Palladium-Catalyzed Alkoxycarbonylation of Unactivated Secondary Alkyl Bromides at Low Pressure

Article abstract of DOI:10.1021/jacs.6b04610

Catalytic carbonylations of organohalides are important C-C bond formations in chemical synthesis. Carbonylations of unactivated alkyl halides remain a challenge and currently require the use of alkyl iodides under harsh conditions and high pressures of CO. Herein we report a palladium-catalyzed alkoxycarbonylation of secondary alkyl bromides that proceeds at low pressure (2 atm CO) under mild conditions. Preliminary mechanistic studies are consistent with a hybrid organometallic-radical process. These reactions efficiently deliver esters from unactivated alkyl bromides across a diverse range of substrates and represent the first catalytic carbonylations of alkyl bromides with carbon monoxide.

Full text of DOI:10.1021/jacs.6b04610

Subscriber access provided by Weizmann Institute of Science
Communication
Palladium-Catalyzed Alkoxycarbonylation of
Unactivated Secondary Alkyl Bromides at Low Pressure
Brendon T. Sargent, and Erik J. Alexanian
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04610 • Publication Date (Web): 06 Jun 2016
Downloaded from http://pubs.acs.org on June 7, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 4
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Alkoxycarbonylation of Unactivated Secondary
Alkyl Bromides at Low Pressure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Brendon T. Sargent and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
Supporting Information Placeholder
The oxidative addition of alkyl halides is expected to be more
ABSTRACT: Catalytic carbonylations of organohalides are
important C–C bond formations in chemical synthesis. Car-
bonylations of unactivated alkyl halides remain a challenge, and
currently require the use of alkyl iodides under harsh condi-
challenging in the presence of π-acidic CO, which would de-
crease the electron density on the metal center.8 Moreover,
should a successful oxidative addition take place, undesired β-
hydride elimination of an alkylmetal intermediate is prone to
tions and high pressures of CO. Herein, we report a palladium-
occur,9 especially at lower CO pressures. Herein, we report the
catalyzed alkoxycarbonylation of secondary alkyl bromides that
development of an efficient catalytic alkoxycarbonylation of
proceeds at low pressure (2 atm CO) under mild conditions.
unactivated secondary alkyl bromides that overcomes these
Preliminary mechanistic studies are consistent with a hybrid
challenges. This palladium-catalyzed transformation enables a
organometallic-radical process. These reactions efficiently deliv-
mild, low-pressure synthesis of diverse esters and constitutes the
first examples of catalytic carbonylations of unactivated alkyl
bromides with CO.
er esters from unactivated alkyl bromides across a diverse range
of substrates and represent the first catalytic carbonylations of
alkyl bromides with carbon monoxide.
Our studies commenced with the alkoxycarbonylation of un-
activated secondary alkyl bromide 1 (Table 1). We determined
that a catalytic system comprised of 5 mol % Pd(PPh3)2Cl2 and
10 mol % of the N-heterocyclic carbene ligand IMes (IMes =
N,N’-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) facilitated an
efficient alkoxycarbonylation of substrate 1, providing ester 2 in
high yield (85%, entry 1).10 Other palladium precatalysts, such
as [Pd(allyl)Cl]2 and PdCl2, were inferior to Pd(PPh3)2Cl2 (en-
tries 2–3). Decreasing the amount of IMes ligand (5 mol %)
slightly reduced the reaction yield (80% yield instead of 85%
yield, entry 4). Substituting less electron-donating SIMes (SIMes
= N,N’-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)
for IMes greatly reduced reaction efficiency, and the absence of
IMes led to no alkoxycarbonylation (entries 5–6). Amine bases
did not facilitate the reaction (entry 7), and the use of 1 atm of
CO (balloon) was inferior to the optimized conditions (2 atm,
entry 8). Performing the reaction in n-BuOH diminished the
yield (entry 9), and no product was formed in the absence of
Pd(PPh3)2Cl2 (entry 10).
The catalytic carbonylation of organohalides is a fundamen-
tal transformation of organometallic catalysis, most notably
demonstrated by the Monsanto-Cativa acetic acid synthesis.1
Carbonylations of aryl or vinyl electrophiles, or activated sp3-
hybridized substrates, have also been used in diverse transfor-
mations for the synthesis of small molecules (Figure 1).2 Con-
versely, there are few efficient catalytic carbonylations of unacti-
vated alkyl halides.3,4 Recent studies have demonstrated the
utility of palladium catalysts in these processes, but require the
use of alkyl iodides under high pressures of CO (∼50 atm) using
elevated temperatures or intense Xe lamp irradiation.3b,5,6 Alter-
natively, nickel-catalyzed carboxylations of unactivated alkyl
halides have recently been reported; however, substrates are
limited to primary bromides.7 The lack of simple, general pro-
tocols for carbonylations of unactivated alkyl halides significant-
ly limits applications in chemical synthesis.
Carbonylations of activated substrates
Carbonylations of alkyl iodides
Table 1. Palladium-catalyzed alkoxycarbonylation of an unac-
tivated secondary alkyl bromide.
O
Pd catalyst
CO, R2OH
Pd catalyst
CO, R3OH
R1
I
R1
R1X
R1CO2R2
OR3
R2
X = I, Br, Cl, OTf
R2
5 mol % Pd(PPh3)2Cl2
10 mol % IMes
2 atm CO
High pressures of CO required (~50 atm)
X
O
X
N
N
Mes
R1X =
Mes
Ph
Br
Ph
Elevated temperature or irradiation
required (500 W Xe lamp)
or
OBu
2 equiv Cs2CO3
n-heptane:n-BuOH 1:1, 50 oC, 24 h
IMes
1
2
aryl/vinyl
benzylic/allylic
Unsuccessful with alkyl bromides
This work: alkoxycarbonylation of unactivated secondary alkyl bromides
entry
1
variation from standard conditions above
none
% yielda
85
5 mol % Pd(PPh3)2Cl2
10 mol % IMes
2 atm CO
Low pressures of CO
O
R1
Br
Mild conditions with good
chemoselectivity
R1
2
2.5 mol % [Pd(allyl)Cl]2 instead of Pd(PPh3)2Cl2
5 mol % PdCl2 instead of Pd(PPh3)2Cl2
5 mol % IMes instead of 10 mol % IMes
10 mol % SIMes instead of IMes
no IMes
53
OBu
2 equiv Cs2CO3
n-heptane:n-BuOH 1:1, 50 oC, 24 h
R2
3
6
R2
Efficient reactions with
unactivated alkyl bromides
4
80
5
6
6
<2
<2
31
Figure 1. Palladium-catalyzed carbonylations of organohalides.
7
2 equiv Et3N instead of Cs2CO3
1 atm (balloon) CO instead of 2 atm CO
no n-heptane
8
There are a number of challenges inherent to a catalytic car-
bonylation of unactivated alkyl halides with carbon monoxide.
9
35
10
no Pd(PPh3)2Cl2
<2
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 4
a
a
b
Reactions were performed with [substrate]0 = 0.5 M. Yields de-
termined by 1H NMR spectroscopy of crude reaction mixture using
an internal standard.
See Table 1 for conditions. Isolated yield. Reaction yields de-
termined by 1H NMR spectroscopy of crude reaction mixtures
using an internal standard.
1
2
3
4
5
6
7
8
9
Upon identifying suitable conditions for the alkoxycarbonyl-
ation, we surveyed reactions involving a range of alkyl bromides
(Table 2). A variety of aryl-substituted substrates provided esters
in good yields, including one with pendant benzamide func-
tionality (entries 1–5). Aliphatic substrate 2-bromooctane deliv-
ered butyl ester 12 in moderate yield (65%, entry 6), indicating
that the aryl ring plays no role in substrate activation. Silyl pro-
tecting groups were compatible with the catalytic conditions, as
demonstrated by the reaction of tert-butyldimethylsilyl ether 13
(entry 7). While pendant ester functionality was tolerated under
the reaction conditions, transesterification necessitated the use
of n-butyl esters (entry 8). The alkoxycarbonylation of substitut-
ed N-methylpyrrole 17 delivered ester 18 in good yield, high-
lighting the utility of the reaction in the presence of electron-
rich aromatic systems (entry 9). Five- and six-membered carbo-
cycles and heterocycles also reacted efficiently using our ap-
proach. Substrates examined included cyclohexyl, cyclopentyl,
and tetrahydropyranyl bromides, in addition to Boc-protected
piperidine and pyrrolidine substrates (entries 10–14). Lastly,
exo-bromonorbornane 29 yielded primarily the exo-
alkoxycarbonylation product 30 (5.4:1 dr, entry 15). Control
experiments indicated that formation of the minor endo prod-
uct is most likely the result of partial epimerization of the exo
product under the basic reaction conditions.11
We next surveyed a range of alcohols in the alkoxycarbonyla-
tion (Table 3). Importantly, these studies demonstrate the via-
bility of the transformation when the alcohol is used in slight
excess (2 equiv) rather than as reaction co-solvent. A number of
primary alcohols, including those with β-branching, delivered
the respective ester products in useful yields with only 2 equiva-
lents of the alcohol as nucleophile (entries 1-5). Secondary al-
cohols were also effective in the alkoxycarbonylation (entries 6-
8), but the reactions of isopropanol and cyclohexanol were
more efficient using our standard conditions (n-heptane:alcohol
1:1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Alkoxycarbonylations of an unactivated secondary
alkyl bromide with diverse alcohols.
5 mol % Pd(PPh3)2Cl2
10 mol % IMes
2 atm CO
MeO
MeO
O
Br
OR
2 equiv Cs2CO3
solvent, ROH, 50 oC, 24 h
entry
alcohol
yield (%)a
64b
1
2
OH
70b
OH
OH
3
4
5
61b
72b
41b
Table 2. Low-pressure alkoxycarbonylations of secondary alkyl
bromides.
OH
yield
entry
substrate
product
(%)a
R
R
O
OH
Br
CO2Bu
6
53c
1
2
3
4
5
1: R = H
3: R = Cl
5: R = F
7: R = OMe
9: R = CONEt2
2: R = H
4: R = Cl
6: R = F
8: R = OMe
10: R = CONEt2
CO2Bu
72
70
83
81
75
OH
7
8
53b,d
OH
Br
6
65
59c
12
14
16
11
13
OH
7
8
73
87
aIsolated yield. bReactions were performed with [substrate]0 = 1.0
c
M in PhCF3 with 2 equiv of alcohol. Reactions were performed
Br
CO2Bu
BuO2C
BuO2C
with [substrate]0 = 0.5 M in a mixture of n-heptane:alcohol = 1:1.
dReaction time 48 h.
15
17
The relative stability of alkyl bromides over alkyl iodides
combined with the ease of accessing alkyl bromides from their
parent alcohols offers attractive opportunities for late stage C—
C bond formation. As an initial demonstration of a late-stage
alkoxycarbonylation, we studied the reaction of androsterone
bromide 31 (eq 1). Under our optimized conditions for this
substrate, the catalytic alkoxycarbonylation delivered n-butyl
ester 32 in moderate yield as a mixture of diastereomers (53%
isolated yield, 1.4:1 dr). The mild, catalytic transformation is
successful in the presence of ketone functionality, which would
present challenges in classical carboxylation using stoichio-
metric organometallic reagents.4e
9
86
18
Br
CO2Bu
X
X
10
11
12
49b
70
19: X = CH2
20: X = CH2
21: X = NBoc
22: X = NBoc
23: X = O
24: X = O
75
Br
CO2Bu
X
X
25: X = CH2
26: X = CH2
13
14
70
74b
27: X = NBoc
28: X = NBoc
79
5.4:1 dr
15
CO2Bu
Br
29
30
ACS Paragon Plus Environment

Page 3 of 4
Journal of the American Chemical Society
O
O
Me
H
Me
A mechanistic proposal consistent with our current studies
5 mol % [Pd(allyl)Cl]2
20 mol % IMes
2 atm CO
1
2
3
4
5
6
7
Me
H
is depicted in Scheme 2. The palladium catalyst irreversibly
abstracts a bromine atom from the substrate (1), generating a
carbon-centered radical (35) and a palladium(I) intermediate.
This step is followed either by radical addition to a bound CO
ligand, or CO migratory insertion of a putative alkylpalladi-
um(II) intermediate formed by recombination of the carbon-
centered radical and the catalyst. Both of these potential path-
ways have been proposed in carbonylation catalysis,17 and fur-
ther studies are required to distinguish between the two possi-
bilities. Either of these two mechanistic variants delivers an
acylpalladium(II) species (36) which, upon nucleophilic dis-
placement by butoxide, furnishes the product ester 2.
Me
H
(1)
2 equiv K3PO4, 70 o
C
H
H
H
BuO
PhH:n-BuOH 1:1, 48 h
Br
H
H
O
31
androsterone bromide
32
53% isolated yield, dr = 1.4:1
(72% yield brsm)
The potential for palladium to react with alkyl electrophiles
via both two-electron (SN2) and single-electron pathways opens
the door to a number of possible pathways for the catalytic
alkoxycarbonylation.8,12 Our initial mechanistic studies com-
menced with reaction of alkenyl radical clock substrate 33. Un-
der our reaction conditions, substituted cyclopentane ester 34
was the sole product, in which 5-exo cyclization preceded the
carbonylation step. Importantly, the diastereoselectivity ob-
served in the reaction is similar to reported free radical cycliza-
tions of similar substrates (Scheme 1).3b,13 In addition, primary
alkyl bromides failed to carbonylate under our conditions de-
spite the known faster rate for SN2 oxidative addition of these
substrates.11,12b These results are both consistent with the partic-
ipation of radical intermediates in the carbonylation process.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Plausible Catalytic Cycle for the Alkoxycarbonyla-
tion
Ph
+
CO2Bu
Ph
Br
LnPd0
base
H
Br
2
1
n-BuOH + base
O
LnPdIBr
In order to uncover further details regarding the radical na-
ture of the reaction, we studied the effect of radical inhibitors
and varying pressures of carbon monoxide (Scheme 1). Reac-
tions performed in the presence of radical inhibitors BHT and
hydroquinone provided esters with only a modest decrease in
yield (52% and 57% yield, respectively).14 These results are con-
sistent with a metal-catalyzed process involving tightly associated
or caged radical intermediates instead of a purely free radical
carbonylation with no metal involvement.15 Furthermore, in
contrast to standard, high-pressure free radical carbonylation,4a-c
we found that the efficiency of the catalytic process decreased
with increasing pressures of carbon monoxide. This observation
is consistent with the necessity of an open coordination site on
the palladium center in an inner-sphere substrate activation
step, and provides evidence against an outer-sphere electron
transfer.8 The high oxidation potential of alkyl bromides (∼2.5
V versus SCE)16 disfavors an outer-sphere electron transfer
mechanism as well. We currently favor an activation involving
bromine atom abstraction by the palladium center.8 Finally, the
carbonylation of an enantioenriched form of substrate 1 (96%
ee) stopped at partial conversion returned the substrate with no
erosion of enantiopurity, consistent with an irreversible activa-
tion step.11
Ph
Ph
PdIIBrLn
35
36
LnPdIBr
CO
PdIIBrLn
Ph
C
O
Ph
or
migratory CO
insertion
radical addition to
bound CO ligand
In conclusion, we have developed a mild, low-pressure palla-
dium-catalyzed alkoxycarbonylation applicable to diverse unac-
tivated alkyl bromides. Employing a strongly donating NHC
ligand enabled the development of a catalytic, fundamental C–
C bond-forming transformation with simple alkyl halide build-
ing blocks which previously required harsh conditions, more
reactive iodide substrates, and high pressures of carbon monox-
ide. Mechanistic investigations support a proposed hybrid or-
ganometallic-radical pathway instead of more common two-
electron transformations. Applications in complex organic
synthesis and the development of enantioselective variants of
the current reactions are underway.
Scheme 1. Studies Probing the Reaction Mechanism
ASSOCIATED CONTENT
Alkenyl Radical Clock Substrate:
O
5 mol % Pd(PPh3)2Cl2
10 mol % IMes
Br
Supporting Information. Experimental procedures and spectral
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
2 atm CO
BuO
2 equiv Cs2CO3
n-heptane:BuOH 1:1, 50 o
C
33
34
71% isolated yield, 3:1 dr
AUTHOR INFORMATION
Reactions with Radical Inhibitors:
standard
% yield
additive
O
Corresponding Author
Ph
Br
none
81
52
57
conditions
Ph
1 equiv BHT
OBu
*eja@email.unc.edu
20 mol % hydroquinone
1
2
Reactions with increased CO pressure:
standard
ACKNOWLEDGMENT
% yield
CO pressure (atm)
O
This work was supported by Award No. R01 GM107204 from the
National Institute of General Medical Sciences.
Ph
Br
2
81
65
10
conditions
Ph
10
30
OBu
1
2
REFERENCES
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 4
(1) (a) Dekleva, T. W.; Forster, D. J. Am. Chem. Soc. 1985, 107, 3565;
of alkyl iodides: (c) Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetrahedron
Lett. 1991, 32, 6923.
(7) Liu, Y.; Cornella, J.; Martin, R. J. Am. Chem. Soc. 2014, 136,
11212.
(8) Hartwig, J. Organotransition Metal Chemistry: From Bonding to Ca-
talysis; University Science Books: Sausalito, CA, 2010; pp. 301–320.
(9) Bissember, A. C.; Levina, A.; Fu, G. C. J. Am. Chem. Soc. 2012,
134, 14232.
1
2
3
4
5
6
(b) Haynes, A.; Maitlis, P. M.; Morris, G. E.; Sunley, G. J.; Adams, H.;
Badger, P. W.; Bowers, C. M.; Cook, D. B.; Elliott, P. I. P.; Ghaffar, T.;
Green, H.; Griffin, T. R.; Payne, M.; Pearson, J. M.; Taylor, M. J.;
Vickers, P. W.; Watt, R. J. J. Am. Chem. Soc. 2004, 126, 2847.
(2) (a) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem. Int.
Ed. 2009, 48, 4114; (b) Wu, L.; Fang, X.; Liu, Q.; Jackstell, R.; Beller,
M.; Wu, X.-F. ACS Catal. 2014, 4, 2977.
7
8
9
(3) (a) Frisch, A. C.; Beller, M. Angew. Chem. Int. Ed. 2005, 44, 674;
(b) Sumino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014,
47, 1563.
(4) Non-metal-catalyzed carbonylations or carboxylations: (a) Ryu, I.;
Sonoda, N. Angew. Chem. Int. Ed. 1996, 35, 1050; (b) Nagahara, K.;
Ryu, I.; Komatsu, M. Sonoda, N. J. Am. Chem. Soc. 1997, 119, 5465; (c)
Ryu, I. Chem. Soc. Rev. 2001, 30, 16; (d) Kobayashi, K.; Kondo, Y. Org.
Lett. 2009, 11, 2035; (e) Smith, M. B. March's Advanced Organic Chemis-
try, 7th ed. John Wiley & Sons: Hoboken, 2013; p. 1132.
(5) (a) Urata, H.; Maekawa, H.; Takahashi, S.; Fuchikami, T. J. Org.
Chem. 1991, 56, 4320; (b) Fukuyama, T.; Nishitani, S.; Inouye, T.;
Morimoto, K.; Ryu, I. Org. Lett. 2006, 8, 1383; (c) Fusano, A.; Sumino,
S.; Nishitani, S.; Inouye, T.; Morimoto, K.; Fukuyama, T.; Ryu, I.
Chem. Eur. J. 2012, 18, 9415.
(6) There are limited examples of catalytic carbonylative reactions of
alkyl iodides at low pressure. For examples of reactions involving UV
irradiation: (a) Kondo, T.; Tsuji, Y.; Watanabe, Y. Tetrahedron Lett.
1988, 29, 3833; (b) Kondo, T.; Sone, Y.; Tsuji, Y.; Watanabe, Y. J.
Organomet. Chem. 1994, 473, 163. Carbonylative Suzuki cross-couplings
(10) Secondary alkyl chlorides and tertiary alkyl bromides were un-
reactive under these conditions. Secondary alkyl iodides were viable
substrates, albeit with decreased yields owing to their relative instabil-
ity. See the Supporting Information for details.
(11) See the Supporting Information for reaction details.
(12) (a) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434; (b)
Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2003,
42, 5749.
(13) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
(14) A reaction with 1,1-diphenylethylene as a radical inhibitor de-
livered no carbonylation product; the mass of a radical addition prod-
uct was observed via GC-MS. See the Supporting Information for de-
tails.
(15) Loy, R. N.; Sanford, M. S. Org. Lett. 2011, 13, 2548.
(16) (a) Roth, H.; Romero, N.; Nicewicz, D. Synlett 2016, 27, 714;
(b) Grimshaw, J. Electrochemical Reactions and Mechanisms in Organic
Chemistry. Elsevier: Amsterdam, 2000.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) Hasanayn, F.; Nsouli, N. H.; Al-Ayoubi, A.; Goldman, A. S. J.
Am. Chem. Soc. 2008, 130, 511.
5 mol % Pd(PPh3)2Cl2
10 mol % IMes
2 atm CO
Br
CO2Bu
2 equiv Cs2CO3
n-heptane:n-BuOH 1:1, 50 oC, 24 h
N
N
Boc
Boc
mild, low pressure carbonylations of
unactivated alkyl bromides
70% isolated yield
ACS Paragon Plus Environment