv.)

(h)

Product (yield, %)

1

3

17

16

A

B

C

D

A

Alkyne 1 (1.2)

TBTA (1%)

Et₃SiH (1.2)

—

18

3

24

20 (55%)

20 (68%)

20 (20%)

20 (35%)

19 (62%)

19i (65%)

corresponding reactions with CuSO₄/ascorbate provided lower

yields and required substantially longer reaction times. In both

series, signicant amounts of the peroxyazide were recovered.

Although analysis of these reactions was complicated by the

presence of inseparable byproducts, we could verify that little or

no aldehyde was generated under these conditions.

(6)

Secondary silyl peroxide 13 failed to give clicked products

(eqn (6)); instead, producing a mixture of reduction and frag-

mentation products.^1a,31In the absence of alkyne, 13 was stable

to both the CuI or CuSO₄reagent systems (not shown).

Inuence of peroxides on the CuAAC reaction

The lower reactivity and yields observed with the peroxy-

substituted azides led us to investigate whether the presence

of a peroxide was exerting a general dampening inuence on the

CuAAC reaction. The reaction of 1-hexyne (14) and phenylalkyl

44412 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

Table 5 CuAAC reaction of longer dialkyl peroxide

Alkyne, azide

X

Cu(I)^a

CuI

Conv. (%)

87.6

Peroxide (yield, %)

Aldehyde (yield, %)

2, 16

H

22 (68%)

22i (6%)

22 (41%)

22i (76%)^b

22 (50%)

22i (3%)

23 (55%)

23i (4%)

23 (39%)

24 (11%)

2, 16

4, 16

2, 16

H

I

H

CuSO₄

CuI

90

94

ꢀ10

24 (37%)

—

CuI^c

2, 17

H

CuI

87

89

25 (29%)

2, 17

CuSO₄

25 (50%)

a

b

c

CuI/Et₃N (0.2 equiv.), THF; CuSO₄/sodium ascorbate, DCM/H₂O (biphasic). Signicant amount of unidentied polar byproduct. Et₃SiH (1.9

equiv.) also present.

azide 17, which went to completion in just a few minutes under

our typical reaction conditions, failed to proceed at all in the

presence of a stoichiometric amount of peroxide 13 (eqn (7)).

Nanoparticle functionalization

Having identied useful conditions for CuAAC reactions of

alkynyl peroxides and peroxyacetals, we became interested in

applying the chemistry to functionalization of nanoparticles.

CuAAC-based functionalization of AuNPs, which exploits the

high aﬃnity of thiols for gold and the resulting ability to create

azide-functionalized nanoparticles, has been widely applied to

(7)

a

variety of applications in both organic and aqueous

media,^{11,14a,32–37}and we focused our attention on this system.

Azide-functionalized nanoparticles (N₃Au) were prepared

using

a variant of a reported procedure in which Au

Table 6 Click chemistry of hexynyl peroxyacetals

t

(h)

Alkyne

Azide

Cu(I) source

CuI, Et₃N

CuSO₄, ascorbate

CuI, Et₃N

Product (yield^a, %)

9

11

17

16

3

24

18

26 (45%)

Nr

27i (33%)

a

Isolated.

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44413

View Article Online

RSC Advances

Paper

Table 7 CuAAC chemistry with peroxyalkyl azides

Alkyne

Reagents

t (h)

Conv. (12)

Product (yield, %)

14

15

CuI/Et₃N

CuSO₄/Na ascorbate

CuI/Et₃N

3

24

3

71%

80%

76%

42%

28 (34%)

28 (29%)

29 (15%)

29 (#5%)

CuSO₄/Na ascorbate

24

Scheme 4 Synthesis of peroxide-functionalized nanoparticles.

nanoparticles (AuNP) are subsequently reacted with a passiv- isolated and puried using centrifugation and resuspension.

ating and then a functionalized thiol (Scheme 4).³⁸Addition of The presence of the azide was evident from the strong IR

a slight excess of pentanethiol to a biphasic mixture of HAuCl₃absorbance at 2094 cm^ꢂ1(Fig. 3, compare panels a and b) and

and tetraoctylammonium bromide resulted in a white suspen-

sion which reacted with freshly prepared aqueous sodium

borohydride to generate a dark and opaque suspension of

pentanethiolate-functionalized nanoparticles (C₅SAu). The

partially passivated nanoparticles were isolated by cen-

trifugation.^11cTEM (Fig. 2) spectra conrmed the presence of 2–

5 nm particles. The presence of the alkylthio chains was evident

by the ¹H signals for a terminal methyl group and the methylene

groups at C₃/C₄(ESI-Fig. 1†).³⁹XPS analysis revealed the surface

region of the nanoparticles to consist of 50.1% Au, 43.9% C, and

6.0% S, suggesting that approximately 75% of the Au surface

remained accessible for further functionalization (ESI-Fig. 2–4†).⁴⁰

Repetition of the procedure using dodecanethiol, the preliminary

passivating agent described in the original report, generated

nanoparticles with similar properties (ESI-Fig. 5–8†).^11c

Treatment of the C₅SH-Au with excess 6-azidohexane thiol

furnished the azide-modied nanoparticle (N₃Au) which was Fig. 2 TEM of C5SAu. Scale bar ¼ 5 nm.

44414 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

Fig. 3 IR of nanoparticles: (a) C₅SAu; (b) N₃Au; (c) after click with peroxyalkyne 1; (d) after click with alkynyl peroxyacetal 9.

by the new ¹H NMR signal at 3.31 ppm corresponding to CH₂N₃established a product composition of 26.4% Au and 73.6%

(ESI-Fig. 9†); this signal was easily distinguished from signal for pentanethiol and peroxide triazole (ESI-Fig. 15–19†).

unbound azide (3.50 ppm), which was also observed in inade-

We also investigated click functionalization of azidoNP with

quately washed samples. The ꢀ2 : 3 ratio of the integrals for the alkynyl peroxy acetal 9. Consumption of the azide was obvious

signals corresponding to CH₂N₃vs. CH₂CH₃suggests a similar in the lack of the ꢀ2100 cm^ꢂ1IR stretch and the observation of

extent of coverage. XPS suggested a surface composition of a new C–H stretch at 2921 cm^ꢂ1(Fig. 3d). Although ester

54.0% Au, 34.2% C, 8.5% S, and 3.3% (ESI-Fig. 10–13†).

formation was equally obvious as an IR stretch at 1738 cm^ꢂ1

,

the limited magnitude of this peak, combined with the

comparison in the ¹H NMR (ESI-Fig. 20†) of signals for the

MeOO (3.54 ppm) and the gem-dimethyl groups of the acetal

(1.57 ppm) vs. the peak group at 3.86 ppm (CH₂O) of both acetal

and ester, suggested the majority of the functionalized chain

remained as peroxyacetal. XPS (ESI-Fig. 21–25†) suggested

a surface composition of 20.0% Au and 80.0% pentanethiol and

peroxyacetal triazole.

Peroxide functionalization of nanoparticles

Addition of triethylamine and cat. copper iodide into a THF

solution containing peroxyalkyne 1 and N₃Au led to the imme-

diate appearance of a new peroxide-active spot on TLC (see

Experimental details).²⁶Aer being quenched with aq. NH₄Cl,

the reaction was concentrated and the residue puried away

from residual reactant by repeated resuspension (MeOH) and

centrifugation. The azide stretch was now absent in the IR

spectrum (Fig. 3d), which instead showed weak tetrazole-related

Discussion

stretches at 1723 cm^ꢂ1and 1559 cm^ꢂ1and only minimal Our results demonstrate that both peroxides and peroxyacetals

absorptions associated with an aldehyde (1705–1710 cm^ꢂ1). can, under suitable conditions, serve as modular components

Evidence for the click reaction could also be seen in the ¹H NMR for Cu-promoted CuAAC click reactions. The click reactions of

(ESI-Fig. 14†) as the loss of the d 3.31 signal corresponding to the alkynyl peroxides and peroxyacetals proceed at rates in line

the CH₂N₃and new signals at 1.27 (t-Bu) and 3.99 (OO). XPS with literature reports, with reactions times of 0.5–1 h for

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44415

View Article Online

RSC Advances

Paper

terminal alkynes and #0.75 h for 1-iodoalkynes.^12,27This is

consistent with Zhu's observation that electron-poor alkynes are

excellent substrates for CuAAC reactions.⁴¹An “isomeric” set of

click reactions involving simple alkynes and azidoalkyl perox-

ides is less eﬃcient. The basis for inhibition of azide reactivity

at a four-carbon distance from a peroxide remains unclear;

however, we should note that we have observed a dampening

inuence of peroxides on S_N2 reactions across a similar span.⁴²

The use of CuI in organic solvents gives more consistent and

oen superior results compared to the use of CuSO₄/ascorbate

in biphasic media. The alkynyl peroxides and alkynyl perox-

yacetal substrates, although stable towards Cu(^I), are both prone

to decomposition reactions in the presence of the reaction

intermediates (Scheme 5). Interestingly, the eﬃciency of the

reactions, the nature of the decomposition reactions, and the

approaches to control of decomposition, are diﬀerent for the

two classes of substrates.

The dialkyl peroxides give modest to moderate yields under

traditional CuAAC conditions due to the accumulation of

a byproduct derived from fragmentation of the peroxide to an

aldehyde. Aldehyde formation can be suppressed by use of an

iodinated alkyne substrate, by performance of reactions in the

presence of excess alkyne or added silane; under these condi-

tions the yield of clicked peroxide is in the range of 62–68%. For

the peroxyacetals, reactions proceed in lower yield, and, in the

case of a shorter chain series (8), generate a signicant amount

of a byproduct in which the peroxyacetal has been fragmented

to an acetoxy group. The formation of the ester is largely sup-

pressed in a longer-chain peroxyacetal or for reactions of

iodoalkynyl peroxyacetals. However, regardless of conditions,

the yields obtained from peroxyacetals do not rival those ob-

tained from the dialkyl peroxides.

An interpretation of our results in the context of the accepted

mechanism of the CuAAC reaction (Scheme 6) suggests the

decomposition reactions result from interaction of the peroxide

or peroxyacetal with a heteroaryl organocopper intermediate

generated at C₅of the developing triazole.¹²Evidence in support

of this hypothesis includes: the instability of the peroxyalkyne

to any mixture containing Cu(^I) and triazole; the lack of frag-

mentation observed for iodoalkynes; and the minimization of

fragmentation the presence of excess alkyne or added trie-

thylsilane, either of which would be expected to protonate the

Scheme 6 CuAAC mechanism and potential pathways for peroxide

fragmentation.

sp²-RCu.³⁰The clean formation of aldehyde, and the high

barriers associated with electrochemical or chemical reduction

of dialkyl peroxides,⁴³suggest the decomposition is a heterolytic

process involving abstraction of the adjacent C–H.^1a

The formation of an ester group (acetoxy) from fragmenta-

tions of the hydroperoxyacetals suggests the intermediacy of an

alkoxy radical derived from cleavage of the peroxyacetal by an

electron-donor; the likely reducing agent is the metalated tri-

azole described above (Scheme 6).⁴⁴In contrast to the reactions

of dialkyl peroxides, byproduct formation for the peroxyacetals

is not suppressed by the presence of excess alkyne or added

silane; it is suppressed by use of iodoalkynyl substrates or by

increasing the peroxide/alkyne distance.

It is interesting to compare our results with reported CuAAC

reactions of alkynyl derivatives of artemisinin-derived propargyl

acetals and amides (Fig. 4); the approximate distance between

the peroxide and the reaction site is similar in both systems.¹³

The heterolytic fragmentation we observed with dialkyl perox-

ides is not available in the artemisinin derivatives due to the

lack of adjacent C–H groups. However, the fact that radical

fragmentations are not observed in the artemisinin derivatives

may indicate that the SET fragmentation requires close

approach of the organocopper intermediates and the perox-

yacetal, something that is possible in A and B and not possible

in C or D.

CuAAC-based functionalization of AuNPs, which exploits the

high aﬃnity of thiols for gold has been widely applied to

a

variety of applications in both organic and aqueous

media.^{11c,14b,c,32–37}At the outset of our studies, we were concerned

by reports suggesting that CuAAC reactions on gold nano-

particles require longer reaction periods or use of microwave

heating,^45,46and can be accompanied by nanoparticle aggrega-

tion and precipitation.^45,47Our results indicated that modular

introduction of peroxides on nanoparticles via CuAAC suﬀers

Scheme 5 Overview of decomposition processes.

44416 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

surfaces. Reactions are rapid, proceed to high conversion of

nanoparticle surface functionality, and can be accomplished

under mild conditions and without nanoparticle aggregation.

Peroxide-functionalized surfaces could provide the basis for

reactive or antimicrobial coatings,⁵¹as well as a platform for

investigating spatially-constrained interactions or reactions of

peroxides or derived reactive oxygen species.⁵²Along these lines,

the peroxyacetals investigated here, in addition to oﬀering

a source of alkoxy radicals, are known to be easily hydrolyzed to

generate free hydroperoxides,¹⁶while the simple t-alkyl perox-

ides, although nearly inert to simple reducing agents and Fe(^II),

are known to be activated photochemically^52,53or by iron/thiol

complexes.⁴³

Fig. 4 Comparison with artemisinin-derived “click” substrates.

from no such limitations, and can be performed in less than

eight hours and in the absence of microwave heating. Installa-

tion of dialkyl peroxides proceeds cleanly even in the absence of

additives required in solution reactions, suggesting that the

high local concentration of alkyne relative to the surface N₃

groups suppresses aldehyde formation. Peroxyacetals, which

are much more activated than dialkyl peroxides towards

cleavage,^6,43also undergo successful click reactions on surfaces.

However, in this case, the side reaction observed in solution

phase chemistry continued to be observed in reactions on

nanoparticles. This reaction, in contrast to some results on the

extremely hindered peroxyacetal core of artemisinin, is sup-

pressed by the use of a substrate containing a greater span

between the peroxide and alkyne groups.

With the exception of functionalized SAMs displaying

peroxides (via ozonolysis of alkene-terminated monolayers)⁸

or diacyl peroxides (via condensation of H₂O₂with carboxylic

acids),^48,49there are few examples of covalent introduction of

peroxide on surfaces. Much of this is likely to relate to

concerns about compatibility of the surface with the func-

tionalization method; for example, ozone is known to attack

the thiol/Au interface and is incompatible with many

electron-rich groups.^18b,50Our work demonstrates that the

CuAAC reaction can be used to install both dialkyl peroxides

and the more reactive peroxyacetals on nanoparticle

surfaces.

Experimental procedures

General methods

All reagents and solvents were used as purchased except for

CH₂Cl₂(distilled from CaH₂), DMF (vacuum distilled from

CaH₂), and THF (distilled from Na/Ph₂CO). All nonaqueous

reactions were conducted under an atmosphere of N₂in ame-

dried glassware. Thin layer chromatography (TLC) was per-

formed on 0.25 mm hard-layer silica plates. Developed plates

were visualized by 254 nm UV lamp and/or by staining: 2.5%

ammonium molybdate and 0.5% ceric sulfate in 10% aqueous

sulfuric acid (general stain, aer heating); 1% aq. potassium

permanganate (alkynes); 1% N,N⁰-dimethyl-p-phenylenedi-

amine in 1 : 20 : 100 acetic acid/water/methanol (specic for

peroxides; dialkyl peroxides and peroxyacetals can be visualized

as a reddish or reddish-green spot upon heating);²⁶or vanillin

and sulfuric acid (3% each) in ethanol (general stain, aer

heating). Unless otherwise described, chromatography refers to

silica ash chromatography.

NMR spectra were acquired in CDCl₃at 400 (¹H) or 100 MHz

(¹³C) unless otherwise noted. Chemical shis are reported

relative to residual chloroform (7.26 ppm, ¹H; 77.36 ppm, ¹³C).

¹H spectra are reported as chemical shi (multiplicity, J

couplings in Hz, number of protons). IR spectra were recorded

as neat lms on a ZrSe crystal; selected absorbances are re-

ported in cm^ꢂ1. High resolution mass spectra (HRMS) were

obtained at the Nebraska Center for Mass Spectrometry at UNL.

XPS and TEM spectra were acquired in the Nebraska Center for

Nanoscience and Materials on a Thermo Scientic K-Alpha X-

Conclusions

Our work, the rst systematic investigation of the factors ray photoelectron spectrometer using a monochromated Al Ka

inuencing the use of click reactions for installing organic (1486.6 eV) X-ray source and a dual-beam ood source using

peroxides, demonstrates that the copper-assisted click oﬀers

a

FEI Tecnai Osiris (scanning) transmission electron

a practical approach for modular introduction of dialkyl microscope.

peroxides and peroxyacetals. The best results are obtained with

CAUTION: Although we experienced no exotherms or

dialkyl peroxides; a side reaction involving heterolytic frag- explosions during the reported investigations, any work with

mentation of the peroxide can be easily circumvented by choice peroxides of moderate or high active oxygen content, in

of substrate or additive. Although installation of more reactive particular any steps involving heating and/or concentration,

peroxyacetals can be complicated by a radical fragmentation, should be conducted following standard precautions (adjusting

this process can be minimized by use of a greater span between scale to perceived hazard; concentration, and when necessary,

the peroxide and the reaction site.

reaction behind shields; some analysis of the thermal sensitivity

Our work also provides rst example of the use of click of new products). Readers are directed towards a web-published

chemistry for modular introduction of organic peroxides on overview of peroxide safety.^10d

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44417

View Article Online

RSC Advances

Paper

as an ꢀ5.5 M solution in decane (1.36 mL, 7.48 mmol, 1.2

equiv.). The reaction was stirred at room temperature for 18

hours. The reaction was quenched with saturated aqueous

Na₂S₂O₃(10 mL), washed with brine (10 mL), and extracted with

EA (15 mL ꢃ 3). The combined organic layers were dried with

Na₂SO₄, and the residue concentrated under reduced pressure

to yield 1.1083 g (75%) of iodoalkynyl peroxide 3 as a light yellow

oil: R_f¼ 0.55 (20% EA/Hex); ¹H d 3.95 (t, J ¼ 6.3, 2H), 2.40 (t, J ¼

6.8, 2H), 1.70 (p, J ¼ 6.1, 2H), 1.59 (p, J ¼ 7.0, 2H), 1.24 (s, 9H)

¹³C d 94.4, 80.3, 74.4, 27.2, 26.5, 25.4, 20.8, ꢂ6.8; IR 2925, 1362,

1196, 877; HRMS (ESI⁺, TOF) calcd for C₁₀H₁₇INaO₂[M + Na]⁺:

319.0171; found: 319.0174.

1-Iodo-8-tert-butylperoxy octyne (4). By a similar procedure

as employed for synthesis of iodohexynyl peroxide 3, reaction of

8-(tert-butylperoxy)-1-octyne (714.9 mg, 3.60 mmol), KI

(685.5 mg, 4.13 mmol, 1.2 equiv.), and TBHP (1.0 mL, 5.5 mmol,

1.5 equiv.) furnished, aer column chromatography (10% EA/Hex),

901.1 mg (77%) of iodooctynyl peroxide 4 as a light yellow oil: R_f:

0.57 (20% EA/Hex); ¹H d 3.95 (t, J ¼ 6.7, 2H), 2.38 (t, J ¼ 7.0, 2H),

1.62 (p, J ¼ 7.1, 2H), 1.54 (p, J ¼ 7.0, 2H), 1.26–1.36 (m, 4H), 1.26 (s,

9H); ¹³C d 94.8, 80.2, 75.0, 28.7, 28.5, 27.9, 26.5, 25.8, 20.9, ꢂ7.4; IR:

2977, 2937, 2860, 1362, 1197; HRMS (ESI⁺, TOF) calcd for

C₁₂H₂₁INaO₂[M + Na]⁺: 347.0484; found: 347.0485.

Synthesis of peroxyalkynes

6-(tert-Butylperoxy)-1-hexyne (1) was prepared by an adaptation

of published procedures.⁵⁴To a solution of 6-chloro-1-hexyne

(4.66 g, 40.0 mmol) in acetone (150 mL) was added sodium

iodide (32.98 g, 220.0 mmol, 5.5 equiv.). The reaction was stir-

red under reux for 18 hours. The cooled reaction was then

diluted with water (50 mL) and extracted with hexanes (50 mL ꢃ

3). The combined organic layers were dried with Na₂SO₄and the

residue concentrated under reduced pressure to yield 7.5307 g

(91%) of 6-iodo-1-hexyne as a yellow oil which was used without

purication. Spectral details matched those previously re-

ported.^15,55R_f¼ 0.42 (10% EA/Hex); ¹H d 3.20 (t, J ¼ 8.0, 2H), 2.22

(td, J ¼ 3.5, J ¼ 9.3, 2H), 1.92 (t, J ¼ 9.3, 1H), 1.63 (p, J ¼ 6.4, 2H);

¹³C d 83.7, 69.0, 32.3, 29.2, 17.5, 6.2.

To a solution of CsOH monohydrate (4.50 g, 30.0 mmol, 1.2

equiv.) in DMF (100 mL) at 0 ^ꢁC was added dropwise TBHP as an

ꢀ5.5 M solution in decane (6.81 mL, 37.5 mmol, 1.5 equiv.). The

mixture was stirred for 30 min, whereupon 6-iodo-1-hexyne

(5.20 g, 25.0 mmol) was added. The reaction was allowed to

slowly warm to room temperature. Aer 5 h, the reaction was

quenched with water (30 mL) and extracted with hexanes (30 mL

ꢃ 3). The combined organic layers were dried with Na₂SO₄,

concentrated under reduced pressure and the residue puried

by column chromatography (5% EA/Hex) to yield 3.981 g (94%)

of 6-(tert-butylperoxy)-1-hexyne as a colorless oil. Spectral

details matched previous reports:^54aR_f¼ 0.56 (10% EA/Hex) ¹H

d 3.96 (t, J ¼ 6.4, 2H), 2.22 (td, J ¼ 7.0, J ¼ 2.6, 2H), 1.94 (t, J ¼ 2.6,

1H), 1.72 (m, 2H), 1.61 (m, 2H), 1.24 (s, 9H); ¹³C d 84.3, 80.2,

74.5, 68.6, 27.2, 26.5, 25.4, 18.4; IR: 3314, 2924, 2119, 1362,

1198, 628; HRMS (ESI⁺, TOF) calcd for C₁₀H₁₈NaO₂[M + Na]⁺:

193.1204; found: 193.1205.

Synthesis of alkynyl peroxyacetals

3-((2-Hydroperoxypropan-2-yl)oxy)-1-propyne(5) and 3-((2-((2-

hydroperoxypropan-2-yl)peroxy)propan-2-yl)oxy)-1-propyne (5a)

were prepared using a procedure reported for unsaturated

alcohols.¹⁹To a solution of propargyl alcohol (0.97 mL,

16.9 mmol, 3 equiv.) in CH₂Cl₂(50 mL) was added 2,3-dimethyl-

2-butene (0.65 mL, 5.47 mmol). This mixture was cooled to

ꢂ78 ^ꢁC whereupon a gaseous stream of O₃/O₂was admitted

(pipette, ꢀ0.5–1 mmol O₃/minute). When the reaction was

complete (TLC) introduction of O₃/O₂was halted and N₂was

briey bubbled through the reaction mixture. The solution was

carefully concentrated under reduced pressure (CAUTION) and

the residue puried by column chromatography (5% ether/

pentane) to yield 210.8 mg (20%) of hydroperoxyperoxide 5a

as a colorless oil, followed by traces of volatile hydro-

peroxyacetal 5. (CAUTION: the nearly 16% active oxygen content

of hydroperoxyperoxide 5a suggests a moderate to high poten-

tial for exothermic decomposition.) As a result, this preparation

was conned to <20 mmol scale and products were handled

carefully (see general Discussion on safety, above).^10d

8-(tert-Butylperoxy)-1-octyne (2) was prepared by a similar

procedure as described above. Reaction of 8-chloro-1-octyne

(3.3914 g, 23.45 mmol) and sodium iodide (19.366 g,

129.2 mmol, 5.5 equiv.) furnish 5.0135 g (91%) of 8-iodo-1-octyne

as a yellow oil which was used without further purication. Spec-

tral details matched those previously reported:⁵⁶R_f: 0.43 (10% EA/

Hex); ¹H d 3.19 (t, J ¼ 7.0, 2H), 2.19 (td, J ¼ 6.6, J ¼ 2.2, 2H), 1.94 (t, J

¼ 2.6, 1H), 1.83 (p, J ¼ 6.7, 2H), 1.53 (m, 2H), 1.41–1.43 (m, 4H); ¹³

d 84.5, 68.4, 33.5, 30.1, 28.3, 27.7, 18.4, 7.1.

C

By the same method as employed for synthesis of 1, reaction

of the iodooctyne (3.8046 g, 16.50 mmol) with CsOH mono-

hydrate (3.310 g, 22.1 mmol, 1.3 equiv.) and TBHP as an ꢀ5.5 M

solution in decane (4.50 mL, 24.75 mmol, 1.5 equiv., ꢀ5.5 M

solution in decane) in DMF, furnished 3.0118 g (92%) of 8-(tert-

butylperoxy)-1-octyne (2) as a colorless oil: R_f: 0.55 (10% EA/

5a: R_f¼ 0.46 (20% EA/Hex); ¹H d 9.61 (s, 1H), 4.31 (t, J ¼ 2.4,

2H), 2.43 (t, J ¼ 2.3, 1H), 1.51 (s, 6H), 1.42 (s, 6H); ¹³C d 109.4,

106.8, 80.4, 74.3, 51.2, 23.5, 20.9; IR: 3362, 3286, 2999, 2946,

1369, 1176, 1034, 826, 620; HRMS (ESI⁺, TOF) calcd for

C₉H₁₆NaO₅[M + Na]⁺: 227.0895; found: 227.0896.

1

Hex); H d 3.93 (t, J ¼ 6.6, 2H), 2.18 (td, J ¼ 6.9, J ¼ 2.5, 2H),

1.93 (t, J ¼ 2.6, 1H), 1.50–1.64 (m, 4H), 1.35–1.46 (m, 4H), 1.24 (s,

9H); ¹³C d 84.7, 80.2, 75.1, 68.3, 28.7, 28.5, 27.9, 26.4, 25.8, 18.4

IR: 3312, 2945 (s), 2956, 1456, 1360 (s), 1198 (s); HRMS (ESI⁺,

TOF) calcd for C₁₂H₂₂NaO₂[M + Na]⁺: 221.1517; found:

221.1510.

5: (trace byproduct; incompletely characterized as a colorless

1

oil): R_f¼ 0.43 (20% EA/Hex); H d 9.88 (s, 1H), 4.20 (t, J ¼ 2.4,

2H), 2.45 (t, J ¼ 2.4, 1H), 1.41 (s, 6H); ¹³C d 105.9, 81.3, 73.7, 49.9,

22.7.

1-Iodo-6-tert-butylperoxy hexyne (3) was prepared using an

adaptation of a published procedure.¹⁷To a solution of 6-(tert-

butylperoxy)-1-hexyne (850 mg, 4.99 mmol) in MeOH (20 mL)

was added KI (1.02 g, 6.13 mmol, 1.2 equiv.), followed by TBHP

4-((2-Hydroperoxypropan-2-yl)oxy)-1-butyne (6) and 4-((2-((2-

hydroperoxypropan-2-yl)peroxy)propan-2-yl)oxy)-1-butyne (6a)

were prepared using the same procedure described above. To

44418 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

a solution of 3-butyn-1-ol (1.97 mL, 26.0 mmol, 2 equiv.) in

CH₂Cl₂(125 mL) was added 2,3-dimethyl-2-butene (1.56 mL,

13.1 mmol). This mixture was cooled to ꢂ78 ^ꢁC whereupon

a gaseous stream of O₃/O₂was admitted (approximately 1 mmol

O₃/minute). When the reaction as judged complete, by TLC,

introduction of O₃/O₂was halted and N₂was briey bubbled

through the reaction mixture. The solution was carefully

concentrated under reduced pressure and the residue

(CAUTION) puried by column chromatography (5% ether/

pentane) to yield 455.6 mg (24%) of 6 as an colorless oil,

accompanied by 141.5 mg (5%) of 6a. CAUTION: The products

shown here are hydroperoxides or peroxy hydroperoxides with

active oxygen contents suggesting a moderate to high potential

for exothermic decomposition. These reactions were deliber-

ately run on a modest scale and products should be handled

carefully.

6-((2-Methylperoxypropan-2-yl)oxy)-1-hexyne (9). By a similar

procedure as described for above, a solution of hydro-

peroxyacetal 7 (146 mg, 0.85 mmol) in THF (5 mL) was reacted

with potassium tert-butoxide (114 mg, 1.02 mmol, 1.2 equiv.)

and methyl iodide (0.10 mL, 1 mmol, 1.2 equiv.), to furnish,

aer purication, 142.5 mg (90%) of peroxyacetal 9 as an

colorless oil: R_f¼ 0.45 (20% EA/Hex); ¹H d 3.84 (s, 3H), 3.53 (t, J

¼ 8.3, 2H), 2.23 (td, J ¼ 9.3, J ¼ 3.4, 2H), 1.93 (t, J ¼ 3.1, 1H),

1.71–1.59 (m, 4H), 1.38 (s, 6H); ¹³C d 104.7, 84.6, 68.4, 63.3, 61.0,

29.1, 25.4, 23.5, 23.2, 18.3; IR: 3294, 2943, 2117, 1365, 1205,

1153, 1067, 1015, 869, 629; HRMS (ESI⁺, TOF) calcd for

C

₁₀H₁₈NaO₃[M + Na]⁺: 209.1154; found: 209.1153.

1-Iodo-4-((2-methylperoxypropan-2-yl)oxy)-1-butyne (10). By

a similar procedure as employed for synthesis of iodoalkynyl

peroxide 3, reaction of peroxyacetal 8 (141 mg, 0.89 mmol) in

MeOH (3 mL) with KI (183 mg, 1.10 mmol, 1.2 equiv.) followed

by TBHP as an ꢀ5.5 M solution in decane (0.25 mL, 1.38 mmol,

1.2 equiv.) furnished, aer concentration under reduced pres-

sure. 206.7 mg (81%) of iodoalkynyl peroxyacetal 10 as a light

yellow oil: R_f¼ 0.54 (10% EA/Hex); ¹H d 3.85 (s, 3H), 3.64 (t, J ¼

7.3, 2H), 2.64 (t, J ¼ 7.4, 2H), 1.39 (s, 6H); ¹³C d 104.9, 91.5, 63.4,

60.2, 23.2, 22.6, ꢂ5.4; IR: 2992, 2940, 2891, 1366, 1199, 1152,

1073, 1013, 862; HRMS (ESI⁺, TOF) calcd for C₈H₁₃INaO₂[M +

Na]⁺: 306.9807; found: 306.9811.

1-Iodo-6-((2-methylperoxypropan-2-yl)oxy)-1-hexyne (11). By

a similar procedure as employed for synthesis of 3, reaction of

peroxyacetal 9 (242 mg, 1.30 mmol) in MeOH (10 mL) with KI

(267 mg, 1.61 mmol, 1.2 equiv.) and TBHP as an ꢀ5.5 M solu-

tion in decane (0.36 mL, 1.98 mmol, 1.5 equiv.) furnished

iodoalkynyl peroxyacetal 11 (400.8 mg, 98%) of as a light yellow

oil: R_f¼ 0.49 (10% EA/Hex); ¹H d 3.85 (s, 3H), 3.52 (t, J ¼ 6.5, 2H),

2.40 (t, J ¼ 6.8, 2H), 1.69–1.54 (m, 4H), 1.38 (s, 6H); ¹³C d 104.7,

94.7, 63.3, 61.0, 29.2, 25.4, 23.2, 20.8, ꢂ7.1; IR: 3299, 2940, 1466,

1378, 1365, 1204, 1152, 1013, 858, 632; HRMS (ESI⁺, TOF) calcd

for C₁₀H₁₇INaO₂[M + Na]⁺: 335.0120; found: 335.0126.

6a: R_f¼ 0.46 (20% EA/Hex); ¹H d 9.75 (s, 1H), 3.80 (t, J ¼ 9.6,

2H), 2.59 (td, J ¼ 6.1, J ¼ 3.6, 2H), 2.01 (t, J ¼ 3.6, 1H), 1.53 (s,

6H), 1.47 (s, 6H); ¹³C d 109.4, 106.8, 80.4, 74.3, 51.2, 23.5, 20.9;

IR: 3293, 2997, 2946, 1367, 1196, 1177, 1141, 1045, 834, 636;

HRMS (ESI⁺, TOF) calcd for C₉H₁₆NaO₅[M + Na]⁺: 241.1052;

found: 241.1052.

6: R_f¼ 0.53 (20% EA/Hex); ¹H d 8.46 (s, 1H), 3.65 (t, J ¼ 5.4,

2H), 2.50 (td, J ¼ 6.0, J ¼ 2.6, 2H), 2.09 (t, J ¼ 2.6, 1H), 1.49 (s,

6H); ¹³C d 105.7, 83.7, 69.8, 60.0, 22.6, 20.5; IR: 3427, 3287, 2995,

2947, 1367, 1201, 1158, 1051, 816, 639; HRMS (ESI⁺, TOF) calcd

for C₇H₁₂NaO₃[M + Na]⁺: 167.0684; found: 167.0681.

6-((2-Hydroperoxypropan-2-yl)oxy)-1-hexyne (7). By a similar

procedure as described above, a mixture of 5-hexyn-1-ol (0.88

mL, 7.98 mmol, 3 equiv.) in CH₂Cl₂(30 mL) and 2,3-dimethyl-2-

butene (0.32 mL, 2.69 mmol) were reacted with O₃/O₂to

generate, aer careful concentration and chromatography

328.6 mg (71%) of hydroperoxyacetal 7 as a colorless oil: R_f¼

1

0.41 (20% EA/Hex); H d 7.89 (s, 1H), 3.51 (t, J ¼ 6.5, 2H), 2.22

(td, J ¼ 6.7, J ¼ 2.6, 2H), 1.95 (t, J ¼ 2.6, 1H), 1.73–1.57 (m, 4H),

1.39 (s, 6H); ¹³C d 105.3, 84.5, 68.7, 61.2, 29.1, 25.3, 22.8, 18.3;

IR: 3296, 2993, 2943, 2872, 2117, 1740, 1366, 1199, 1151, 1061,

866, 629; HRMS (ESI⁺, TOF) calcd for C₉H₁₆NaO₃[M + Na]⁺:

195.0997; found: 195.0995.

Synthesis of peroxy azides

1-Azido-(4-(tert-butylperoxy))butane (12). To a solution of 1-

4-((2-Methylperoxypropan-2-yl)oxy)-1-butyne

(8)

was bromo-4-chlorobutane (2.57 g, 15.0 mmol) in DMF (40 mL) was

prepared using an adaptation of a reported procedure.^21,57To added sodium azide (1.96 mg, 30.1 mmol, 2 equiv.). The reac-

a solution of hydroperoxyacetal 6 (359 mg, 2.49 mmol) in THF tion was stirred at room temperature for 24 hours. The reaction

(10 mL) was added potassium tert-butoxide (350 mg, 3.12 mmol, was diluted with (20 mL) water and extracted with hexanes

1.2 equiv.), followed by methyl iodide (0.19 mL, 3.05 mmol, 1.2 (15 mL ꢃ 3). The combined organic layers were dried with

equiv.). Aer the reaction had stirred at room temperature for 5 Na₂SO₄and the residue concentrated under reduced pressure to

minutes, it was quenched with water (10 mL) and the resulting yield 1.8975 g (95%) of 1-azido-4-chlorobutane as a colorless oil

mixture extracted with ether (15 mL ꢃ 3). The combined which was used without further purication: R_f¼ 0.49 (10% EA/

organic layers were dried with Na₂SO₄and concentrated under Hex). Spectral details matched those previously reported.²²R_f¼

reduced pressure. The residue was puried by column chro- 0.49 (10% EA/Hex).

matography (10% ether/pentane) to yield 262.2 mg (66%) of

A solution of the 1-azido-4-chlorobutane (2.40 g, 18.0 mmol)

peroxyacetal 8 as a colorless oil: R_f¼ 0.54 (20% EA/Hex); ¹H and sodium iodide (15.0 g, 100 mmol, 5.5 equiv.) was reuxed in

d 3.85 (s, 3H), 3.66 (t, J ¼ 9.8, 2H), 2.47 (td, J ¼ 9.8, J ¼ 3.6, 2H), acetone (150 mL) for 18 hours. The reaction was then diluted

1.97 (t, J ¼ 3.6, 1H), 1.40 (s, 6H); ¹³C d 104.9, 81.5, 69.4, 63.4, with water (60 mL) and extracted with hexanes (50 mL ꢃ 3). The

60.2, 23.2, 20.3; IR: 2992, 2943, 2894, 1379, 1200, 1152, 1042, combined organic layers were dried with Na₂SO₄and the

864; HRMS (ESI⁺, TOF) calcd for C₈H₁₄NaO₃[M + Na]⁺: residue concentrated under reduced pressure to yield 3.6943 g

181.0814; found: 181.0841.

(91%) of 1-azido-4-iodobutane as an orange oil which was used

without further purication. Spectral details matched those

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44419

View Article Online

RSC Advances

Paper

previously reported.²²R_f¼ 0.5 (10% EA/Hex); ¹H d 3.32 (t, J ¼ 6.6,

2H), 3.20 (t, J ¼ 6.7, 2H), 1.91 (p, J ¼ 7.4, 2H), 1.71 (p, J ¼ 7.4,

2H); ¹³C d 50.5, 30.6, 30.0, 7.2.

Hexyne (14) was used as received

Hex-5-yn-1-yl benzene (15) (100848-88-2). Alkyne 15 was

prepared using a variant of a reported procedure.⁶⁰To a solution

of ethynyl trimethylsilane (998.3 mg, 3.84 mmol) in THF (10 mL)

was added n-BuLi (2.7 mL, 4.32 mmol, 1.1 equiv.) at ꢂ78 ^ꢁC,

followed by 4-(iodobutyl)benzene (386.2 mg, 3.93 mmol, 1.02

equiv.). The reaction was allowed to warm to room temperature

and stirred for 4 hours. The reaction was quenched with water

(30 mL) and the combined ethyl acetate extracts (3 ꢃ 30 mL)

were dried with Na₂SO₄. Concentration under reduced pressure

yielded 825.2 mg (85%) of trimethyl(6-phenylhex-1-yn-1-yl)

silane (2253948-27-3) as a colorless oil which was used directly

in the following reaction. R_f¼ 0.60 (10% EA/Hex). Spectra

details matched those in a literature report.⁶¹

To a solution of the crude alkynyl silane (743.2 mg, 3.09

mmol) in methanol (25 mL) was added potassium hydroxide

(304.0 mg, 5.42 mmol, 1.75 equiv.). The reaction was stirred at

room temperature for 2 hours.⁶²The reaction was quenched

with water (40 mL) and extracted with hexanes (30 mL ꢃ 3).

The combined organic layers were dried with Na₂SO₄,

concentrated under reduced pressure and the residue puried

by column chromatography (5% EA/Hex) to yield 499.0 mg

(89%) of the hex-5-yn-1-yl benzene as a colorless oil. Spectral

details matched those previously reported:^61,63R_f¼ 0.65 (10%

EA/Hex); ¹H d 7.31 (m, 2H), 7.24–7.21 (m, 3H), 2.67 (t, J ¼ 7.9,

2H), 2.25 (td, J ¼ 2.6, J ¼ 7.1, 2H), 1.98 (t, J ¼ 2.6, 1H), 1.78 (p, J

¼ 7.8, 2H), 1.61 (p, 7.5, 2H); ¹³C d 142.4, 128.5, 128.4, 125.9,

84.5, 68.4, 35.5, 30.5, 28.1, 18.4; IR: 3305, 2927, 2854, 1495,

1453, 744, 696.

3-Azidopropylbenzene (16). Iodine (11.74 g, 46.3 mmol),

PPh₃(11.89 g, 45.3 mmol) and imidazole (3.16 g, 46.4 mmol)

were sequentially added to a solution of CH₂Cl₂(300 mL). The

mixture was stirred for 15 minutes at 0 ^ꢁC, whereupon 3-phenyl-

1-propanol (5.07 g, 37.2 mmol) was added. The reaction was

stirred at room temperature for 5 hours and ltered through

a ꢀ3⁰⁰pad of silica with hexanes (600 mL). The ltrate was

concentrated under reduced pressure to yield 9.05 g (98%) of 3-

iodopropylbenzene as a light orange oil which was used without

further purication. Spectral details matched those previously

reported.⁶⁴R_f: 0.50 (10% EA/Hex); ¹H d 7.33 (t, J ¼ 7.4, 2H), 7.26

(t, J ¼ 8.1, 1H), 7.24 (d, J ¼ 6.6, 2H), 3.21 (t, J ¼ 6.8, 2H), 2.77 (t, J

¼ 7.3, 2H), 2.17 (p, J ¼ 7.2, 2H); ¹³C d 140.5, 128.7, 128.6, 126.3,

36.4, 35.0, 6.5.

To a solution of the iodopropyl benzene (1.10 g, 4.48 mmol)

in DMF (20 mL) was added sodium azide (875.6 g, 13.4 mmol, 3

equiv.). The reaction was stirred at room temperature for 18

hours. The reaction was diluted with water (10 mL) and

extracted with CH₂Cl₂(15 mL ꢃ 3). The combined organic

layers were dried with Na₂SO₄and the residue concentrated

under reduced pressure to yield 694.1 mg (96%) of 3-azidopro-

pylbenzene as a colorless oil. Spectral details matched those

previously reported.⁶⁵R_f: 0.52 (10% EA/Hex); ¹H d 7.34 (t, J ¼ 7.4,

2H), 7.26 (t, J ¼ 7.4, 1H), 7.22 (d, J ¼ 7.3, 2H), 3.32 (t, J ¼ 6.8, 2H),

2.75 (t, J ¼ 7.5, 2H), 1.95 (p, J ¼ 7.2, 2H); ¹³C d 141.0, 128.6,

128.6, 126.3, 50.8, 32.9, 30.6.

By a similar procedure as applied for synthesis of peroxide

1, reaction of CsOH monohydrate (127 mg, 0.85 mmol, 1.2

equiv.) in DMF (12 mL) at 0 ^ꢁC, TBHP as an ꢀ5.5 M solution in

decane (0.19 mL, 1.05 mmol, 1.5 equiv., ꢀ5.5 M solution in

decane), and 1-azido-4-iodobutane (158 mg, 0.70 mmol) fur-

nished, aer purication by chromatography (5% EA/Hex),

80.9 mg (62%) of the azidobutyl t-butyl peroxide (12) as

a colorless oil (CAUTION: low molecular weight azide/

1

peroxide): R_f¼ 0.51 (10% EA/Hex); H d 3.96 (m, 2H), 3.30 (t,

J ¼ 6.4, 2H), 1.71–1.66 (m, 4H), 1.24 (s, 9H); ¹³C d 80.3, 74.7,

51.4, 26.5, 26.0, 25.4; IR: 2977, 2931, 2093, 1456, 1362, 1245,

1196, 881; HRMS (ESI⁺, TOF) calcd for C₈H₁₇N₃NaO₂[M + Na]⁺:

210.1218; found: 210.1213.

((6-Azidohexan-2-yl)peroxy)triethylsilane (13). Into a RBF

containing CH₂Cl₂(300 mL), were added sequentially iodine

(7.61 g, 30.0 mmol), PPh₃(7.87 g, 30.0 mmol) and imidazole

(2.04 g, 30.0 mmol). The mixture was stirred for 15 minutes at

0 ^ꢁC, followed by the addition of 5-hexenol (2.50 g, 25.0 mmol).

Reaction was stirred at room temperature and ltered through

silica with hexanes (600 mL). The ltrate was concentrated

under reduced pressure to yield 3.8557 g (75%) of 6-iodohex-

ene as a light orange oil which was used without further

purication. Spectral details matched those previously re-

1

ported.⁵⁸R_f¼ 0.58 (10% EA/Hex); H d 5.02 (dq, J ¼ 17.0, J ¼

1.8, 1H), 4.96 (ddt, J ¼ 10.0, 1.8, 0.9, 1H), 5.78 (dddd, J ¼ 17.2, J

¼ 10.5, J ¼ 6.7, J ¼ 6.7, 1H), 3.19 (t, J ¼ 7.0, 2H), 2.08 (q, J ¼ 7.0,

2H), 1.84 (p, J ¼ 7.5, 2H), 1.50 (p, J ¼ 7.5, 2H); ¹³C d 138.2,

115.1, 33.0, 32.7, 29.8, 7.0.

To a solution of the iodohexene (1.20 g, 5.71 mmol) in DMF

(20 mL) was added sodium azide (1.11 g, 17.1 mmol, 3 equiv.).

The reaction was stirred at room temperature for 18 hours and

then diluted with water (10 mL). The combined hexane extracts

(3 ꢃ 15 mL) were dried with Na₂SO₄and the residue concen-

trated under reduced pressure to yield 688.5 mg (98%) of 6-

azido-hexene as a colorless oil which was used without further

purication. Spectral details matched those previously re-

ported:⁵⁹R_f¼ 0.59 (10% EA/Hex); ¹H d 5.01 (dq, J ¼ 17.2, J ¼ 1.6,

1H), 4.97 (d, J ¼ 10.2, 1H), 5.79 (dddd, J ¼ 17.0, J ¼ 10.5, J ¼ 6.7, J

¼ 6.7, 1H) 3.27 (t, J ¼ 6.8, 2H), 2.09 (q, J ¼ 7.1, 2H), 1.62 (p, J ¼

7.5, 2H), 1.48 (p, J ¼ 7.6, 2H); ¹³C d 138.3a 115.1, 51.5, 33.3, 28.4,

26.0.

To a solution of the azidohexene (113 mg, 0.90 mmol) in

EtOH (10 mL) was added triethylsilane (0.29 mL, 1.82 mmol, 2

equiv.), followed by Co(acac)₂(25.7 mg, 0.10 mmol, 0.1 equiv.).

The reaction was stirred at room temperature under O₂for 18

hours.²³The solution was concentrated under reduced pressure

and the residue puried by column chromatography (5% EA/

Hex) to yield 114.0 mg (46%) of azido peroxide 13 as a color-

less oil: R_f¼ 0.5 (10% EA/Hex); ¹H d 4.01 (s, J ¼ 5.8, 1H), 3.27 (t, J

¼ 6.9, 2H), 1.61–1.40 (m, 6H), 1.20 (d, J ¼ 6.2, 3H), 0.99 (t, J ¼

7.9, 9H), 0.69 (q, J ¼ 8.0, 6H); ¹³C d 81.2, 51.5, 34.0, 29.1, 22.8,

18.5, 6.9, 3.9; IR; 2938, 2877, 2093, 1459, 1242, 1006, 796, 727;

HRMS (ESI⁺, TOF) calcd for C₁₂H₂₇N₃NaO₂Si [M + Na]⁺:

296.1770; found: 296.1772.

44420 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

4-Azidobutylbenzene (17). Using a similar procedure as

RSC Advances

organic layers were dried with Na₂SO₄and the residue

concentrated under reduced pressure to yield 762.6 mg (94%) of

azido/ethioester as an orange oil which was used without

further purication. Spectral details matched those previously

reported.⁶⁹R_f¼ 0.32 (5% EA/Hex); ¹H d 3.25 (t, J ¼ 7.1, 2H), 2.86

(t, J ¼ 7.1, 2H), 2.32 (s, 3H), 1.54–1.61 (m, 4H), 1.37–1.40 (m,

4H); ¹³C d 196.0, 51.5, 30.8, 29.5, 29.0, 28.8, 28.4, 26.3; IR: 2933,

2090, 1688, 1256, 1132, 951, 624.

The deblocking of the thioacetate employed a procedure

reported for a nine-carbon homolog.⁷⁰To a solution of S-(6-

azidohexyl)ethanethioate (762.6 g, 3.79 mmol) in MeOH (70 mL)

was added conc. aq. HCl (4.0 mL). The reaction was stirred at

reux for 3 hours and then allowed to cool. The reaction was

diluted with water (20 mL) and extracted with diethyl ether

(25 mL ꢃ 3). The combined organic layers were dried with

Na₂SO₄and the residue concentrated under reduced pressure to

yield 559.8 mg (93%) of 6-azidohexane-1-thiol as a strong-

smelling orange oil. R_f¼ 0.35 (5% EA/Hex); ¹H d 3.27 (t, J ¼

6.6, 2H), 2.53 (q, J ¼ 7.2, 2H), 1.57–1.64 (m, 4H), 1.37–1.43 (m,

4H); IR: 3930, 3857, 2400 (w); 2086 (s); 1454, 1253; ¹³C d 51.5,

33.9, 28.9, 28.0, 26.3, 24.6 IR: 2930, 2087, 1254; HRMS (ESI⁺,

TOF) calcd for C₆H₁₃N₃S [M]⁺: 159.0830; found: 159.0867,

316.1512 (disulde).

described above, reaction of a solution of iodine (7.18 g, 28.3

mmol), PPh₃(7.40 g, 28.2 mmol), imidazole (1.91 g, 28.1 mmol)

and 4-phenyl-1-butanol (3.47 g, 23.1 mmol) in CH₂Cl₂(300 mL)

furnished 4.6282 g (77%) of 4-iodobutylbenzene as a light

orange oil. Spectral details matched those previously reported.⁶⁶

R_f¼ 0.51 (10% EA/Hex); ¹H d 7.32 (dt, J ¼ 5.4, J ¼ 1.5, 2H), 7.24

(dt, J ¼ 8.4, 1.2, 1H), 7.21 (d, J ¼ 6.8, 2H), 3.23 (t, J ¼ 6.8, 2H),

2.67 (t, J ¼ 7.6, 2H), 1.89 (m, 2H), 1.77 (m, 2H); ¹³C d 141.9,

128.5, 126.0, 34.9, 33.1, 32.3, 6.9.

Using a similar procedure as described above, reaction of the

4-iodobutylbenzene (1.25 g, 4.81 mmol) with sodium azide

(969 mg, 14.9 mmol, 3 equiv.) in DMF (20 mL) furnished 811.7 mg

(97%) of 4-azidobutylbenzene (17) as a colorless oil. Spectral details

matched those previously reported.⁶⁶R_f¼ 0.53 (10% EA/Hex); ¹H

d 7.32 (t, J ¼ 7.3, 2H), 7.22 (t, J ¼ 7.3, 1H), 7.21 (d, J ¼ 7.3, 2H), 3.31

(t, J ¼ 6.5, 2H), 2.68 (t, J ¼ 7.6, 2H), 1.75 (m, 2H), 1.67 (m, 2H); ¹³

d 142.0, 128.5, 128.5, 126.0, 51.5, 35.5, 28.6.

C

6-Azidohexane-1-thiol (18). This molecule, which is

commercially available, has been previously described without

characterization.⁶⁷

Synthesis of S-(6-hydroxyhexyl)ethanethioate was adapted

from a reported procedure.⁶⁷To a solution of 6-bromohexanol

(3.07 g, 17.0 mmol) in acetone (175 mL) was added potassium

thioacetate (3.92 g, 34.3 mmol, 2 equiv.). The reaction was

General procedure for click reactions

ꢁ

stirred at 40 C for 18 hours. The reaction was then quenched

Click reactions were conducted based upon adaptations of

a reported procedure.^25b

with 1 M NaHCO₃(50 mL) and the mixture extracted with ether

(50 mL ꢃ 3). The combined organic layers were dried with

Na₂SO₄, concentrated under reduced pressure, and the residue

was puried by column chromatography (5–20% ether/pentane)

to yield 1.89 g (63%) of the thioester as a red oil. Spectral details

matched those previously reported.⁶⁸R_f¼ 0.30 (30% EA/Hex);

¹H d 3.62 (t, J ¼ 6.4, 2H), 2.86 (t, J ¼ 6.8, 2H), 2.31 (s, 3H),

1.53–1.62 (m, 4H), 1.35–1.43 (m, 4H); ¹³C d 196.2, 62.9, 32.7,

30.8, 29.6, 29.1, 28.6, 25.3; IR: 3292, 2944, 1380, 1205, 1157,

1064, 831, 630.

General procedure for click reactions with CuI. To a solution

of alkyne (1 equiv.) and azide (1 equiv.) in THF was added CuI

(0.2 equiv.), followed by triethylamine (3 equiv.). The reaction

was stirred at room temperature for 3 hours, then diluted with

water and extracted with ethyl acetate (ꢃ3). The combined

organic layers were dried with Na₂SO₄, concentrated under

reduced pressure and the residue puried by column

chromatography.

General procedure for click reactions with CuSO₄. To

a solution of alkyne (1 equiv.) and azide 16 (1 equiv.) in CH₂Cl₂

was added an aqueous solution containing CuSO₄(0.2 equiv.)

and sodium ascorbate (0.2 equiv.). Aer stirring at rt for 3 h, the

reaction was diluted with water and extracted with ethyl acetate

(ꢃ3). The combined organic layers were dried with Na₂SO₄,

concentrated under reduced pressure and the residue puried

by column chromatography.

The following reagents were sequentially added to CH₂Cl₂

(300 mL): iodine (2.86 g, 11.3 mmol, 1.2 equiv.), PPh₃(2.96 g,

11.3 mmol, 1.2 equiv.) and imidazole (769.3 mg, 11.3 mmol, 1.2

ꢁ

equiv.). The mixture was stirred for 15 minutes at 0 C, where-

upon S-(6-hydroxyhexyl)ethanethioate (1.66 g, 9.42 mmol) was

added. The reaction was stirred at room temperature for 5 hours

and ltered through a 7.5 cm pad of silica with hexanes (600

mL). The ltrate was concentrated under reduced pressure to

yield 1.98 g (73%) of S-(6-iodohexyl)ethanethioate as a brown oil

which was used directly for the next reaction: R_f¼ 0.40 (5% EA/

Hex); ¹H d 3.20 (t, J ¼ 7.0, 2H), 2.89 (t, J ¼ 7.3, 2H), 2.35 (s, 3H),

4-(4-(tert-Butylperoxy)butyl)-1-(3-phenylpropyl)-1H-1,2,3-tri-

azole (19). To a solution of peroxyhexyne 1 (203 mg, 1.19 mmol)

and azide 16 (193 mg, 1.20 mmol) in THF (5 mL) was added CuI

(47.6 mg, 0.25 mmol, 0.2 equiv.),^25bfollowed by triethylamine

(0.50 mL, 3.6 mmol, 3 equiv.) and triethylsilane (0.21 mL,

1.3 mmol, 1.1 equiv.). The reaction was stirred at room

temperature for 24 hours. The reaction was diluted with water

(10 mL) and extracted with EA (15 mL ꢃ 3). The combined

organic layers were dried with Na₂SO₄, concentrated under

reduced pressure and the residue puried by column chroma-

tography (10% EA/Hex) to yield 156.2 mg (38%) of triazole 19 as

1.84 (p, J ¼ 6.8, 2H), 1.61 (p, J ¼ 6.9, 2H), 1.37–1.47 (m, 4H); ¹³

C

d 196.1, 33.4, 30.8, 30.1, 29.4, 29.1, 27.8, 7.0; IR: 2929, 1686,

1132, 954, 623; HRMS (ESI⁺, TOF) calcd for C₈H₁₅IOS [M]⁺:

285.9888; found: 285.9898.

To a solution of S-(6-azidohexyl)ethanethioate (1.16 g, 4.05

mmol) in DMF (20 mL) was added sodium azide (1.45 g,

22.3 mmol, 5.5 equiv.). The reaction was stirred at room

temperature for 18 hours. The reaction was diluted with water

(10 mL) and extracted with CH₂Cl₂(15 mL ꢃ 3). The combined

1

a yellow oil: R_f¼ 0.28 (40% EA/Hex); H d 7.29 (t, J ¼ 7.4, 2H),

7.26 (s, 1H), 7.23 (t, J ¼ 7.4, 1H), 7.19 (d, J ¼ 7.1, 2H), 4.33 (t, J ¼

RSC Adv., 2020, 10, 44408–44429 | 44421

This journal is © The Royal Society of Chemistry 2020

View Article Online

RSC Advances

Paper

7.1, 2H), 3.99 (t, J ¼ 6.3, 2H), 2.77 (t, J ¼ 7.4, 2H), 2.67 (t, J ¼ 7.5, concentrated under reduced pressure to yield 153.4 mg (90%) of

2H), 2.25 (p, J ¼ 7.3, 2H), 1.78 (m, 2H), 1.69 (m, 2H), 1.25 (s, 9H); recovered starting material as a colorless oil: R_f¼ 0.55 (10% EA/

¹³C d 148.0, 140.4, 128.7, 128.5, 126.4, 120.7, 80.2, 74.8, 49.5, Hex).

32.7, 31.8, 27.6, 26.5, 26.2, 25.6; IR: 2976, 2932, 2866, 1497,

1454, 1362, 1196, 1046, 878, 746, 670, 493; HRMS (ESI⁺, TOF) Reactions in the presence of TBTA

calcd for C₁₉H₂₉N₃NaO₂[M + Na]⁺: 354.2157; found: 354.2155.

4-(4-(tert-Butylperoxy)butyl)-1-(4-phenylbutyl)-1H-1,2,3-tri-

azole (20) and 4-(4-(tert-butylperoxy)butyl)-5-iodo-1-(4-phenyl-

CuSO₄. To 6-(tert-butylperoxy)-1-hexyne 1 (272 mg, 1.6 mmol)

and 4-phenyl-butyl-azide 17 (228 mg, 1.3 mmol) in 1 : 1 DMSO/

water (10 mL) was added CuSO₄(25.5 mg, 0.16 mmol, 0.1

butyl)-1H-1,2,3-triazole (20i). To

a

solution of 6-(tert-

equiv.), sodium ascorbate (47.5 mg, 0.24 mmol, 0.15 equiv.),

and TBTA (8.4 mg, 0.016 mmol, 0.01 equiv.). The reaction was

stirred at room temperature for 1.5 hours. The reaction was

quenched with water and extracted with ethyl acetate (15 mL ꢃ

3). The combined organic layers were dried with Na₂SO₄,

concentrated under reduced pressure and puried by column

chromatography (10% EA/Hex) to yield 89.9 mg (20%) of triazole

20 as a yellow oil: R_f¼ 0.28 (40% EA/Hex).

butylperoxy)-1-hexyne (238 mg, 1.40 mmol) and 4-azidobu-

tylbenzene (209 mg, 1.19 mmol) in THF (5 mL) was added CuI

(47.6 mg, 0.25 mmol, 0.2 equiv.), followed by triethylamine (0.60

mL, 4.29 mmol, 3 equiv.).⁴⁶The reaction was stirred at room

temperature for 1 hour. The reaction was diluted with water (10

mL) and extracted with EA (15 mL ꢃ 3). The combined organic

layers were dried with Na₂SO₄, concentrated under reduced

pressure and the residue puried by column chromatography

(10% EA/Hex) to yield 154.4 mg (37%) of triazole 20 as a yellow

oil. Reactions conducted in the presence of CuI oen contained

traces of the corresponding 5-iodotriazole (20i).

CuI. To 6-(tert-butylperoxy)-1-hexyne 1 (238 mg, 1.4 mmol)

and azide 17 (245 mg, 1.4 mmol) in DMSO : water (2.5 mL : 2.5

mL) was added CuI (57 mg, 0.30 mmol, 0.2 equiv.) and trie-

thylamine (0.6 mL, 4.2 mmol, 3 equiv.), followed by TBTA

(7.4 mg, 0.014 mmol, 0.01 equiv.). The reaction was stirred at

room temperature for 3 hours. The reaction was quenched with

water and extracted with ethyl acetate (15 mL ꢃ 3). The

combined organic layers were dried with Na₂SO₄, concentrated

under reduced pressure and puried by column chromatog-

raphy (10% EA/Hex) to yield 166.3 mg (35%) of triazole 20 as

a yellow oil: R_f¼ 0.28 (40% EA/Hex).

20: R_f¼ 0.27 (40% EA/Hex); ¹H d 7.29 (t, J ¼ 7.4, 2H), 7.24 (s,

1H), 7.21 (t, J ¼ 7.4, 1H), 7.16 (d, J ¼ 7.2, 2H), 4.33 (t, J ¼ 7.2, 2H),

3.98 (t, J ¼ 6.1, 2H), 2.75 (t, J ¼ 7.2, 2H), 2.66 (t, J ¼ 7.5, 2H), 1.93

(p, J ¼ 7.5, 2H), 1.80–1.62 (m, 6H), 1.25 (s, 9H); ¹³C d 150.0,

141.6, 128.5, 128.5, 126.1, 120.6, 80.2, 74.8, 50.1, 35.3, 29.9, 28.3,

27.6, 26.4, 26.2, 25.6 ppm; IR: 3026, 2934, 1454, 1362, 1196,

1044, 747, 699; HRMS (ESI⁺, TOF) calcd for C₂₀H₃₁N₃NaO₂[M +

Na]⁺: 368.2314; found: 368.2312.

20i: R_f¼ 0.31 (40% EA/Hex); ¹H d 7.21 (t, J ¼ 7.2, 2H), 7.18 (m,

3H), 4.37 (t, J ¼ 7.2, 2H), 3.99 (t, J ¼ 6.4, 2H), 2.70 (t, J ¼ 7.2, 2H),

2.68 (t, J ꢀ 7, 2H), 1.95 (p, J ¼ 7.2, 2H), 1.80 (m, 2H), 1.76 (m,

4H), 1.25 (s, 9H); ¹³C d 151.60, 141.7, 128.58, 128.55, 126.1,

120.6, 80.3, 78.1, 74.8, 50.6, 35.3, 29.5, 28.2, 27.6, 26.4, 26.1,

25.8 ppm; IR: 2976, 2936, 1454, 1362, 1197, 1044, 743, 699;

HRMS (ESI⁺, TOF) calcd for C₂₀H₃₀IN₃NaO₂[M + Na]⁺: 494.1280;

found: 494.1276.

Reaction of iodoalkyne

4-(4-(tert-Butylperoxy)butyl)-5-iodo-1-(3-phenylpropyl)-1H-

1,2,3-triazole (19i). To a solution of 1-iodo-6-tert-butylperoxy

hexyne 3 (118 mg, 0.40 mmol) and 3-azidopropylbenzene 16

(64.5 mg, 0.41 mmol) in THF (3.5 mL) was added CuI (7.6 mg,

0.04 mmol, 0.1 equiv.), followed by triethylamine (0.12 mL,

0.86 mmol, 2 equiv.).¹²The reaction was stirred at room

temperature for 24 hours. The reaction was diluted with water

(10 mL) and extracted with EA (15 mL ꢃ 3). The combined

organic layers were dried with Na₂SO₄, concentrated under

reduced pressure and the residue puried by column chroma-

tography (10% EA/Hex) to yield 116.4 mg (64%) of iodotetrazole

19i as a yellow oil: R_f¼ 0.36 (20% EA/Hex); ¹H d 7.32 (t, J ¼ 7.5,

2H), 7.24 (t, J ¼ 7.5, 1H), 7.22 (d, J ¼ 7.6, 2H), 4.37 (t, J ¼ 7.3, 2H),

3.99 (t, J ¼ 6.4, 2H), 2.70 (td, J ¼ 7.5, J ¼ 3.4, 4H), 2.25 (p, J ¼ 7.4,

4-(1-(4-Phenylbutyl)-1H-1,2,3-triazol-4-yl)butanal (21). This

colorless oil, which coelutes with the parent peroxide, was

a minor byproduct in many of the click reactions but became

a major byproduct for reactions conducted for long periods or

when the peroxy triazole products were resubjected to reaction

1

conditions: R_f¼ 0.27 (40% EA/Hex); H d 9.79 (t, J ¼ 0.7, 1H),

7.32–7.16 (m, 6H), 4.34 (t, J ¼ 7.2, 2H), 2.78 (t, J ¼ 7.4, 2H), 2.68

(t, J ¼ 7.5, 2H), 2.55 (td, J ¼ 1.4, J ¼ 7.3, 2H), 2.04 (p, J ¼ 7.3, 2H),

1.94 (p, J ¼ 7.6, 2H), 1.67 (m, 2H); ¹³C (176 MHz) d 202.2, 147.2,

141.6, 128.6, 128.5, 126.2, 120.8, 50.2, 43.3, 35.3, 32.1, 28.3, 27.2,

21.9; IR: 3135, 3025, 2925, 2723, 1722, 1454, 1275, 748, 701;

HRMS (ESI⁺, TOF) calcd for C₂₀H₃₁N₃NaO₂[M + Na]⁺: 294.1582;

found: 294.1588.

2H), 1.80 (p, J ¼ 7.6, 2H), 1.68 (p, J ¼ 6.3, 2H), 1.25 (s, 9H); ¹³

C

d 151.6, 140.4, 128.7, 128.6, 126.4, 80.2, 78.1, 74.7, 50.1, 32.6,

31.3, 27.6, 26.5, 26.0, 25.8; IR: 3031, 2936, 2098, 1461, 1361,

1196 1022, 880, 752, 699, 509; HRMS (ESI⁺, TOF) calcd for C₁₉

H₂₈IN₃NaO₂[M + Na]⁺: 480.1124; found: 480.1126.

-

Competition of iodoalkynyl peroxide with simple alkyne

Stability of peroxyalkyne towards CuI

To a solution of 6-(tert-butylperoxy)-1-iodohexyne 3 (0.5 mmol),

To 6-(tert-butylperoxy)-1-hexyne 1 (170 mg, 1.0 mmol) in THF (5 5-hexyn-1-ol (0.5 mmol) and 3-phenylpropyl azide 16 (0.5 mmol)

mL) was added CuI (38 mg, 0.20 mmol, 0.2 equiv.). The reaction in THF (5 mL) was added CuI (0.050 mmol, 0.1 equiv.), followed

was stirred at room temperature for 24 hours. The reaction was by triethylamine (1.0 mmol, 2 equiv.). The reaction was stirred

quenched with water and extracted with ethyl acetate (15 mL ꢃ at room temperature for 18 hours. The reaction was quenched

3). The combined organic layers were dried with Na₂SO₄, with water and extracted with ethyl acetate (15 mL ꢃ 3). The

44422 | RSC Adv., 2020, 10, 44408–44429

This journal is © The Royal Society of Chemistry 2020

View Article Online

Paper

RSC Advances

combined organic layers were dried with Na₂SO₄, concentrated 1,2,3-triazole (22) accompanied by 139.0 mg (37%) of aldehyde

under reduced pressure and puried by column chromatog- 24.

raphy (10% EA/Hex) to yield 64.5 mg (29%) of 4-(4-(tert-butyl-

4-(6-(tert-Butylperoxy)hexyl)-1-(3-phenylpropyl)-1H-1,2,3-tri-

peroxy)butyl)-5-iodo-1-(3-phenylpropyl)-1H-1,2,3-triazole (19i) azole (22) in presence of silane. To a solution of 8-(tert-

as a yellow oil.

butylperoxy)-1-octyne 2 (263.8 mg, 1.33 mmol) and 3-azidopro-

pylbenzene 16 (261.0 mg, 1.34 mmol, 1.0 equiv.) in THF (5 mL)

4-(6-(tert-Butylperoxy)hexyl)-1-(3-phenylpropyl)-1H-1,2,3-tri-

azole (6/3) (22) and 4-(6-(tert-butylperoxy)hexyl)-5-iodo-1-(3- was added CuI (53.1 mg, 0.28 mmol, 0.2 equiv.),¹²followed by

phenylpropyl)-1H-1,2,3-triazole and 6-(1-(3-phenylpropyl)-1H- triethylamine (0.60 mL, 4.3 mmol, 3 equiv.) and triethylsilane

1,2,3-triazol-4-yl)hexanal (24). To

a

solution of 8-(tert- (0.45 mL, 2.50 mmol, 1.9 equiv.). The reaction was stirred at

butylperoxy)-1-octyne 2 (304.1 mg, 1.53 mmol) and 3-azidopro- room temperature for 24 hours. The reaction was diluted with

pylbenzene 16 (268.4 mg, 1.66 mmol, 1.1 equiv.) in THF (6 mL) water (10 mL) and extracted with EA (15 mL ꢃ 3). The combined

was added CuI (64.8 mg, 0.25 mmol, 0.2 equiv.), followed by organic layers were dried with Na₂SO₄, concentrated under

triethylamine (0.65 mL, 4.66 mmol, 3 equiv.).³The reaction was reduced pressure and the residue puried by column chroma-

stirred at room temperature for 3 hours. The reaction was tography (10% EA/Hex) to yield 239.0 mg (50%) of 4-(6-(tert-

diluted with water (10 mL) and extracted with EA (15 mL ꢃ 3). butylperoxy)hexyl)-1-(3-phenylpropyl)-1H-1,2,3-triazole

as

The combined organic layers were dried with Na₂SO₄, concen- a yellow oil (spectra described previously).

trated under reduced pressure and the residue puried by

4-(6-(tert-Butylperoxy)hexyl)-5-iodo-1-(3-phenylpropyl)-1H-

column chromatography (10% EA/Hex) to yield 374.3 mg (68%) 1,2,3-triazole (22i) from iodoalkyne 3. To a solution of 1-iodo-8-

of peroxy triazole 22, 45.9 mg (6%) of iodotriazole 22i and tert-butylperoxy octyne 4 (297.2 mg, 0.917 mmol) and 3-azido-

47.1 mg (11%) of aldehyde 24.

propylbenzene 16 (159.0 mg, 0.99 mmol, 1.1 equiv.) in THF (6

1

22: R_f: 0.28 (40% EA/Hex); H d 7.31 (t, J ¼ 7.5, 2H), 7.24 (s, mL) was added CuI (28.3 mg, 0.15 mmol, 0.2 equiv.), followed by

1H), 7.22 (t, J ¼ 7.6, 1H), 7.19 (d, J ¼ 7.4, 2H), 4.33 (t, J ¼ 7.1, 2H), triethylamine (0.30 mL, 2.15 mmol, 2 equiv.).^27cThe reaction

3.94 (t, J ¼ 6.5, 2H), 2.73 (t, J ¼ 7.6, 2H), 2.66 (t, J ¼ 7.5, 2H), 2.25 was stirred at room temperature for 24 hours. The reaction was

(p, J ¼ 7.3, 2H), 1.69 (p, J ¼ 7.4, 2H), 1.61 (p, J ¼ 6.8, 2H), 1.36–1.45 diluted with water (10 mL) and extracted with EA (15 mL ꢃ 3).

(m, 4H), 1.25 (s, 9H); ¹³C d 148.4, 140.4, 128.7, 128.5, 126.4, 120.6, The combined organic layers were dried with Na₂SO₄, concen-

80.2, 75.1, 49.4, 32.7, 31.8, 29.5, 29.2, 27.9, 26.5, 26.1, 25.7; IR: 2976, trated under reduced pressure and the residue puried by

2933, 2859, 1454, 1361, 1197, 1047; HRMS (ESI⁺, TOF) calcd for column chromatography (10% EA/Hex) to yield 338.4 mg (76%)

C₂₁H₃₃N₃NaO₂[M + Na]⁺: 382.2470; found: 382.2467.

of iodotriazole 22i as a yellow oil (described previously).

4-(6-(tert-Butylperoxy)hexyl)-1-(4-phenylbutyl)-1H-1,2,3-tri-

22i: R_f: 0.32 (40% EA/Hex); ¹H d 7.31 (t, J ¼ 7.3, 2H), 7.21–7.24

(m, 3H), 4.36 (t, J ¼ 7.2, 2H), 3.94 (t, J ¼ 6.6, 2H), 2.68 (app p, J ¼ azole (23), 4-(6-(tert-butylperoxy)hexyl)-5-iodo-1-(4-phenyl-

8.1, J ¼ 7.6, 4H), 2.25 (p, J ¼ 7.2, 2H), 1.71 (p, J ¼ 7.1, 2H), 1.61 butyl)-1H-1,2,3-triazole (23i) and 6-(1-(4-phenylbutyl)-1H-1,2,3-

(p, J ¼ 6.6, 2H), 1.40–1.41 (m, 4H), 1.25 (s, 9H); ¹³C d 151.9, triazol-4-yl)hexanal (25). To a solution of 8-(tert-butylperoxy)-1-

140.4, 128.7, 128.6, 126.4, 80.1, 78.0, 75.1, 50.1, 32.6, 31.3, 29.1, octyne 2 (305.4 mg, 1.54 mmol) and 4-azidobutylbenzene 17

29.0, 27.9, 26.5, 26.1, 26.1; IR: 2974, 2934, 2861, 1453, 1362; (277.0 mg, 1.58 mmol, 1.0 equiv.) in THF (6 mL) was added CuI

HRMS (ESI⁺, TOF) calcd for C₂₁H₃₂IN₃NaO₂[M + Na]⁺: 508.1437; (64.2 mg, 0.34 mmol, 0.2 equiv.), followed by triethylamine (0.65

found: 508.1423.

mL, 4.66 mmol, 3 equiv.). The reaction was stirred at room

24: R_f: 0.27 (40% EA/Hex); ¹H d 9.76 (t, J ¼ 1.69, 1H), 7.30 (t, J temperature for 24 hours. The reaction was diluted with water

¼ 7.4, 2H), 7.25 (s, 1H), 7.22 (t, J ¼ 7.2, 1H), 7.18 (d, J ¼ 7.3, 2H), (10 mL) and extracted with EA (15 mL ꢃ 3). The combined

4.32 (t, J ¼ 7.2, 2H), 2.73 (t, J ¼ 7.6, 2H), 2.65 (t, J ¼ 7.6, 2H), 2.44 organic layers were dried with Na₂SO₄, concentrated under

(td, J ¼ 1.7, J ¼ 7.3, 2H), 2.24 (p, J ¼ 7.6, 2H), 1.69 (m, 2H), 1.58 (p, J reduced pressure and the residue puried by column chroma-

¼ 6.8, 2H) 1.42 (m, 2H); ¹³C (176 MHz) d 202.7, 148.4, 140.4, 128.7, tography (10% EA/Hex) to yield 315.7 mg (55%) of 29.8 mg (4%)

128.5, 126.4, 120.6, 62.9, 49.5, 43.9, 32.7, 31.8, 25.5, 21.9, 14.3; IR: of iodotriazole 23i, 315.7 mg (55%) of triazole 23 and 134.6 mg

2928, 2856, 1720, 1453, 1212, 1047, 1029 cm^ꢂ1; HRMS (ESI⁺, TOF) (45%) of aldehyde 25.

1

calcd for C₁₇H₂₃N₃NaO [M + Na]⁺: 308.1739; found: 308.1734.

23: R_f: 0.28 (40% EA/Hex): H d 7.30 (t, J ¼ 7.3, 2H), 7.22 (s,

1H), 7.21 (t, J ¼ 7.5, 1H), 7.16 (d, J ¼ 7.4, 2H), 4.33 (t, J ¼ 7.2, 2H),

4-(6-(tert-Butylperoxy)hexyl)-1-(3-phenylpropyl)-1H-1,2,3-tri-

azole (22) via CuSO₄. To a solution of 8-(tert-butylperoxy)-1- 3.94 (t, J ¼ 6.6, 2H), 2.72 (t, J ¼ 7.7, 2H), 2.67 (t, J ¼ 7.5, 2H), 1.94

octyne 2 (301.6 mg, 1.52 mmol) and 3-azidopropylbenzene 16 (p, J ¼ 7.6, 2H), 1.58–1.72 (m, 6H), 1.40–1.41 (m, 4H), 1.26 (s,

(260.5 mg, 1.62 mmol, 1.1 equiv.) in CH₂Cl₂(4 mL) was added 9H); ¹³C d 148.4, 141.6, 128.5, 128.5, 126.1, 120.5, 80.2, 75.1,

2 mL of an aqueous solution containing CuSO₄(50.7 mg, 50.1, 35.3, 29.9, 29.5, 29.2, 28.3, 27.9, 26.5, 26.1, 25.7; IR: 2977,

0.32 mmol, 0.2 equiv.) and sodium ascorbate (65.4 mg, 2920, 2860, 1454, 1362; HRMS (ESI⁺, TOF) calcd for

0.33 mmol, 0.2 equiv.).^12,29Aer stirring at rt for 3 h, the reaction

was diluted with water (10 mL) and extracted with EA (15 mL ꢃ

C

₂₂H₃₅N₃NaO₂[M + Na]⁺: 396.2627; found: 396.2612.

23i:²⁷R_f: 0.32 (40% EA/Hex) ¹H d 7.30 (t, J ¼ 6.8, 2H), 7.22 (t, J

3). The combined organic layers were dried with Na₂SO₄, ¼ 7.2, 1H), 7.18 (d, J ¼ 7.0, 2H), 4.37 (t, J ¼ 7.3, 2H), 3.95 (t, J ¼

concentrated under reduced pressure and the residue puried 6.3, 2H), 2.64–2.70 (m, 4H), 1.96 (p, J ¼ 7.0, 2H), 1.68–1.73 (m,

by column chromatography (10% EA/Hex) to yield 223.9 mg 4H), 1.62 (p, J ¼ 6.5, 2H), 1.38–1.46 (m, 4H), 1.26 (s, 9H); ¹³C

(41%) of 4-(6-(tert-butylperoxy)hexyl)-1-(3-phenylpropyl)-1H- d 151.9, 141.6, 128.5, 128.5, 126.1, 80.2, 77.9, 75.1, 50.6, 35.2,

29.8, 29.5, 29.1, 29.0, 28.1, 27.9, 26.5, 26.1; IR: 2088, 2920, 2858,

This journal is © The Royal Society of Chemistry 2020

RSC Adv., 2020, 10, 44408–44429 | 44423

View Article Online

RSC Advances

Paper

1454, 1361; HRMS (ESI⁺, TOF) calcd for C₂₂H₃₄IN₃NaO₂[M + concentrated under reduced pressure and the residue puried

Na]⁺: 522.1593; found: 522.1581.

by column chromatography (10% EA/Hex) to yield 88.5 mg

25: R_f: 0.27 (40% EA/Hex); ¹H d 9.77 (t, J ¼ 1.7, 1H), 7.30 (t, J ¼ (45%) of the peroxyacetal/triazole 26 as a yellow oil: R_f¼ 0.28

7.4, 2H), 7.22 (s, 1H), 7.21 (t, J ¼ 7.4, 1H), 7.16 (d, J ¼ 7.4, 2H), (30% EA/Hex); ¹H d 7.32 (t, J ¼ 7.3, 2H), 7.27 (s, 1H), 7.23 (t, J ¼

4.33 (t, J ¼ 7.2, 2H), 2.73 (t, J ¼ 7.6, 2H), 2.67 (t, J ¼ 7.6, 2H), 1.94 7.4, 1H), 7.19 (d, J ¼ 7.2, 2H), 4.33 (t, J ¼ 7.1, 2H), 3.85 (s, 3H),

(p, J ¼ 7.7, 2H), 1.63–1.73 (m, 4H), 1.59 (p, J ¼ 6.6, 2H), 1.37–1.45 3.56 (t, J ¼ 6.5, 2H), 2.77 (t, J ¼ 7.5, 2H), 2.67 (t, J ¼ 7.5, 2H), 2.25

(m, 4H); ¹³C (176 MHz) d 202.8, 148.4, 141.6, 128.5, 128.5, 126.1, (p, J ¼ 7.3, 2H), 1.82–1.56 (m, 4H), 1.40 (s, 6H); ¹³C d 148.0,

120.5, 62.9, 50.1, 43.9, 35.3, 32.7, 29.9, 28.3, 25.5, 21.9; IR: 2920, 140.4, 128.7, 128.6, 126.4, 120.7, 104.7, 63.3, 61.3, 49.5, 32.7,

2858, 1721, 1454; HRMS (ESI⁺, TOF) calcd for C₁₈H₂₅N₃NaO [M + 31.8, 29.6, 26.2, 25.6, 23.2; IR: 3025, 2926, 2858, 2202, 1736,

Na]⁺: 322.1895⁰; found: 322.1882.

4-(6-(tert-Butylperoxy)hexyl)-1-(4-phenylbutyl)-1H-1,2,3-tri-

azole (23) and 6-(1-(4-phenylbutyl)-1H-1,2,3-triazol-4-yl)hexanal

1454, 1365, 1207, 1066, 748, 701; HRMS (ESI⁺, TOF) calcd for

C

₁₉H₂₉N₃NaO₃₀. [M + Na]⁺: 370.2107; found: 370.2103.

5-Iodo-4-(4-((2-(methylperoxy)propan-2-yl)oxy)butyl)-1-(3-

(25). To

a

solution of 8-(tert-butylperoxy)-1-octyne

2

phenylpropyl)-1H-1,2,3-triazole (27i). To a solution of 1-iodo-6-

(305.1 mg, 1.54 mmol) and 4-azidobutylbenzene 17 (272.3 mg, ((2-methylperoxypropan-2-yl)oxy)-1-hexyne 11 (172 mg, 0.55

1.55 mmol, 1.0 equiv.) in CH₂Cl₂(4 mL) was added a solution of mmol) and 3-azidopropylbenzene 16 (96.7 mg, 0.60 mmol) in

CuSO₄(59.2 mg, 0.37 mmol, 0.2 equiv.) and sodium ascorbate THF (5 mL) was added CuI (10.5 mg, 0.055 mmol, 0.1 equiv.),

(75.5 mg, 0.38 mmol, 0.2 equiv.) in water (2 mL).¹²The reaction was followed by triethylamine (0.15 mL, 1.08 mmol, 2 equiv.). The

stirred at room temperature for 24 hours. The reaction was diluted reaction was stirred at room temperature for 24 hours. The

with water (10 mL) and extracted with EA (15 mL ꢃ 3). The reaction was diluted with water (10 mL) and extracted with EA

combined organic layers were dried with Na₂SO₄, concentrated (15 mL ꢃ 3). The combined organic layers were dried with

under reduced pressure and the residue puried by column Na₂SO₄, concentrated under reduced pressure and the residue

chromatography (10% EA/Hex) to yield 225.7 mg (39%) of peroxy puried by column chromatography (10% EA/Hex) to yield

triazole 23 as a yellow oil accompanied by 231.4 mg (50%) of 84.5 mg (33%) of peroxyacetal/iodotriazole 27i as a light yellow

aldehyde 25.

oil: R_f¼ 0.31 (30% EA/Hex); ¹H d 7.31 (t, J ¼ 7.0, 2H), 7.23 (t, J ¼

7.0, 1H), 7.21 (d, J ¼ 7.7), 4.36 (t, J ¼ 7.2, 2H), 3.85 (s, 3H), 3.56 (t,

J ¼ 6.6, 2H), 2.70 (t, J ¼ 7.6, 2H), 2.25 (p, J ¼ 7.4, 2H), 1.84–1.62

(m, 4H), 1.40 (s, 6H); ¹³C d 151.7, 140.4, 128.6, 128.5, 126.4,

Click reaction of peroxyacetals

To a solution of 4-((2-methylperoxypropan-2-yl)oxy)-1-butyne 8 104.7, 78.1, 63.3, 61.3, 50.1, 32.6, 31.3, 29.5, 26.0, 25.7, 23.2; IR:

(166 mg, 1.05 mmol) and 4-azidobutylbenzene 17 (193 mg, 1.10 3356, 3026, 2934, 2860, 1733, 1453, 1210, 1028, 745, 699; HRMS

mmol) in THF (6 mL) was added CuI (38.1 mg, 0.20 mmol, 0.2 (ESI⁺, TOF) calcd for C₁₅H₂₀IN₃NaO [(M ꢂ C₄H₈O₂) + Na]⁺; elim.

equiv.), followed by triethylamine (0.28 mL, 2.01 mmol, 3 with loss of peroxyacetal]⁺: 408.0549; found: 408.0549.

equiv.). The reaction was stirred at room temperature for 1.5

hours. The reaction was diluted with water (10 mL) and extrac-

Click reaction with azidoalkyl peroxides

ted with EA (15 mL ꢃ 3). The combined organic layers were dried

with Na₂SO₄, concentrated under reduced pressure and the

4-Butyl-1-(4-(tert-butylperoxy)butyl)-1H-1,2,3-triazole (28). To

residue puried by column chromatography (10% EA/Hex) to yield a solution of 1-azido-(4-(tert-butylperoxy)butane 12 (142 mg, 0.76

a light yellow oil as a nearly inseparable mixture of 4-(2-((2- mmol) and 1-hexyne 14 (65.7 mg, 0.80 mmol) in THF (3.5 mL) was

(methylperoxy)propan-2-yl)oxy)ethyl)-1-(4-phenylbutyl)-1H-1,2,3-tri- added CuI (30.5 mg, 0.16 mmol, 0.2 equiv.), followed by triethyl-

azole and 4-(2-acetoxyethyl)-1-(4-phenylbutyl)-1H-1,2,3-triazole. The amine (0.32 mL, 2.30 mmol, 3 equiv.). Aer stirring for 3.5 hours,

peroxyacetal, typically formed in less than 10% yield, was the reaction was diluted with water (10 mL). The combined EA

contaminated with variable amounts of the ester.

extracts (15 mL ꢃ 3) were dried with Na₂SO₄, and concentrated

4-(2-((2-(Methylperoxy)propan-2-yl)oxy)ethyl)-1-(4-phenyl-

under reduced pressure. The residue was puried by column

butyl)-1H-1,2,3-triazole. R_f¼ 0.34 (30% EA/Hex); ¹H d 7.32 (t, J ¼ chromatography (10% EA/Hex) to yield 69.5 mg (34%) of peroxy

7.1, 2H), 7.27 (s, 1H), 7.24 (t, J ¼ 7.7, 1H), 7.23 (d, J ¼ 7.5, 2H), triazole 28 as a light yellow oil: R_f¼ 0.25 (40% EA/Hex); ¹H d 7.26 (s,

4.38 (t, J ¼ 7.2, 2H), 3.86 (t, J ¼ 7.6, 2H), 3.84 (s, 3H), 2.97 (t, J ¼ 1H), 4.34 (t, J ¼ 7.2, 2H), 3.95 (t, J ¼ 6.2, 2H), 2.70 (t, J ¼ 7.7, 2H),

7.5, 2H), 2.71 (t, J ¼ 7.3, 2H), 2.26 (p, J ¼ 7.4, 2H), 1.28 (s, 6H); 1.98 (p, J ¼ 7.5, 2H), 1.64 (p, J ¼ 7.4, 2H), 1.62 (p, J ¼ 7.4, 2H), 1.37

¹³C d 149.3, 140.4, 128.7, 128.6, 126.4, 104.9, 63.3, 60.7, 50.2, (tt, J ¼ 14.9, J ¼ 7.4, 2H), 1.22 (s, 9H), 0.92 (t, J ¼ 7.3, 3H); ¹³C

32.6, 31.4, 29.8, 27.4, 23.2.

4-(4-((2-(Methylperoxy)propan-2-yl)oxy)butyl)1-(3-phenyl-

propyl)-1H-1,2,3-triazole (26). To

d 148.5, 120.6, 80.4, 74.2, 50.0, 31.7, 27.5, 26.4, 25.5, 25.1, 22.4, 14.0;

IR: 3133, 2931, 2097, 1458, 1362, 1196, 1046, 880; HRMS (ESI⁺, TOF)

a

solution of 6-((2- calcd for C₁₄H₂₇N₃NaO₂[M + Na]⁺: 292.2001; found: 292.2003.

methylperoxypropan-2-yl)oxy)-1-hexyne 10 (102 mg, 0.55 mmol)

4-(4-(tert-Butylperoxy)butyl)-1-(4-phenylbutyl)-1H-1,2,3-tri-

and 4-azidobutylbenzene 17 (98.1 mg, 0.56 mmol) in THF (5 mL) azole (29). By a similar procedure as for synthesis of 28 (above),

was added CuI (20.9 mg, 0.11 mmol, 0.2 equiv.), followed by reaction of a THF solution (3.5 mL) of 1-azido-(4-(tert-butyl-

triethylamine (0.23 mL, 1.7 mmol, 3 equiv.). The reaction was peroxy)butane 12 (140 mg, 0.75 mmol) and 5-hexynyl benzene

stirred at room temperature for 3 hours. The reaction was 15 (125 mg, 0.79 mmol), CuI (30.5 mg, 0.16 mmol, 0.2 equiv.),

diluted with water (10 mL) and extracted with EA (15 mL ꢃ 3). and triethylamine (0.32 mL, 2.30 mmol, 3 equiv.) furnished

The combined organic layers were dried with Na₂SO₄, 38.5 mg (15%) of peroxy triazole 29 as a light yellow oil: R_f¼

44424 | RSC Adv., 2020, 10, 44408–44429

View Article Online

Paper

RSC Advances

0.23 (40% EA/Hex); ¹H d 7.31–7.17 (m, 6H), 4.39 (t, J ¼ 7.3, 2H),

3.99 (t, J ¼ 6.2, 2H), 2.77–2.64 (m, 4H), 2.02 (m, 2H), 1.83–1.61

(m, 6H), 1.26 (s, 9H); ¹³C d 152.1, 142.5, 128.6, 128.5, 128.4,

125.8, 80.3, 74.0, 50.6, 35.7, 31.0, 28.7, 27.0, 26.5, 26.1, 25.1; IR:

3026, 2925, 2155, 2032, 1454, 1362, 1196, 699; HRMS (ESI⁺,

TOF) calcd for C₂₀H₃₁N₃NaO₂[M + Na]⁺: 368.2314; found:

368.2313.

Dodecanethiolate functionalized gold nanoparticles.

Synthesis of dodecanethiolate functionalized gold nano-

particles were prepared following a reported procedure.^38aAn

aqueous solution of hydrogen tetrachloroaurate (10 mL,

30 mmol, 30 mM) was vigorously stirred with a toluene solution

of tetraoctylammonium bromide (27 mL, 50 mmol, 50 mM)

until the tetrachloroaurate was transferred into the organic

toluene layer. Dodecanethiol (57 mg) was then added to the

organic phase, followed by the addition of freshly prepared

aqueous solution of sodium borohydride (8.33 mL, 3.3 mmol,

0.4 M). The reaction was stirred for 3 hours at room tempera-

ture. Aer 3 hours of stirring at room temperature, the organic

layer was separate, and concentrated under reduced pressure to

1 mL, and mixed with 125 mL of methanol to remove excess

thiol and kept at ꢂ18 C for 4 hours. The solution was centri-

fuged and washed with methanol (25 mL ꢃ 3) to yield (73.1 mg)

4-Butyl-1-(4-(tert-butylperoxy)butyl)-1H-1,2,3-triazole

(28,

CuSO₄catalyst). To a solution of azidoperoxide 12 (0.80 mmol)

and 1-hexyne 14 (0.9 mmol) in CH₂Cl₂(3.5 mL) was added

a solution of CuSO₄(0.16 mmol, 0.2 equiv.) and sodium ascor-

bate (0.16 mmol, 0.2 equiv.) in water (1.5 mL). Aer stirring for

24 h, the reaction was diluted with water. The combined ethyl

acetate extracts (3 ꢃ 15 mL) were dried with Na₂SO₄, concen-

trated under reduced pressure and puried by column chroma-

tography (10% EA/Hex) to yield 61.7 mg (29%) of peroxy triazole

28 as a light yellow oil: R_f¼ 0.25 (40% EA/Hex).

1

a black precipitate: H d 1.27 (10H), 0.91 (3H); IR: 2956, 2920;

4-(4-(tert-Butylperoxy)butyl)-1-(4-phenylbutyl)-1H-1,2,3-tri-

azole (29, CuSO₄catalyst). By a similar procedure as described

above for synthesis of 28, reaction of azidoperoxybutane 12 and

hexynyl benzene (15) with CuSO₄and sodium ascorbate in

CH₂Cl₂water furnished 7.1 mg (5%) of peroxy triazole 29.

UV-vis: 520.65 nm (diagnostic signal; see ESI†); elemental

analysis: Au, 78.4; C, 17.7; S, 3.9%; XPS (binding energies): Au

4f_7/2(82.9 eV), Au 4f_5/2(86.6 eV), C 1s (283.8 eV), S 2p (161.0 eV).

Azide functionalized gold nanoparticles (N₃Au) were

prepared via a modication of reported procedures.³⁶To

a solution of C₅SH-Au P (47.9 mg) in CH₂Cl₂(5 mL) was added 6-

azidohexane-1-thiol (142.5 mg). Aer stirring for 3 days at room

temperature under nitrogen, the reaction solution was

concentrated under reduced pressure and pelleted/

resuspended (6 ꢃ 10 mL, methanol) to yield (62.3 mg)

Unsuccessful click reaction involving silylperoxy/azide 13

Reaction of peroxide 13 with alkynes 14 or 15 in the presence of

20% CuI/Et₃N under conditions similar to those described

earlier furnished a mixture of peroxide decomposition prod-

ucts. The same reaction, when conducted in the presence of

20% CuSO₄/sodium ascorbate resulted in no detectable reaction

(TLC) and extensive recovery of 13.

1

a brown precipitate: H d 3.31 (2H), 1.45 (2H), 1.28 (4H), 0.87

(3H); IR: 2922, 2851, 2094; elemental analysis: Au, 54.0; C, 34.2;

S, 8.5; N, 3.3%; XPS (binding energies): Au 4f_7/2(83.1 eV), Au 4f_5/

₂(86.9 eV), C 1s (283.9 eV), S 2p (162.0 eV), N 1s (398.3 eV).

Peroxide functionalized gold nanoparticles (PeroxideAu)

were prepared via a modication of reported procedures.³⁷To

a solution of 6-(tert-butylperoxy)-1-hexyne (182.9 mg, 1.07

mmol) and azidoalkylthiolate Au-NP (23.4 mg) in THF (5 mL)

was added CuI (41.7 mg, 0.22 mmol, 0.2 equiv. per alkyne),

followed by triethylamine (0.50 mL, 3.6 mmol, 3 equiv. per

alkyne). The reaction was stirred at room temperature for 8

hours. The reaction was diluted with saturated aqueous solu-

tion of NH₄Cl (10 mL) and the organic layer was washed with

water (10 mL ꢃ 3). The organic layer was dried with Na₂SO₄,

concentrated under reduced pressure and washed with meth-

anol (10 mL ꢃ 6) to remove excess alkyne to yield (29.8 mg)

Preparation of functionalized nanoparticles

Synthesis of pentanethiolate functionalized gold nanoparticles

was adapted from a reported procedure.^38aAn aqueous solution

of hydrogen tetrachloroaurate (10 mL, 30 mmol, 30 mM) was

vigorously stirred with a toluene solution of tetraoctylammo-

nium bromide (27 mL, 50 mmol, 50 mM) until the tetra-

chloroaurate was transferred into the organic toluene layer.

Pentanethiol (42 mg) was then added to the organic phase,

followed by the addition of freshly prepared aqueous solution of

sodium borohydride (8.33 mL, 3.3 mmol, 0.4 M). Aer the reaction

had stirred for 3 hours at room temperature, the organic layer was

separated and concentrated under reduced pressure to a volume of

ꢀ1 mL. The concentrated layer was mixed with 125 mL of meth-

anol and held at ꢂ18 C for 4 hours. The resulting solution was

centrifuged. The nanoparticle-containing pellet was resuspended

(methanol, 25 mL) and again centrifuged (3ꢃ) to yield (73.1 mg)

1

a light brown precipitate: H d 3.99 (2H), 2.47 (2H), 1.60–1.75

(8H), 1.26–1.30 (11H), 0.88 (1.5 H) IR: 2975, 2926, 2865, 1723,

1559, 1463, 1362, 1022, 803; elemental analysis: Au, 26.4; C,

49.9; S, 4.7; N, 5.1; O, 13.9%; XPS (binding energies): Au 4f_7/2

(84.0 eV), Au 4f_5/2(87.8 eV), C 1s (284.3 eV), S 2p (162.9 eV), N 1s

(399.6 eV), O 1s (531.5 eV).

Peroxyacetal functionalized gold nanoparticles (Perox-

yacetalAu). To a solution of 6-((2-peroxypropan-2-yl)oxy)-1-

hexyne (197.9 mg, 1.06 mmol) and azidoalkylthiolate Au-NP

(28.2 mg) in THF (5 mL) was added CuI (41.4 mg, 0.22 mmol,

0.2 equiv. per alkyne), followed by triethylamine (0.50 mL,

3.6 mmol, 3 equiv. per alkyne). The reaction was stirred at room

temperature for 8 hours. The reaction was diluted with

1

a brown precipitate: H d 1.32 (4H), 0.92 (3H);³⁹IR: 2956, 2921;

elemental analysis: Au, 50.1; C, 43.9; S, 6.0%; XPS (binding ener-

gies): Au 4f_7/2(82.6 eV), Au 4f_5/2(86.4 eV), C 1s (284.3 eV), S 2p

(161.2 eV). Solutions of the nanoparticles displayed a broad

absorption in the following paragraph, a dodecanethiol-passivated

set of nanoparticles prepared as a standard, and which did display

the small 520 nm bump, otherwise exhibited identical properties

to the C5 nanoparticles.⁷¹

RSC Adv., 2020, 10, 44408–44429 | 44425

View Article Online

RSC Advances

Paper

saturated aqueous solution of NH₄Cl (10 mL) and the organic

layer was washed with water (10 mL ꢃ 3). The organic layer was

dried with Na₂SO₄, concentrated under reduced pressure and

washed with methanol (10 mL ꢃ 6) to remove excess alkyne to

3 G. O. Wilson, J. W. Henderson, M. M. Caruso, B. J. Blaiszik,

P. J. McIntire, N. R. Sottos, S. R. White and J. S. Moore,

Evaluation

of

peroxide

initiators

for

radical

polymerization-based self-healing applications, J. Polym.

Sci., Part A: Polym. Chem., 2010, 48, 2698–2708.

1

yield (14.1 mg) a yellow precipitate: H d 3.86 (2H), 2.05 (2H),

1.67 (2H), 1.57 (6H), 1.39 (5 H), 1.28 (4H), 1.12 (4H), 0.91 (5H);

IR: 3411, 2921, 2851, 1738, 1240, 1065; elemental analysis: Au,

20.0; C, 52.6; S, 4.3; N, 4.6; O, 18.5%; XPS (binding energies): Au

4f_7/2(83.9 eV), Au 4f_5/2(87.6 eV), C 1s (284.0 eV), S 2p (163.2

eV), N 1s (399.3 eV), O 1s (531.5 eV).

4 P. M. O'Neill, V. E. Barton and S. A. Ward, The molecular

mechanism of action of artemisinin—the debate

continues, Molecules, 2010, 15, 1705–1721.

5 P. H. Dussault, A. D. George and T. K. Trullinger, Peroxides

as oxidative enzyme inhibitors: mechanism-based

inhibition of a cysteine protease by an amino acid ozonide,

Bioorg. Med. Chem. Lett., 1999, 9, 3255–3258.

6 S. Kyasa, R. N. Meier, R. A. Pardini, T. K. Truttmann,

K. T. Kuwata and P. H. Dussault, Synthesis of Ethers via

Reaction of Carbanions and Monoperoxyacetals, J. Org.

Chem., 2015, 80, 12100–12114.

7 (a) N. A. Porter, A perspective on free radical autoxidation:

the physical organic chemistry of polyunsaturated fatty

acid and sterol peroxidation, J. Org. Chem., 2013, 78, 3511–

3524; (b) A. Bodin, M. Linnerborg, J. L. G. Nilsson and

A.-T. Karlberg, Structure Elucidation, Synthesis, and

Abbreviations

Hexane(s)

EA

THF

Hex

Ethyl acetate

Tetrahydrofuran

N,N-Dimethylformamide

Dimethyl sulfoxide

Ethanol

DMF

DMSO

EtOH

MeOH

TEA

Methanol

Triethylamine

Contact Allergenic Activity of

a Major Hydroperoxide

Na ascorb. Sodium ascorbate

Formed at Autoxidation of the Ethoxylated Surfactant

C12E5, Chem. Res. Toxicol., 2003, 16, 575–582.

TBHP

tert-Butyl hydroperoxide

TBTA

Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine

8 (a) T. M. McIntire, O. Ryder and B. Finlayson-Pitts, Secondary

ozonide formation from the ozone oxidation of unsaturated

self-assembled monolayers on zinc selenide attenuated total

reectance crystals, J. Phys. Chem. C, 2009, 113, 11060–11065;

(b) A. Razgon, R. G. Bergman and C. N. Sukenik, Ozonolysis-

based route to the in situ formation of aldehyde-bearing self-

assembled monolayer surfaces, Langmuir, 2008, 24, 2545–

2552.

Co(acac)₂

Cobalt(II) acetylacetonate

Conﬂicts of interest

There are no conicts of interest to declare.

9 (a) H. X. Jin, H. H. Liu, Q. Zhang and Y. Wu, On the

susceptibility of organic peroxy bonds to hydride

reduction, J. Org. Chem., 2005, 70, 4240–4247; (b)

I. Opsenica, D. Opsenica, K. S. Smith, W. K. Milhous and

Acknowledgements

Funding was provided by NSF (CHE 1464914) and by Dr In Quen

Lee. Materials characterization was performed in part in the

Nebraska Nanoscale Facility: National Nanotechnology Coor-

dinated Infrastructure and the Nebraska Center for Materials

and Nanoscience, facilities supported by NSF (ECCS 1542182)

and the Nebraska Research Initiative. We thank Prof. Martha

Morton, Ms Nataliia Vorobyova, Dr Moriah Locklear, and Mr

Boone Evans for technical assistance and/or insightful

suggestions.

ˇ

B. A. Solaja, Chemical stability of the peroxide bond

enables diversied synthesis of potent tetraoxane

antimalarials, J. Med. Chem., 2008, 51, 2261–2266; (c)

P. Dussault, The peroxide changes everything: new

methodology for the synthesis of peroxide-containing

natural products, Synlett, 1995, 997–1003; (d) H. O'Dowd,

P. Ploypradith, S. Xie, T. A. Shapiro and G. H. Posner,

Antimalarial

artemisinin

analogs.

Synthesis

via

chemoselective C-C bond formation and preliminary

biological evaluation, Tetrahedron, 1999, 55, 3625–3636; (e)

P. H. Dussault and C. T. Eary, Palladium-Mediated

References

1 (a) I. A. Yaremenko, V. A. Vil, D. V. Demchuk and

A. O. Terent'ev, Rearrangements of organic peroxides and

related processes, Beilstein J. Org. Chem., 2016, 12, 1647–

1748; (b) P. Dussault, Reactions of Hydroperoxides and

Carbon– Carbon Bond Forming Reactions as

a New

Method for the Synthesis of Peroxides and Hydroperoxides,

J. Am. Chem. Soc., 1998, 120, 7133–7134.

Peroxides, in Active Oxygen In Chemistry, Chapman & Hall, 10 (a) J. Zabicky, Analytical and Safety Aspects of Organic

London, 1995, pp. 141–203; (c) The Chemistry of Peroxides,

ed. J. F. Liebman and A. Greer, Wiley, 2014, vol. 3, p. 1120,

ISBN: 978-1-118-41271-8.

2 For example, see: A. Banerjee and H. Yamamoto, Direct N–O

bond formation via oxidation of amines with benzoyl

peroxide, Chem. Sci., 2019, 10, 2124–2129.

Peroxides and Related Functional Groups, in The Chemistry

of the Peroxide Group, ed. Z. Rappoport, John Wiley & Sons,

Chichester, 2006, vol. 2, pt 2, pp. 597–773; ISBN: 978-0-470-

86274-2; (b) D. E. Clark, Peroxides and Peroxide-forming

Compounds, J. Chem. Health Saf., 2001, 8, 12–21; (c)

G. D. Kozak, A. N. Tsvigunov and N. I. Akinin, Similarities

44426 | RSC Adv., 2020, 10, 44408–44429

View Article Online

Paper

RSC Advances

and Diﬀerences in Explosion Hazards of Organic Peroxides

and High Explosives: an Experimental Study, Cent. Eur. J.

Silica-Coated Gold Nanoparticles: Robust Bioprobes, Adv.

Funct. Mater., 2005, 15, 961–967.

Energ. Mater., 2011, 8, 249–260; (d) P. H. Dussault, Working 15 X.-R. Jiang, P. Wang, C. L. Smith and B. T. Zhu, Synthesis of

with Organic Peroxides in the Academic Lab, Department of

Chemistry, University of Nebraska-Lincoln; Digital

Commons@University of Nebraska Lincoln; DOI: 10.13014/

K2GT5KCJ; accessed July 2020.

Novel Estrogen Receptor Antagonists Using Metal-Catalyzed

Coupling Reactions and Characterization of Their Biological

Activity, J. Med. Chem., 2013, 56, 2779–2790.

16 P. Dussault and A. Sahli, 2-Methoxy-2-propyl hydroperoxide:

a convenient reagent for the synthesis of hydroperoxides and

peracids, J. Org. Chem., 1992, 57, 1009–1012.

11 (a) C. S. McKay and M. G. Finn, Click chemistry in complex

mixtures: bioorthogonal bioconjugation, Chem. Biol., 2014,

21, 1075–1101; (b) W. H. Binder and R. Sachsenhofer, 17 K. Rajender Reddy, M. Venkateshwar, C. Uma Maheswari

‘Click’ chemistry in polymer and materials science,

Macromol. Rapid Commun., 2007, 28, 15–54; (c) J. E. Moses

and A. D. Moorhouse, The growing applications of click

and P. Santhosh Kumar, Mild and eﬃcient oxy-iodination

of alkynes and phenols with potassium iodide and tert-

butyl hydroperoxide, Tetrahedron Lett., 2010, 51, 2170–2173.

chemistry, Chem. Soc. Rev., 2007, 36, 1249–1262; (d) 18 (a) Y. Yamamoto, E. Niki and Y. Kamiya, Ozonization of

H. C. Kolb and K. B. Sharpless, The growing impact of

click chemistry on drug discovery, Drug Discovery Today,

2003, 8, 1128–1137; (e) R. Chelmowski, D. Kafer,

Organic Compounds. Relative Reactivity of Protic Solvents

Toward Carbonyl Oxide, Bull. Chem. Soc. Jpn., 1982, 55,

2405–2406; (b) T. Fisher and P. H. Dussault, Alkene

Ozonolysis, Tetrahedron, 2017, 73, 4233–4258.

¨

S. D. Koster, T. Klasen, T. Winkler, A. Terfort, N. Metzler-

¨

Nolte and C. Woll, Postformation modication of SAMs: 19 P. H. Dussault and D. R. Davies, Synthesis of 1,2-dioxanes,

using click chemistry to functionalize organic surfaces,

Langmuir, 2009, 25, 11480–11485.

12 (a) M. Meldal and C. W. Tornøe, Cu-catalyzed azide– alkyne

1,2,4-trioxanes, and 1,2,4-trioxepanes via cyclizations of

unsaturated hydroperoxyacetals, Tetrahedron Lett., 1996,

37, 463–466.

cycloaddition, Chem. Rev., 2008, 108, 2952–3015; (b) 20 The pK_aof propargyl alcohol is 13.2. Triuoroethanol (pK_aꢀ

J. E. Hein and V. V. Fokin, Copper-catalyzed azide-alkyne

cycloaddition and beyond: new reactivity of copper

acteylides, Chem. Soc. Rev., 2011, 39, 1302–1315; (c) L. Zhu,

C. J. Brassard, X. Zhang, P. M. Guha and R. J. Clark, On

12.4) has been employed as a nonnucleophilic polar solvent

for ozonolysis: K. J. McCullough, H. Tokuhara, A. Masuyama

and M. Nojima, New approaches to the synthesis of spiro-

peroxylactones, Org. Biomol. Chem., 2003, 1, 1522–1527.

the Mechanism of Copper(I)-Catalyzed Azide–Alkyne 21 Y. Hamada, H. Tokuhara, A. Masuyama, M. Nojima,

Cycloaddition, Chem. Rec., 2016, 16, 1501–1517.

H. S. Kim, K. Ono, N. Ogura and Y. Wataya, Synthesis and

notable antimalarial activity of acyclic peroxides, 1-

(alkyldioxy)-1-(methyldioxy) cyclododecanes, J. Med. Chem.,

2002, 45, 1374–1378.

13 (a) S. Jana, S. Iram, J. Thomas, S. Liekens and W. Dehaen,

Synthesis and anticancer activity of novel aza-artemisinin

derivatives, Bioorg. Med. Chem., 2017, 25, 3671–3676; (b)

´

H. M. Ismail, V. E. Barton, M. Panchana, 22 L. Yao, B. T. Smith and J. Aube, Base-Promoted Reactions of

S. Charoensutthivarakul, G. A. Biagini, S. A. Ward and

P. M. O'Neill, Click Chemistry-Based Proteomic

Approach Reveals that 1,2,4-Trioxolane and Artemisinin

Bridged Ketones and 1,3- and 1,4-Haloalkyl Azides:

Competitive Alkylation vs. Azidation Reactions of Ketone

Enolates, J. Org. Chem., 2004, 69, 1720–1722.

A

Antimalarials Share a Common Protein Alkylation Prole, 23 (a) S. Isayama and T. Mukaiyama, A New Method for

Angew. Chem., Int. Ed., 2016, 55, 6401–6405; (c) W. Li,

Y. Zhou, G. Tang and Y. Xiao, Characterization of the

Artemisinin Binding Site for Translationally Controlled

Tumor Protein (TCTP) by Bioorthogonal Click Chemistry,

Bioconjugate Chem., 2016, 27, 2828–2833; (d) L. H. Binh,

N. T. T. Van, V. T. Kien, N. T. T. My, L. Van Chinh,

N. T. Nga, H. X. Tien, D. T. Thao and T. K. Vu, Synthesis

and in vitro cytotoxic evaluation of new triazole derivatives

Preparation of Alcohols from Olens with Molecular

Oxygen and Phenylsilane by the use of Bis(acetylacetonato)

cobalt(II), Chem. Lett., 1989, 18, 1071–1074; (b)

T. Tokuyasu, S. Kunikawa, A. Masuyama and M. Nojima,

Co(III)-alkyl complex- and Co(III)-alkylperoxo complex-

catalyzed triethylsilylperoxidation of alkenes with

molecular oxygen and triethylsilane, Org. Lett., 2002, 4,

3595–3598.

¨

based on artemisinin via click chemistry, Med. Chem. Res., 24 (a) Organic azides: syntheses and applications, ed. S. Brase and

¨

2016, 25, 738–750.

K. Banert, John Wiley & Sons, 2010; (b) T. M. Klapotke,

14 (a) Y. Chen, J. Q. Ren, X. G. Zhang, D. Y. Wu, A. G. Shen and

J. M. Hu, Alkyne-Modulated Surface-Enhanced Raman

Scattering-Palette for Optical Interference-Free and

Multiplex Cellular Imaging, Anal. Chem., 2016, 88, 6115–

T. Rotariu, B. Stiasny, J. Stierstorfer, S. Wiegmann and

T. Zecheru, Azido (tert-butylperoxy) methyl Compounds–An

Exceptional Class of Energetic Materials, Eur. J. Org. Chem.,

2016, 4382–4386.

6119; (b) R. Kozlowski, A. Ragupathi and R. B. Dyer, 25 (a) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev,

Characterizing the Surface Coverage of Protein-Gold

Nanoparticle Bioconjugates, Bioconjugate Chem., 2018, 29,

2691–2700; (c) S. Liu and M. Han, Synthesis,

Functionalization, and Bioconjugation of Monodisperse,

L. Noodlesman, K. B. Sharpless and V. V. Fokin, Copper(I)-

Catalyzed Synthesis of Azoles. DFT Study Predicts

Unprecedented Reactivity and Intermediates, J. Am. Chem.

Soc., 2005, 127, 210–216; (b) P. Wu and V. V. Fokin,

RSC Adv., 2020, 10, 44408–44429 | 44427

View Article Online

RSC Advances

Paper

Catalytic Azide-Alkyne Cycloaddition: Reactivity and 36 P. Zhao, M. Grillaud, L. Salmon, J. Ruiz and D. Astruc, Click

Applications, Aldrichimica Acta, 2007, 40, 7–17.

26 L. L. Smith and F. L. Hill, Detection of sterol hydroperoxides

on thin-layer chromatoplates by means of the Wurster dyes,

J. Chromatogr., 1972, 66, 101–109.

27 (a) D. N. Barsoum, N. Okashah, X. Zhang and L. Zhu,

Mechanism of Copper(I)-Catalyzed 5-Iodo-1,2,3-triazole

Functionalization of Gold Nanoparticles Using the Very

Eﬃcient Catalyst Copper(I) (Hexabenzyl)tris(2-aminoethyl)-

amine Bromide, Adv. Synth. Catal., 2012, 354, 1001–1011.

37 E. Boisselier, L. Salmon, J. Ruiz and D. Astruc, How to very

eﬃciently functionalize gold nanoparticles by “click”

chemistry, Chem. Commun., 2008, 5788–5790.

¨

Formation from Azide and Terminal Alkyne, J. Org. Chem., 38 (a) M. Brust, M. Walker, D. Bethell, D. J. Schiﬀrin and

2015, 80, 9542–9551; (b) D. N. Barsoum, C. J. Brassard,

J. H. A. Deeb, N. Okashah, K. Sreenath, J. T. Simmons and

L. Zhu, Synthesis of 5-Iodo-1,2,3-triazoles from organic

azides and terminal alkynes: Ligand Acceleration Eﬀect,

Substrate Scope, and Mechanistic Insights, Synthesis, 2013,

45, 2372–2386; (c) J. E. Hein, J. C. Tripp, L. B. Krasnova,

R. Whyman, Synthesis of Thiol-derivatised Gold

Nanoparticles in a Two-phase Liquid-Liquid System, Chem.

Commun., 1994, 801–802; (b) M. Brust, J. Fink,

D. J. Schiﬀrina, D. Bethella and C. Kielyb, Synthesis and

Reactions of Functionalised Gold Nanoparticle, Chem.

Commun., 1995, 1655–1656.

K. B. Sharpless and V. V. Fokin, Copper (I)-catalyzed 39 Due to limited freedom of rotation, hydrogens near the Au–S

cycloaddition of organic azides and 1-iodoalkynes, Angew.

Chem., Int. Ed., 2009, 48, 8018–8021.

28 P. S. Donnelly, S. D. Zanatta, S. C. Zammit, J. M. White and

S. J. Williams, “Click” cycloaddition catalysts: copper(i) and

copper(ii) tris(triazolylmethyl)amine complexes, Chem.

Commun., 2008, 2459.

interface are oen invisible to solution phase NMR. (a)

C. Guo and J. L. Yarger, Characterizing gold nanoparticles

by NMR spectroscopy, Magn. Reson. Chem., 2018, 56, 1074–

1082; (b) L. E. Marbella and J. E. Millstone, NMR

Techniques for Noble Metal Nanoparticles, Chem. Mater.,

2015, 27, 2721–2739.

29 (a) B. T. Worrell, J. A. Malik and V. V. Fokin, Direct Evidence 40 Oxford Instruments, EDS in the TEM Explained (12 pages),

of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide- 2013, https://nano.oxinst.com/product/eds-for-tem.

Alkyne Cycloadditions, Science, 2013, 80(340), 457–460; (b) 41 X. Zhang, P. Liu and L. Zhu, Structural Determinants of

R. Berg and B. F. Straub, Advancements in the mechanistic

understanding of the copper-catalyzed azide–alkyne

cycloaddition, Beilstein J. Org. Chem., 2013, 9, 2715–2750.

30 B. H. Lipshutz, W. Chrisman and K. Noson, Hydrosilylation

of aldehydes and ketones catalyzed by [Ph₃P(CuH)]₆, J.

Organomet. Chem., 2001, 624, 367–371.

Alkyne Reactivity in Copper-Catalyzed Azide-Alkyne

Cycloadditions, Molecules, 2016, 21, 1–17.

42 A. Horn and P. H. Dussault, Synthesis of a-cyano and a-

sulfonyl cyclic ethers via intramolecular reactions of

peroxides with sulfone-and nitrile-stabilized carbanions, J.

Org. Chem., 2019, 84, 14611–14626.

31 N. Kornblum and H. E. DeLaMare, The base catalyzed 43 A. S. Olson, A. J. Jameson, S. K. Kyasa, B. W. Evans and

decomposition of a di-alkyl peroxide, J. Am. Chem. Soc.,

1951, 73, 880–881.

P. H. Dussault, Reductive Cleavage of Organic Peroxides by

Iron Salts and Thiols, ACS Omega, 2018, 3, 14054–14063.

32 (a) E. W. Elliott, A. L. Ginzburg, Z. C. Kennedy, Z. Feng and 44 X. Wang, Y. Dong, S. Wittlin, D. Creek, J. Chollet,

J. E. Hutchison, Single-Step Synthesis of Small, Azide-

Functionalized Gold Nanoparticles: Versatile, Water-

Dispersible Reagents for Click Chemistry, Langmuir, 2017,

33, 5796–5802; (b) D. Baranov and E. N. Kadnikova,

Synthesis and characterization of azidoalkyl-functionalized

S. A. Charman, J. Santo Tomas, C. Scheurer, C. Snyder and

J. L. Vennerstrom, Spiro-and dispiro-1,2-dioxolanes:

contribution of iron (II)-mediated one-electron vs. two-

electron reduction to the activity of antimalarial peroxides,

J. Med. Chem., 2007, 50, 5840–5847.

gold nanoparticles as scaﬀolds for “click”-chemistry 45 D. A. Fleming, C. J. Thode and M. E. Williams, Triazole

derivatization, J. Mater. Chem., 2011, 21, 6152.

Cycloaddition as a General Route for Functionalization of

33 Y. Zhou, S. Wang, K. Zhang and X. Jiang, Visual Detection of

Au Nanoparticles, Chem. Mater., 2006, 18, 2327–2334.

Copper(II) by Azide- and Alkyne-Functionalized Gold 46 W. J. Sommer and M. Weck, Facile functionalization of gold

Nanoparticles Using Click Chemistry, Angew. Chem., Int.

Ed., 2008, 47, 7454–7456.

nanoparticles

cycloaddition, Langmuir, 2007, 23, 11991–11995.

via

microwave-assisted

1,3

dipolar

34 J. L. Brennan, N. S. Hatzakis, T. R. Tshikhudo, 47 (a) W. Limapichat and A. Basu, Reagentless

N. Dirvianskyte, V. Razumas, S. Patkar, J. Vind,

A. Svendsen, R. J. M. Nolte, A. E. Rowan and M. Brust,

Bionanoconjugation via Click Chemistry: The Creation of

Functional Hybrids of Lipases and Gold Nanoparticles,

Bioconjugate Chem., 2006, 17, 1373–1375.

functionalization of gold nanoparticles via a 3 + 2 Huisgen

cycloaddition, J. Colloid Interface Sci., 2008, 318, 140–144;

(b) C. J. Thode and M. E. Williams, Kinetics of 1,3-dipolar

cycloaddition on the surfaces of Au nanoparticles, J.

Colloid Interface Sci., 2008, 320, 346–352.

35 V. Poonthiyil, T. K. Lindhorst, V. B. Golovko and 48 R. Cohen, Y. Mazuz, M. Tikhonov and C. M. Sukenik,

A. J. Fairbanks, Recent applications of click chemistry for

the functionalization of gold nanoparticles and their

conversion to glyco-gold nanoparticles, Beilstein J. Org.

Chem., 2018, 14, 11–24.

Carboxylic Acid Decorated Self-Assembled Monolayer

Films: New Acid Synthesis Chemistry and Reaction

Chemistry Including Bridged Diacyl Peroxide Preparation,

Langmuir, 2015, 31, 3049–3058.

44428 | RSC Adv., 2020, 10, 44408–44429

View Article Online

Paper

RSC Advances

´

˜

´

49 R. Mello and M. E. Gonzalez Nunez, Reactions of Peroxides 59 R. J. Armstrong, W. Niwetmarin and V. K. Aggarwal,

on Solid Surfaces, in PATAI'S Chemistry of Functional

Groups, ed. Z. Rappoport, DOI: 10.1002/

9780470682531.pat0880.

Synthesis of Functionalized Alkenes by a Transition-Metal-

Free Zweifel Coupling, Org. Lett., 2017, 19, 2762–2765.

60 J. van der Louw, J. L. van der Baan, F. J. de Kanter,

F. Bickelhaupt and G. W. Klumpp, Allylmetallation of 1-

silylalkynes by 2-(bromozincmethyl)-2-alkenyl ethers

followed by Pd (0)-catalyzed cyclization: a one-pot synthesis

of 4-methylenecyclopentenes, Tetrahedron, 1992, 48, 6087–

6104.

50 K. L. Norrod and K. L. Rowlen, Ozone-induced oxidation of

self-assembled decanethiol: contributing mechanism for

“photooxidation”?, J. Am. Chem. Soc., 1998, 120(11), 2656–

2657.

51 (a) W. Liu, X. Liu, D. Knaebel, L. Luck and Y. Li, Synthesis

and antibacterial evaluation of novel water-soluble organic 61 B. R. Brutiu, W. A. Bubeneck, O. Cvetkovic, J. Li and

peroxides, Antimicrob. Agents Chemother., 1998, 42, 911–

915; (b) C. G. Burkhart and C. N. Burkhart, Antibacterial

N. Maulide, On the formation of seven-membered rings by

arene-ynamide cyclization, Monatsh. Chem., 2019, 150, 3–10.

properties of soluble benzoyl peroxide, Int. J. Dermatol., 62 M. Schmittel and C. Vavilala, Kinetic isotope eﬀects in the

2008, 47, 301–302.

52 For an example of surface-specic peroxide chemistry

involving an adsorbed peroxide, see: N. Walalawela and

thermal C₂-C₆cyclization of enyne-allenes: experimental

evidence supports a stepwise mechanism, J. Org. Chem.,

2005, 70, 4865–4868.

A. Greer, Heterogeneous photocatalytic deperoxidation 63 J. M. Smith, T. Qin, R. R. Merchant, J. T. Edwards,

with UV and visible light, J. Phys. Org. Chem., 2018, 31, e3807.

53 K. Tokumaru, Complications in photochemistry of organic

peroxides, Res. Chem. Intermed., 1996, 22, 255–273.

L. R. Malins, Z. Liu, G. Che, Z. Shen, S. A. Shaw,

M. D. Eastgate and P. S. Baran, Decarboxylative

Alkynylation, Angew. Chem., Int. Ed., 2017, 56, 11906–11910.

54 (a) R. Willand-Charnley, B. W. Puﬀer and P. H. Dussault, 64 J. Maury, L. Feray, M. P. Bertrand, A. Kapat and P. Renaud,

Oxacycle synthesis via intramolecular reaction of

carbanions and peroxides, J. Am. Chem. Soc., 2014, 136,

5821–5823; (b) L. Lemee, M.-J. Bourgeois and

Unexpected conversion of alkyl azides to alkyl iodides and

of aryl azides to N–tert-butyl anilines, Tetrahedron, 2012,

68, 9606–9611.

E. Montaudon, Decomposition induced by acetylenic 65 S. M. Smith and J. M. Takacs, Amide-Directed Catalytic

peroxides, Bull. Soc. Chim. Belg., 1996, 105, 467–472.

55 M. T. Wlodarczyk, S. A. Dragulska, O. Camacho-Vanegas,

Asymmetric Hydroboration of Trisubstituted Alkenes, J.

Am. Chem. Soc., 2010, 132, 1740–1741.

P. R. Dottino, A. A. Jarz˛ecki, J. A. Martignetti and 66 T. Suzuki, Y. Ota, Y. Kasuya, M. Mutsuga, Y. Kawamura,

A. J. Mieszawska, Platinum (II) complex-nuclear

localization sequence peptide hybrid for overcoming

platinum resistance in cancer therapy, ACS Biomater. Sci.

Eng., 2018, 4, 463–467.

H. Tsumoto, H. Nakagawa, M. G. Finn and N. Miyata, An

unexpected example of protein-templated click chemistry,

Angew. Chem., Int. Ed., 2010, 49, 6817–6820.

67 K. Motesharei and D. C. Myles, Molecular Recognition on

Functionalized Self-Assembled Monolayers of Alkanethiols

on Gold, J. Am. Chem. Soc., 1998, 120, 7328–7336.

56 (a) J. N. Eildal, A. Bach, J. Dogan, F. Ye, M. Zhang, P. Jemth

and K. Strømgaard, Rigidied Clicked Dimeric Ligands for

Studying the Dynamics of the PDZ1-2 Supramodule of 68 M. H. Keylor, J. E. Park, C. J. Wallentin and

´

PSD-95, ChemBioChem, 2015, 16, 64–69; (b) A. Krasinski,

C. R. J. Stephenson, Photocatalytic initiation of thiol-ene

reactions: synthesis of thiomorpholin-3-ones, Tetrahedron,

2014, 70, 4264–4269.

´

Z. Radic, R. Manetsch, J. Raushel, P. Taylor,

K. B. Sharpless and H. C. Kolb, In situ selection of lead

compounds by click chemistry: target-guided optimization 69 C. Ligeour, A. Meyer, J. J. Vasseur and F. Morvan, Bis- and

of acetylcholinesterase inhibitors, J. Am. Chem. Soc., 2005,

127, 6686–6692.

57 P. H. Dussault, I. Q. Lee, H. J. Lee, R. J. Lee, Q. J. Niu,

Tris-Alkyne Phosphoramidites for Multiple 5⁰-Labeling of

Oligonucleotides by Click Chemistry, Eur. J. Org. Chem.,

2012, 1851–1856.

`

J. A. Schultz and U. R. Zope, Peroxycarbenium-mediated C- 70 F. Gonzalez De Rivera, I. Angurell, O. Rossell, M. Seco and

C

bond formation: applications to the synthesis of

J. Llorca, Organometallic surface functionalization of gold

nanoparticles, J. Organomet. Chem., 2012, 715, 13–18.

71 W. Haiss, N. T. K. Thanh, J. Aveyard and D. G. Fernig,

Determination of Size and Concentration of Gold

Nanoparticles from UV-Vis Spectra, Anal. Chem., 2007, 79,

4215–4221.

hydroperoxides and peroxides, J. Org. Chem., 2000, 65,

8407–8414.

58 J. E. Baldwin, L. Bischoﬀ, T. D. W. Claridge, F. A. Heupel,

D. R. Spring and R. C. Whitehead, An approach to the

manzamine alkaloids modelled on a biogenetic theory,

Tetrahedron, 1997, 53, 2271–2290.

RSC Adv., 2020, 10, 44408–44429 | 44429

Article Doi

A click-based modular approach to introduction of peroxides onto molecules and nanostructures

DOI: 10.1039/d0ra09088c

Source and publish data:

Authors:

Article abstract of DOI:10.1039/d0ra09088c

Full text of DOI:10.1039/d0ra09088c

Products guided by the article

R&D Labs maybe for 100848-88-2

Relevant to this article

Hot Product