Alkane desaturation by concerted double hydrogen atom transfer to benzyne

Article abstract of DOI:10.1038/nature12492

The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or σ-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels-Alder cycloisomerization reaction of triyne substrates. We are not aware of any single-step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C-H bonds in the alkane donor.

Full text of DOI:10.1038/nature12492

LETTER
doi:10.1038/nature12492
Alkane desaturation by concerted double hydrogen
atom transfer to benzyne
Dawen Niu1, Patrick H. Willoughby1, Brian P. Woods1, Beeraiah Baire1 & Thomas R. Hoye1
A
)
a
Desaturation of an alkane by a generic 2H acceptor (
The removal of two vicinal hydrogen atoms from analkane to produce
an alkene is a challenge for synthetic chemists1,2. In nature, desa-
turases and acetylenases are adept at achieving this essential oxida-
tive functionalization reaction, for example during the biosynthesis
of unsaturated fatty acids3, eicosanoids, gibberellins4 and carotenoids5.
Alkane-to-alkene conversion almost always involves one or more
chemical intermediates in a multistep reaction pathway; these may
beeitherisolablespecies(suchasalcoholsoralkylhalides)orreactive
intermediates (such as carbocations, alkyl radicals, or s-alkyl-metal
species). Here we report a desaturation reaction of simple, unacti-
vated alkanes that is mechanistically unique. We show that benzynes
are capable of the concerted removal of two vicinal hydrogen atoms
from a hydrocarbon. The discovery of this exothermic, net redox
process was enabled by the simple thermal generation of reactive
benzyne intermediates through the hexadehydro-Diels–Alder cyclo-
isomerization reaction of triyne substrates6. We are not aware of any
single-step, bimolecular reaction in which two hydrogen atoms are
simultaneously transferred from a saturated alkane. Computational
studies indicate apreferred geometry witheclipsed vicinalC–H bonds
in the alkane donor.
H
H
H
H
H
H
A
A
A
The hexadehydro-Diels–Alder cascade: benzyne (3) generation and trapping
b
H
H
H
H
H
H
H
H
H
El
[4+2]
Trap
(HDDA)
Nu–El
Nu
H
H
H
1
2
3a
3b
4
c A specific example of a HDDA cascade involving a novel type of trapping event
O
O
O
O
120 °C
PhMe
TBS
O
O
SitBu(Me)2
O
Arynes7–9 engagein myriad trapping reactions that functionalize adja-
cent sp-hybridized carbons in the o-aryne ring. We recently reported
a general strategy for the formation and subsequent in situ trapping
of benzynes by means of the hexadehydro-Diels–Alder (HDDA)
reaction6,10,11. The simplest imaginable variant (Fig. 1b) is the reaction
of 1,3-butadiyne (2)withethyne(1, the diynophile) to produce o-benzyne
(3). The free energy change for this process is computed to be exo-
thermic by approximately 50 kcal mol21 (refs 6, 12). Trapping of 3
permits the synthesis of many useful benzene derivatives (4). In prac-
tice (Fig. 1c), the HDDA cycloisomerization is effected intramolecu-
larly simply by heating a tethered triyne substrate such as 5 to produce
a fused bicyclic benzyne intermediate such as 6. Trapping leads to a
highly substituted benzenoid product such as 7. In addition to the
preparative value of this de novo generation of benzynes, the HDDA
reaction provides the opportunity to uncover previously unpreced-
ented aryne trapping modes13,14 (for example, the insertion of the
strained benzyne into the silyl ether bond as 6 proceeds to 7). This
is largely because HDDA cyclizations produce reactive benzyne inter-
mediates in the absence of added reagents, by-products or catalysts.
Bimolecular desaturation of an alkane by concerted transfer of two
vicinal hydrogen atoms to a double hydrogen atom (2H) acceptor is
unprecedented(Fig. 1a).Wenowreporta2Htransferreactioninwhich
a HDDA-generated benzynesimultaneously accepts twovicinalhydro-
O
OTBS
5
6
7 (86%)
Figure 1
|
Introduction and background. a, SpeciesA(redsphere)isapotential
doublehydrogenatom(2H)acceptor,inwhichtheacceptingmoietycouldbeeither
monoatomic(forexamplemetal, metal-oxo, carbeneornitrene)orpolyatomic(for
exampleap-bondedspecies)innature.b,TheprototypicalHDDAcascade.Nu–El,
nucleophile–electrophile.c,IntramolecularHDDAcycloisomerizationfollowedby
silyl ether trapping6. TBS, tert-butyldimethylsilyl. Here we show that a benzyne
(such as 3 or 6) functions as species A by extracting two hydrogen atoms from
adjacent carbon atoms of suitable 2H donor substrates.
dinuclear metal complex was reduced to the arene. They demonstrated
that thesolvent (tetrahydrofuran; THF) wasthesourceof the hydrogen
(and, in the case of THF-d8, deuterium17) atoms that appeared in the
reduced benzenoid product. When we heated substrate 8 in THF-h8,
10-h2 was the only product isolated (75%, Fig. 2a, b). Similarly, when 8
was heated in THF-d8, the dideuterated analogue 10-d2 (mass spec-
trometry and 1H NMR) was the only product isolated.
To probe the mechanism of this process further and, in particular,
to distinguish between pathways involving sequential hydrogen atom
abstractionsfromtwosolventmoleculesversusatransferoftwohydro-
gen atoms froma single molecule, we repeatedthegeneration and trap-
ping of benzyne 9, this time in the presence of an equimolar mixture of
THF-h8 and THF-d8. Intriguingly, only the diprotiobenzenoid and
dideuteriobenzenoid products 10-h2 and 10-d2 were produced; none
of the mono-H/mono-D analogue (10-hd) was detected. The observed
10-h2:10-d2 product ratio was 6:1, indicating a significant H/D kinetic
isotope effect for the 2H transfer. In a complementary experiment, we
used a 1:6 molar ratio of THF-h8:THF-d8, which gave a nearly 1:1 ratio
3
3
gen atoms froma suitable alkane 2H donor (H–Csp Csp –H). Thisgives
thecorresponding(oxidized)alkeneand(reduced)benzenoidproducts.
For example, when we heated triyne 8 in cyclooctane to 85 uC, the only
isolated product (89%) was the reduced fluorenone derivative 10-h2
(Fig. 2a, b). Using 1H NMR spectroscopy, we observed that a compar-
able amount of cyclooctene had been formed by desaturation15 (see
Fig. 3b). The only well-characterized example of benzyne reduction by
means of the net addition of two hydrogen atoms is a previous study16
in which a benzyne intermediate derived from a bis-diyne-bridged, of products10-h2:10-d2. The lack of anobservable levelof monodeuterated
1Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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RESEARCH LETTER
a
b
Cyclooctane
(89% yield)
or
O
O
O
H
H
O
D
D
THF
(75% yield)
versus
TMS
TMS
TMS
TMS
85 °C
AcO
AcO
AcO
(CH2)3OAc
10-h2
10-d2
8
9
‡
Product ratio
c
Solvent
(10-h2:10-d2)
H
O
100:0
0:100
6:1*
THF-h8
THF-d8
H
11
THF-h8:THF-d8(1:1)
THF-h8:THF-d8(1:6)
‡
1:1*
H
H
H
H
Dyotropic
reaction
N
N
H
H
Diimide
reduction
Figure 2
|
Both hydrogen atoms come from the same donor molecule.
observed (1H NMR analysis; estimated limit of detection was 6%).
a, Dihydrogen transfer reactions between the HDDA-generated benzyne
c, Representation (11) of simultaneous double hydrogen transfer between an
9 (from the triyne 8) and the 2H donor solvents cyclooctane and THF give the aryne and a THF molecule. Analogous six-atom arrays are involved in the
benzenoid 10-h2. b, Isotope profiling using THF-h8, THF-d8 and mixtures
transition structures of 2H transfer by diimide to an alkene acceptor18,19 and in
thereof shows that both hydrogen atoms in the product originate from a single the class of intramolecular reorganizations known as dyotropic reactions20,21
.
molecule of 2H donor. Asterisk, mono-deuterated product (10-hd) was not
product in any of these experiments is consistent with the concerted The ratio of the alkene resonances of cyclooctene to cyclopentene
transfer to the benzyne of two hydrogen atoms from a single THF (adjusted for the molar ratio of solvents) provides the relative rate ratio
molecule as represented in the depiction of the transition structure (krel) between the two hydrocarbon donors (2.6 for this example). The
11 (Fig. 2c). Although such a description might seem unusual, it can relative intensity of alkene to arene resonances (from 14) as well as the
be noted that the generally accepted mechanism for the reduction of absence of resonances indicative of aromatic by-products shows the
alkenes bydiimide(HN5NH)18,19 andfordyotropicreactionsinwhich overall cleanliness of the reaction.
twohydrogenatomsareshuffledintramolecularly20,21 (Fig. 2c)involves
As stated earlier, cyclohexane (Fig. 3a, entry 5 in the inset table) is
a similar simultaneous transfer.
We next screened a series of cyclic hydrocarbons to explore their (entries1–4). Wespeculatedthatthisimpliesapreferenceforaneclipsed
a considerably poorer 2H donor than the other cyclic hydrocarbons
3
3
relative ability to engage an aryne in a similar hydrogen transfer reac- geometry for the relevant HCsp Csp H subunit within the 2H donor
tion (Fig. 3). We were surprised to observe that cyclohexane was sig- molecule. Accordingly, cyclohexane, dominated by the chair confor-
nificantly less efficient than the other cycloalkanes in its reduction of mation, is least disposedtowards transferof two of its hydrogenatoms,
thebenzyne13(Fig.3a, entries1–5). Thiswasinitiallyseenfromsimple whereas the other hydrocarbons all have low-lying conformers with
3
3
comparison of the chemical yields after the purification of reduced HCsp Csp H dihedral angles much smaller than 60u. That is, those
(benzenoid) product 14. It is relevant that when the HDDA cyclization cyclic hydrocarbons populated to a significant extent by conformers
is performed in the absence of a suitably good trapping agent, we rou- having less highly staggered vicinal C–H bonds are the more reactive
tinely observe the formation of intractable, dark-coloured mixtures of 2H donors. To test this thinking further, we examined 1,4-dioxane as a
oligomeric substances. We speculate that this is because the reactive potential 2H donor. Not surprisingly, use of this chair-like compound
benzyne (for example 13) engages the conjugated diyne unit in another gave none of the reduced product 14 (Fig. 3a, entry 7). In contrast,
molecule of substrate triyne (for example 12) competitively with its norbornane, having a boat-like cyclohexane embedded in its frame-
3
3
abstraction of two hydrogen atoms from a solvent molecule. Thus, for work (and an associated HCsp Csp H moiety with a 0u dihedral angle)
these processes the yield of 14 is a meaningful reflection of the 2H is a kinetically competent donor (entry 4), even though the product
transfer rate from each donor solvent. Use of the acyclic hydrocarbon norbornene comprises a strained alkene.
n-heptane as solvent also resulted in the production of 14, now in 30%
(isolated) yield—that is, heptane is intermediate in reactivity between
cyclopentane and cyclohexane. When the starting concentration of
triyne 12 was decreased tenfold (that is, from 10 mM to 1 mM), the
isolated yield of 14 more than doubled for the reaction in cyclohexane
(from 20% to 53%) or n-heptane (from 30% to 73%). This is consistent
with the hypothesis that the rate of the primary decomposition process
is dependent on the triyne concentration.
Next, usingdensity functionaltheory(DFT) methods (see Supplemen-
tary Information) we computed the transition structure geometry and
the free energy of activation (DG{) for the double hydrogen atom
transfer21 between o-benzyne (3) and each of the seven cyclic donors
shown in entries 1–7 (Fig. 3a). For all 2H donors the calculations indi-
cate a relativelyearly transition structure (for example, comparethe two
distances shown in 15a). This is consistent with the highly exothermic
natureofthe2Htransferstep(forexample, wecomputedthefreeenergy
We then turned to the use of no-deuterium proton NMR (No-D of reaction to be 265.6 kcal mol21 for o-benzyne (3) 1 cyclopentane
NMR) spectroscopy22 to both positively identify the alkene by-product going to benzene 1 cyclopentene). The computed geometries for the
and demonstrate that it was formed in nearly equimolar amounts to cyclopentane and cyclohexane transition structures (15a and 15b, respect-
the reduced benzenoid product 14. A typical No-D spectrum, obtained ively) are shown in Fig. 3c. It is not accidental that the energy difference
with a sample prepared by heating 12 in an equivolume mixture of between the chair and boat conformers of cyclohexane (approximately
cyclooctane and cyclopentane ([12] 5 0.01 M), is shown in Fig. 3b. 6 kcal mol21) issimilar tothecomputed difference inDG{ between15a
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LETTER RESEARCH
Yielda (%)
krel
ΔG‡ e
c
a
2H donor
Entry
Me
Me
Cyclic
Me
3
4
H
H
TMS
O
hydrocarbon
2H donor
TMS
O
Cyclooctane
Cycloheptane
Cyclopentane
Norbornane
Cyclohexane
1
2
3
4
5
97%
94%
84%
66% b
20%
2.6
2.3
17.6
17.7
18.7
18.5
24.1
Me3Si
1.0
95 ºC, 14 h
0.60
0.01
[12] = 0.01 M
5
8
O
6
7
6
7
60% b
0%
0.4 d
–
19.2 f
27.1
THF
1,4-Dioxane
12
13
14
H
Dominant
conformer
b
c
H4
H
14
H
H
H6
H3
Chair
H8
H7
No-D
1H NMR spectrum
H
H
H
H
H5
Boat-
like
1.48 Å
1.24 Å
7.8 7.7 7.6 7.5 7.4 7.3
p.p.m.
6.00
5.95
5.90
p.p.m.
5.85
5.80
15a (ΔG‡ = 18.7 kcal mol–1
)
15b (ΔG‡ = 24.1 kcal mol–1
)
d
TIPSO
TBSO
TMS
O
TMS
O
O
O
PhN
O
OTIPS
H
(CH2)3X
OTBS
H
nPr
H
Ph
H
nHex
H
MeO2C
MeO2C
TsN
H
H
H
H
H
H
H
100 °C, 14 h, 60%
110 °C, 14 h
61%
120 °C, 40 h
53%
120 °C, 20 h
58%
110 °C, 14 h
74%
RT, 48 h
64%
16f (X = Cl)
85 °C, 18 h, 67%
16a
16b
16c
16d
16e
16g (X = H; gram-scale)
Figure 3
|
Dihydrogen transfer between arynes and cyclic hydrocarbons.
Italicized H3 and H4 denote the resonances for the newly introduced pair of
a, Relative efficiency (percentage yield and krel compared with cyclopentane) of hydrogen atoms in product 14. c, Computed transition structure geometries
various hydrocarbon (and cyclic ether) 2H donors for the reduction of aryne
and DG{ for the transfer of two hydrogen atoms to benzyne (3) from
13 to arene 14. For notes a–f in the inset table see Supplementary Information. cyclopentane (15a) and cyclohexane (15b). d, Reduced benzenoid products
b, A representative No-D 1H NMR22 spectrum (this example is of the reaction 16a–g generated by heating the triyne precursor in cyclooctane under the
solution arising from heating 12 (at 10 mM) in a 1.5:1 molar ratio of
cyclopentane:cyclooctane at 95 uC), showing the overall efficiency of the
reaction and validating the krel value (1:2.6) obtained as described in the text.
indicated conditions (starting substrate concentration 10 mM). RT, room
temperature; Ts, para-toluenesulphonyl; TMS, trimethylsilyl; TIPS,
triisopropylsilyl; nPr, n-propyl; nHex, n-hexyl.
and (the boat-like) 15b. The DG{ values computed for all seven donors including the parent 3, is that23 in which 2-trimethylsilylphenyl triflate
are given in the inset table in Fig. 3a. There is a remarkably good (o-TMSPhOTf) is exposed to a fluoride ion source (commonly CsF)
correlation between the computed DG{ values and the observed krel in, most often, THF as the solvent. We speculated that some known
values. These observations are most consistent with the idea of sub- trapping reactions of benzynes generated in THF are compromised in
stantial dependence on dihedral angle for the process, which can only
be true if the double hydrogen atom transfer event is concerted.
Products 16a–g (Fig. 3d) arose from incubating the corresponding
their efficiency as a result of competitive reduction by that solvent.
Indeed, when we exposed o-TMSPhOTf to CsFin THF-d8 intheabsence
of any other trapping agent, we observed the production of benzene
triyne precursor (inferred from the dashed line in each structure; see (C6H4D2, by 1H NMRanalysis). Similarly, benzene (and cyclopentene)
Supplementary Information for details) in cyclooctane under the indi- was seen when CsF and o-TMSPhOTf were reacted in CD3CN that
cated conditions. Notable features include the following: a variety of contained cyclopentane (approximately 25 equivalents). We suggest
functional groups, present in both the triyne precursor and benze- that all traditional benzyne generation methods performed in the pres-
noid product, are readily tolerant of these benign reducing conditions; ence of a potential 2H donor (most typically, THF) are at risk to the
benzynesrepresenting a breadthof electronic activationand/or pertur- unwanted, benzyne-depleting, 2H transfer process, especially when the
bation engage in the reaction; most of the products 16 have a 1,2,3,4- benzyne trapping event is inherently slow. Indeed, we inferthat this has
tetrasubstituted motif, a substitution pattern that can be challenging to
access by classical aromatic synthesis strategies; the double hydrogen
atom transfer process occurs readily even at ambient temperature
(compare 16a); and the reaction is not limited by scale (compare 16g).
already been encountered. Recent reports show THF to be an inferior
medium (compared with 1,4-dioxane24 or diethyl ether25) for some
benzyne trapping reactions. This is consistent with both the results
reported above for the relative efficiencies of THF and 1,4-dioxane as
Finally, anancillarybutimportantpractical considerationhasemerged. a 2H donor (Fig. 3a, entries 6 and 7 in the inset table), and also our
The most common method for generating simple benzyne derivatives, arguments for angle dependence during the 2H transfer.
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RESEARCH LETTER
11. Bradley, A. Z. & Johnson, R. P. Thermolysis of 1,3,8-nonatriyne: evidence for
intramolecular [214] cycloaromatization to a benzyne intermediate. J. Am. Chem.
Soc. 119, 9917–9918 (1997).
12. Ajaz, A. et al. Concerted vs. stepwise mechanisms in dehydro-Diels–Alder
reactions. J. Org. Chem. 76, 9320–9328 (2011).
13. Hoffmann, R. W. & Suzuki, K. A ‘hot, energized’ benzyne. Angew. Chem. Int. Ed. 52,
2–4 (2013).
14. Yun, S. Y., Wang, K.-P., Lee, N.-K., Mamidipalli, P. & Lee, D. Alkane C–H insertion by
aryne intermediates with a silver catalyst. J. Am. Chem. Soc. 135, 4668–4671
(2013).
15. Voica, A.-F., Mendoza, A., Gutekunst, W. R., Fraga, J. O. & Baran, P. S. Guided
desaturation of unactivated aliphatics. Nature Chem. 4, 629–635 (2012).
16. Tsui, J. A. & Sterenberg, B. T. A metal-templated 4 1 2 cycloaddition reaction of an
alkyne and a diyne to form a 1,2-aryne. Organometallics 28, 4906–4908 (2009).
17. de Almeida, G., Townsend, L. C. & Bertozzi, C. R. Synthesis and reactivity of
dibenzoselenacycloheptynes. Org. Lett. 15, 3038–3041 (2013).
18. Hu¨nig, S., Mu¨ller, H. &Thier, W. Reduktionenmitdiimid. Tetrahedr.Lett. 2, 353–357
(1961).
We have described the essential mechanistic features of a double
hydrogen atom transfer process. Both (vicinal) hydrogen atoms come
from the same donor molecule. There is substantial dependence on
dihedral angle: donors with a greater degree of eclipsing among their
low-energy conformers are more reactive. This is reinforced by the
nearly planar geometry of the six reacting atoms in the computed tran-
sition structures. Our observations support a pathway in which both
hydrogen atoms are transferred simultaneously from the saturated
alkane to the benzyne carbon atoms—a process that could be viewed
as a metal-free, double C–H activation event26.
METHODS SUMMARY
A typical double hydrogen atom transfer reaction comprised heating a solution of
HDDA triyne precursor (substrate) in cyclooctane (approximately 0.01 M) in a
closed glass reaction vessel (for example, a screw-capped vial or culture tube).
After the specified time, the reaction mixture was loaded directly onto a bed of
silica gel and eluted first with hexanes to remove the excess cyclooctane and then
with ethyl acetate to capture the reduced benzenoid products. These were further
purified by chromatography on silica gel. Relative rate data (Fig. 3a, b) were
collected by 1H NMR spectroscopy at 500MHz using No-D NMR22 and quant-
itative NMR27 techniques. Details aregiven in Supplementary Information. Details
for the preparation of all new compounds, their full spectroscopic characterization
data and the computational methods used are also provided in Supplementary
Information.
19. Corey, E. J., Pasto, D. J. & Mock, W. L. Chemistry of diimide. II. Stereochemistry of
hydrogen transfer to carbon–carbon multiple bonds. J. Am. Chem. Soc. 83,
2957–2958 (1961).
´
´
20. Fernandez, I., Cossıo, F. P. & Sierra, M. A. Dyotropic reactions: mechanisms and
synthetic applications. Chem. Rev. 109, 6687–6711 (2009).
´
´
21. Fernandez, I., Sierra, M. A. & Cossıo, F. P. In-plane aromaticity in double-group
transfer reactions. J. Org. Chem. 72, 1488–1491 (2007).
22. Hoye, T. R., Eklov, B. M., Ryba, T. D., Voloshin, M. & Yao, L. J. No-D NMR (no
deuterium proton NMR) spectroscopy: a simple yet powerful method for
analyzing reaction and reagent solutions. Org. Lett. 6, 953–956 (2004).
23. Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of
o-trimethylsilylphenyl triflate to benzyne under mild conditions. Chem. Lett. 12,
1211–1214 (1983).
24. Ma, Z.-X., Feltenberger, J. B. & Hsung, R. P. Total syntheses of chelidonine and
norchelidonine via an enamide–benzyne–[212] cycloaddition cascade. Org. Lett.
14, 2742–2745 (2012).
25. Sumida, Y., Kato, T. & Hosoya, T. Generation of arynes via ate complexes of
arylboronic esters with an ortho-leaving group. Org. Lett. 15, 2806–2809 (2013).
26. Davies, H. M. L., Du Bois, J. & Yu, J.-Q. C–H functionalization in organic synthesis.
Chem. Soc. Rev. 40, 1855–1856 (2011).
Received 9 March; accepted 18 July 2013.
1. Linstead, R. P., Braude, E. A., Mitchell, P. W. D., Wooldridge, K. R. H. & Jackman, L. M.
Transfer of hydrogen in organic systems. Nature 169, 100–103 (1952).
2. Bloomfield, D. K. & Bloch, K. The formation of D9-unsaturated fatty acids. J. Biol.
Chem. 235, 337–345 (1960).
27. Paul, G. F., Jak, B. & Lankin, D. A. Routine experimental protocol for qHNMR
illustrated with taxol. J. Nat. Prod. 70, 589–595 (2007).
3. Buist, P. H. Fatty acid desaturases: selecting the dehydrogenation channel. Nat.
Prod. Rep. 21, 249–262 (2004).
4. Bhattacharya, A. et al. Characterization of the fungal gibberellin desaturase as a
2-oxoglutarate-dependent dioxygenase and its utilization for enhancing plant
growth. Plant Physiol. 160, 837–845 (2012).
5. Moran, N. A. & Jarvik, T. Lateral transfer of genes from fungi underlies carotenoid
production in aphids. Science 328, 624–627 (2010).
6. Hoye, T. R., Baire, B., Niu, D., Willoughby, P. H. & Woods, B. P. The hexadehydro-
Diels–Alder reaction. Nature 490, 208–212 (2012).
7. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes (Organic Chemistry Vol. 11)
(Academic, 1967).
Supplementary Information is available in the online version of the paper.
Acknowledgements We thank C. J. Cramer for helpful discussions about the
computational studies. D.N. and P.H.W. thank the University of Minnesota Graduate
School Doctoral Dissertation Fellowship and National Science Foundation Graduate
Research Fellowship program, respectively. Financial support from the National
Institute of General Medical Sciences (GM65597) and the National Cancer Institute
(CA76497) of the US Department of Health and Human Services is acknowledged.
Portions of this work were performed with hardware and software resources available
through the University of Minnesota Supercomputing Institute (MSI).
8. Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural product
total synthesis. Chem. Rev. 112, 3550–3577 (2012).
Author Contributions D.N. made the initial key observations and performed most of
the scope studies. P.H.W. performed most of the mechanistic studies. B.P.W. and B.B.
also performed aspects of the experimental work. All authors interpreted the data and
wrote the manuscript.
9. Baire, B., Niu, D., Willoughby, P. H., Woods, B. P. & Hoye, T. R. Synthesis of complex
benzenoids via the intermediate generation of o-benzynes through the
hexadehydro-Diels–Alder reaction. Nature Protocols 8, 501–508 (2013).
10. Miyawaki, K., Suzuki, R., Kawano, T. & Ueda, I. Cycloaromatization of a non-
conjugated polyenyne system: synthesis of 5H-benzo[d]fluoreno[3,2-b]pyrans
via diradicals generated from 1-[2-{4-(2-alkoxymethylphenyl)butan-1,3-
diynyl}]phenylpentan-2,4-diyn-l-ols and trapping evidence for the 1,2-
didehydrobenzene diradical. Tetrahedr. Lett. 38, 3943–3946 (1997).
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