Idea Transcript
Reductions General Resource: Trost, Comp. Org. Syn. 1991, vol 8 March,1992, chap 19 Carey and Sundberg, vol B, Chap 5 Smith, Organic Synthesis, Chap 4 Material organized (roughly) by transformation
From March, 1992, p1208
H
H
5% Pd/C Supported metal b/c Pd $$$ and tends to clump.
Two general classes: Transition metal hydrogenation and dissolving metal reduction Hydrogenation: Covered in much more detail in Advanced Synthesis and Catalysis.
CH3
CH3
H2 5% Pd/C
O
O no carbonyl reduction
M
H
H
H2
H2 NC
General trends:
NC
Ph
more substituted = slower relationship of pressure:rate often not simple many systems pose fire risk! HOAc/HClO4 AcOH HOH EtOH CH2Cl2 EtOAc
5% Pd/C
N
N Ph Benzyl survives
10% Pd/C -Same deal as 5%, just more reactive -Often used for hydrogenolysis and more difficult hydrogenations -Mechanism of hydrogenolysis unknown
increasing activity
Olefin isomerization sometimes a problem
MeO N
MeO
Ph
H2
MeO
10% Pd/C
MeO
NH 90%
Note:
O2 + H2
Pd/C
Fire
5% Pd/ BaSO4 and 5% Pd/CaCO3/Pb(OAc)2 (Lindlar's cat.) and 5% Pd/C/quinoline
PtO2 (Adams catalyst) general hydrogenation cat; more active than Pd/C
reduced activity
H2/PtO2 AcOH/Benzene
N quinoline 8
O
N
N
H2
H Raney Nickel (RaNi) -various types available that differ in preparation -sold as 50% wt. dispersion in water -usually wash 5x water, 5x solvent (usually MeOH) -Dry solid is pyrophoric!!! -Remove by filtration under N2 or Ar (pretty good idea for all hydrogenation catalysts)
alkyne semi-reduction most common use:
H2 5% Pd/CaCO3/Pb(OAc)2
97% Ph
Wasserman, TL, 1988, 4977
5% Pd/ BaSO4
Ph
8
Ph
O Cl
Ph
H
Ph
Ph
87% stereospecific
Ni/Al
NaOH
Ni/H2
+ NaAl(OH)4
complementary method: slurry has hydrogenation activity without added H2
Na/NH3 97% stereoselective
(more on Na to come)
For some applications, can use Ni/Al in 1M NaOH/MeOH
Raney Ni Applications
OH
Ni2B (Nickel boride) Brown, JACS, 1963, 1004, 1005
H2 (275 atm) Ra-Ni
OH
NaBH4
Ni(OAc)2
Ni2B + H2
(future fuel cell technology??) 86% H2 Ra-Ni
vegtable oil
in water: More reactive than Ra-Ni Less double bond rearragement
margarine in EtOH: Highly selective: Ni2B H2
other uses: O
desulfurization Ra-Ni EtOH
S
97% TL 1994, 5594
S
61% O
Triazene reduction O
O H O
H HO N N N
O
Ra-Ni MeOH no added H2
H O
H HO H2N 95%
Wood, ACIEE, 2004, 1270
Ni2B H2
O
45% Can. J. Chem. 1991, 1554
Diimide Reductions
Examples general trends: rate
H
H
N N diimide
Unstable -generate in situ -use excess No reaction with -CN, -NO2, Not poisioned by heteroatoms
Generation KO2C N
N CO2K
H2N NH2 (hydrazine)
S
R
R
Corey JACS, 2004, 15664
HN
KO2CN=NCO2K
O
II
Δ or base
NH O
Mechanism
88%
N
HOAc also promotes E-Z isomerization JOC, 1965, 3985 Cu , O2
NH2NH2 CuSO4 5 O2 EtOH/MeOH
H N
-2 CO2
HO2C
as substitution
O JOC, 1977, 3987
O
NH
O
Tol
O H2N
H
HOAc
rate
as strain
-HTs R H
N N concerted hydrogen transfter ΔGo ~ -50kcal/mol
R H
HN
NH2NH2 O2, Cu(II)
NH R
Org. Syn. 1969, 30
R
N Corey, JACS, 1961, 2957
OAc
OAc
+ N
KO2CN=NCO2K CD3OD/CD3CO2D
D D syn-exo addition! JACS, 1967, 410
Dissolving Metal Reductions
Enones
polar solvent M+
M
e-
+
Most common solvents: NH3 (b.p. = -33 oC), MeNH2 (b.p. = -6.3 oC)
Li, NH3, 2 equiv EtOH O
O +e-
Competing process: 2 e-
+ 2NH3
slow
2NH2- + H2
(rxn mixture is basic)
O
Birch Reduction review: Rabideau, Marcinov, Org. React, 1992, 42, 1 CN
H
EtOH
CN
Li, NH3, 2 equiv EtOH
vs. H good overlap
EtOH
H
poor overlap
-
+e
EtOH
CN
CN EtOH
CN
+e-
+eO
explain: OMe
OMe
Li, NH3, 2 equiv EtOH
LiO
H
Regioselective enolate generation: Li, NH3; H MeI ~50%
O Deprotonation here R
O
Ph
Na/NH3
R
OH O
H H
O
H Stork, JACS, 1965, 275
Carbonyl Reductions Metal Hydrides-General
RCO2H
RCH2OH
RCO2R
RCH2OH
RCONR2
RCH2NR2
Ionic Metal Hydrides (LiAlH4, NaBH4, etc) LiAlH4 -very strong reducing agent -flammable -Workup can be trouble b/c Al salts; Feiser workup: for ng LiAlH4, add n mL H2O, n mL 15% NaOH, then 3n mLH2O, filter ppt. -related: Red-Al [NaH2Al(OCH2CH2OMe)2; similar reactivity but greater solubility
2
H M L3 O
H
1 2 + M M HL3
O
M1
OH
Reactivity increases with: -increasing electronegative M1 (Li > Na) -increasing electropositive M2 (Al > B) -increasing e- donation of L (Et > H) -increasing electrophilicity of substrate (RCHO > RCOR)
OH
MeO2C MeO2C H
O O
O
THF, reflux 72%
L
H
+ MHL2
CO2H
M O
H L O
OH
Reactivity increases with: -increasing electropositive M (Al > B) -increasing donor ability of substrate (RCO2R > RCOR)
H
O H
H
O
H
OH H
LiAlH4
H
Neutral Metal Hydrides (i-Bu2AlH, AlH3, B2H6)
HO
C(CH3)3
H OH
Helmchen, JOC, 2000, 5072
OBn O
H
O
CO2Me LiAlH4
O
H
OBn O OH
O H
Nicolaou, JACS, 1995, 10252
H
O
H
H
92%
O
Directed reduction proceeds through intramolecular hydride delivery:
H
N
N
LiAlH4 88%
H
H
H Al
Ts
O
O
N
H
O
N H
H2 Al
+
H
R
Overman, JACS, 1999, 700 R LiAlH4 can also reduce alkynes:
THPO
LiAlH4, Δ 73% OH
LiAlH4 120 - 150 oC
HO
H
LiAlH4, Δ 70%
Nearby alcohol accelerates OH LiAlH 4 n
R
Acta. C. Scan. 1073, B27, 2941
90%
TMS
H
H
H
allylic leaving group leads to allene:
forcing conditions are required for unactivated alkynes
OH
TMS
OH n
n = 1, 1h, 66 oC, 68% JOC, 1984, 4092 n = 2, 48h, 85 oC, 84% JOC, 1985, 4014
OH
OH
TL, 1974, 1593
OH LiAlH4 OMe
?????
LiBH4 -Seletive reduction of esters and lactones in presence of acids -acids 'protected' as Li salt -solvent effects: ether>thf>iPrOH HO MeO2C
CO2H
O
O
BH3-THF
H Br
HO
O
H
CO2H
Br
HO
LiBH4
O
OH Corey, JOC, 1975, 579
CO2H 81% JACS, 1075, 4144 hypothetical example:
O
O
H N
O
O
N
O O S
HO
LiBH4
BH3-THF
HO
LiBH4
HO
O I Williams, JOC, 2004, 1028 Borane complexes (BH3-L) -selective reduction of acids in presence of esters, amides, lactones. Will reduce ketones, aldehydes and olefins -BH3-THF and BH3-Me2S available
+
ester
dibal
O B2H6
O OEt
B
O
+ R 3
OH
i-Bu2AlH (aka DIBAL or DIBAL-H) -low temp, 1 equiv, ester -> aldehyde -with XS, get alcohol -gives 1,2 reduction of unsaturated esters -commonly:
O O
OEt
O
I
OH
OH O
OEt O
O N O S
O
45%
O
HO
H N
HO
LiAlH4
OH
Ph
alcohol
[O]
aldehyde
CO2Et O
H
H
OTBS
DIBAL, -78 oC 95%
O
Ph
Brown, JACS, 1960,3866
OH
O
OEt
OTBS H H Nicolaou, Tetrahedron, 1990, 4517 O
Weinreb's amide to aldehyde S MeO2C
H
S OHC
DIBAL -78 oC
H PO
NH
NH
O
OP PO
H O
DIBAL
O
N OMe Al R R
OP
OAlR2 R
H
OMe
O
JACS, 1982, 6460
O
O
N OMe
stable at low T
stable intermediate aminal decomposes to aldehyde on workup
PO
biotin
>70%
O
OP O
PO
OP O
lactone to lactol
Evans, JACS, 1990, 7001
O
O
3o amides to aldehydes
3 equiv. DIBAL H Cl NC
OTIPS
78%
H Cl NC
O O
OTIPS
O
O
O
NMe2
OH
LiAlH(OtBu)3 LiAlH(OEt)3
note: nitrile survives 4 steps!!
Nitrile to aldehyde
xs tBuOH
O O O TMSO OTIPS
63% 92%
NC DIBAL >71% TMSO
O O OTIPS
Corey, JACS, 1993, 8871
LiAlH(OtBu)3
LiAlH4 1.5 EtOAc
LiAlH(OEt)3 Brown, JACS, 1964, 1089
O
Directed Reductions
OH
general reference for directed rxn: Hoveyda, Evans, Chem Rev. 1993, 1307 many many many ways. Focus here on selectivity issues 2 common modes OH
H
O
R
H
OH
D
99 89 80 3 7
Li/NH3 LiAlH4 NaBH4 LiBH(s-Bu)3 (L-selectride) (i-Bu)2AlH
1 11 20 97 93
O D
R
R
H
R'
O
D
M
R'
H-
R'
D = donor
D
M
D
R
O
OH
OH R'
MBH(OAc)3; M usually NMe4 Evans, JACS, 1988, 3560
ax H
O
O
eq disfavored for small H- donors b/c interaction with C2 axial H
H eq
ax disfavored for large H- donors b/c interaction with C3 axial H H
LiAlH4
OH OH
H
OH O
MBH(OAc)3 R -HOAc R'
OH O
MBH(OAc)3 -HOAc
83
17
O
O LiAlH4
?
? ?
92
8
?
acyclic cases usually follow Felkin-Ahn model or chelate model (if chelating group nearby) to varying degrees. For a chronological presentation, see Smith, Organic Synthesis, chap 4.
O
OH
E Me
O H
50:1
O H
R'
MBH(OAc)3
OH OH
OAc B OAc
O R
OH OH
OAc B OAc
O
50:1 O HO H
OH
E Me
one isomer OH O
O
O
MBH(OAc)3 OR
OH OH OH O OR
6:1
MeOB(Et)2/NaBH4 MeOB(Et)2 NaBH4
OH O R
R
Tishchenko Reductions: Evans, Hoveyda, JACS, 1990, 6447 O
Prasad, TL, 1987, 155 H-
Et B Et
O
-MeOH
OH O
OH OH R
O
R
H
cat. SmI2
O
R, R' = alkyl, aryl generally >97:3 OH O
O
R
OEt O OEt
R
O Sm Ln
OEt
MeOB(Et)2 NaBH4
OH O
CH3CHO
OH OH O 5
OEt R
R = Me, Aryl
OAc OH
cat. SmI2
5
96% >99:1
R = Me, Aryl O
O O
OH O
Zn(BH4)2 Oishi, Nakata, Accts. Chem. Res. 1984, 338; Evans JACS 1984, 1154
OH
cat. SmI2
L Zn L O O
95% >99:1
BnO
OBn OP
OH O
OP
OH O
OP
CH3CHO
OAc OH
cat. SmI2 Zn(BH4)2
Me4NBH(OAc)3
OP
OH OH OP
19:1
OP
OP
OH OH OP
4:1
95% >99:1 OP
OH
directed reduction + monoprotection
OH OH O R
H-
O
R
likely Sm+3
MeOB(Et)2 NaBH4
98:2 OH O
R
O
R'CHO
Enantioselective reductions. For metal-catalyzed, see Advanced Synthesis and Catalysis notes. CBS Reduction: from Corey, Bakshi, and Shibata Reviews: Corey, ACIEE, 1998, p1986; Srebnik, Chem Rev, 1993, 763. H Ph NH
H Ph
Ph MeB(OH)2 (1.1 equiv)
OH
N
Ph
O B
(10 mol%) CH3 CBS Catalyst
O R
BH3-THF (0.6 equiv)
R'
OH
OH
RL
R = CH3: 97%ee R = Et: 97% ee R = CH2Cl: 95%ee R = (CH2)2CO2Me: 94% ee OH
N
NO2 MeO
RS 95% ee
RS 93%ee
RL
OTBS O
O
O
BF3
R S CH3 94% ee
OH
MeO
H3C
Br
99% ee
N
OH TBDPSO
OEt
MeO
84% ee
O
91% ee
91% ee O
OH O
Hex
~95% ee MeO
OH
OH RO
HO OR
R
OH
R
CH3
note: some data with alternative boranes or R' B-R groups
HO H
CH3
CH3 SnBu3 94% ee
O
Bu3Sn
CH3
93% ee
95% ee
91% ee OH
H3C
OH
CH3 85% ee
R' R
OEt
R = Ph, R' = n-alk: 70-90 % ee R = Ph, R' = s-alky: 95% ee R = H, R' = alk: ~96% ee R = TIPS, R' = alk: >90% ee
Proposed mechanism for CBS reduction
Important points: • Borane in catalyst is Lewis acid; Nitrogen is Lewis base to coordinate second borane • Borane coordination forms cis-5,5 system (a-face in 5) • Borane coordination increases Lewis acidity of catalyst (at B) and activates BH3 as hydride donor • Carbonyl coordination trans to bulky or electron rich group • Hydride transfer via 6-membered TS • Disproportionation between 8 and BH3 + (RO)2BH allows 80% O
Overman, JACS, 1993, 9293
OH O
O
>80%
O
O
OPMB
N3
N3
OtBu
OtBu
-Ce(+3) coordinates to carbonyl; promotes selective 1,2 addition. -Requires stoichiometric quantity of ANHYDROUS CeCl3 N3
TIPSO
L-selectride; PhNTf2
OtBu
OtBu
75% Heterocycles, 1989, 703
Ionic Reductions
Reductive amination -Usually with NaCNBH3 or NaBH(OAc)3 -Usually in presence of acid to promote imium ion formation -Alternative to amine alkylation (often get over alkylation)
-reduction of cation (usually from protonation) -need to avoid H- + H+ -CF3CO2H/Et3SiH is most common combination OH
OH
CF3CO2H Et3SiH
O
OH
OH O
+
TBSO O
93% Chem Comm. 1986, 1568
O
CHO
+
OAc
N H
NaBH(OAc)3, Sn(OTf)2, 4A MS TBSO
OP O O
OAc
TMSOTf Et3SiH
OAc
O
+
OP O O
N
H H
N
OAc
OMe O O CO2Me
CF3CO2H Et3SiH
N
OMe O O
H
OAc
TL, 2000, 6435
JACS, 2004, 516
N
CO2Me N
N
N H
N H
H OH O
Nicolaou, JACS, 2004, 613
2
+
HN
NH NaBH3CN,
AcOH 95%
H N
HN O
O BocHN
2
O BocHN
N H
HN
JACS, 2004, 557
α,β-unsaturated ketones give olefin migration:
O R
R
R
R O
Reduction of Tosylhydrazones Maryanoff, JACS, 1973, 3662 Baker, JOC, 1975, 1834 O R
H2N-NHTs R
Ts HN
DMF/sulfolane
AcOH/NaCNBH3
N
R
H2NNHTs, HCl, NaCNBH3
Ts HN
R
NNHTs NH
R
NaCNBH3, AcOH
R
-TsH (pKa=7.1)
~75% JOC 1978, 2299
-N2 R
HN
R
N
R
R
2 possible mechanisms:
O
H2NNHTs, TsOH, NaCNBH3 DMF/sulfolane
N Bn
Ts HN
N Bn
H-
79% O
O 3
O
CN
O 3
5
NNHTs H
H
R
O
"
CN
-N2 R
H
R
-N2
N
H
R
How would you distinguish between them?
HO
Boeckman, JACS, 1989, 2737
N
R
ZnCl2, NaCNBH3 ~50%
H
H N
5
75% HO
HN
N
H
H
Related chemistry: TBS N N SO2Ar
Li
R'Li
R
R
Wolf-Kishner Brutal conditions
TBS N N SO2Ar R'
R
N
TBS N
AcOH -N2, -AcOTBS
R' 3
O R
R'
3
synthesis of unfunctionalized sp -sp bonds
EtO2C
N2H4, NaOEt 170 oC
N H
N H
Myers, JACS, 1998, 8891
50-58% Org. Syn. 1995, Coll vol 3, 513 OMOM R
Li
O
1.MeO MeO C4H9
OMe
OMe
C4H9
NN(TBS)Ts AcO
2. HCl, MeOH 73%
R
N2H4 NaOH (HOCH2CH2)2O reflux, then HO 210 oC
O
69% Barton, J. Chem. Soc., 1955, 2056
C4H9 MeO
cylindrocyclophane F MeO
Smith, JACS, 1999, 7423
C4H9
OMe HO
OMe
H2N
B N
HN
N H
H
-N2 H
H
Shapiro reaction useful for difficult olefins; usually low yielding with side products review: Shapiro, Org. Rxns. 1976, 405
TsHN
2 equiv RLi
N
Li TsN
Li N
N
H
Other Methods Clemmensen Reduction review: Vedejs, Org. Rxns. 1975, 22, 401 O Cl
N
Li Cl
Zn(Hg) HCl 56%
-N2 H
generally poor E/Z selectivity in acylic cases
TsHN
Li
BuLi
JOC, 1969, 1109 A fine method if low yields of unfunctionalized products are needed.
Review: Org. Rxns. 1962, 356 Ph
Ph
MeO
Ph
low yield Swenton, JACS, 1971, 4808
N(CHO)Me H SMe SMe H N
O H
O TsHNN TsHNN
Cl
Desulfurization See hydrogenation above. Ra-Ni/H2 almost always used
N
Ph
Cl
Ra-Ni/H2
N(CHO)Me H H N
O H
O
Woodward, JACS, 1948, 2107
MeLi NNHTs
MeO
20% bullvalene TL 1972, 2589
OH
Generally useful method, but: -lota tin -3o thiocarbamates can be difficult to make -1o radicals difficult to form
common methods we won't cover: -alkyl tosylate + LiAlH4 -conversion to halide/dehalogenation -elimination/hydrogenation
S O O S O
O
Barton deoxygenation
N
N
AIBN, Bu3SnH 140 oC
HO
O
O O
CN CN H
CN
N N
AIBN
NC
Bu3SnH
temp 50 70 100
40%
t1/2 74h 4.8h 7.2min
TL, 1988, 281
Im S
S
Bu3Sn
H
O
R
AIBN, Bu3SnH 90 oC O C10H21 91%
O O
O
C10H21
OH
O
JOC, 2000, 6035
Bu3SnH
S O
SnBu3 R
AIBN, Bu3SnH
O
O
O PO S O
SnBu3 R
Barton: Tet, 1983, 2609; 1987, 3541; 1991, 8969 Synthesis, 1988, 417, 489
S
75% JOC, 1989, 5678
O
O
"NBSH"
Myers Diazene method O2 S
N H NO2
PPh3/DEAD/ R
OH
Barton Decarboxylation Barton, Chem. Comm. 1983, 939; Tet, 1987, 2733
NH2 NH2 N SO2Ar
R
O R
O
N
H
R S
-HSO2Ar R
H
-N2
-CO2 R
N
NH
O R
N O
S
Very useful for unhindered alcohols
SSnBu3
-
N SnBu3
note: thiohydroxamic acid often labile enough that no Sn is needed, just ambient light. Photolysis works too. OH
MeO
H3C
PPh3/DEAD/NBSH
N O
S
N
N O
O
MeO
O
Cl
Cl
N OH
PPh3/DEAD/NBSH; O2 ; Me2S
Eaton, ACIEE, 1992, 1421
O
1. i-BuOCOC 2. S
CO2H O H N
N O N H H
N
ONa N
O
3. tBuSH, hν
O H
N H H
Martin, JOC, 1995, 3236
65% OH
Holy cow! How does this happen?
quant.
O N
Myers, JACS, 1997, 8572
O
S
AIBN, Bu3SnH
O
Reductive couplings and related reactions. Reductive cleavage of strained rings:
electron transfer-promoted reductions (part II)
OSmX2 O
SmI2
I
from:
-CH2CH2
O O
SmI2
+ Sm(0)
PMP
O SmI2 HMPA
PMP
O
I -almost always in THF (can do in Me3CCN) -Very air sensitive -reactivity modulated by additives (JACS 2004, 44; JACS 2000, 7718, SYLETT, 1996, 633) -Kagan discovered, Molander exploited, Flowers studied -Rxns usually psycho fast -Reviews: Molander, Chem Rev. 1992, 29; 1996, 307 (example from here).
O
+2
Sm
OSm+3
+2
ROH
OH
Sm
X2Sm
from [2+2] O
AcO
O O
SePh
OH
Sm
OH ROH
O
Guanacastepene A
OH
Sorensen, JACS, 2006, 7025 O
OSm+3
OTBS CO2Me
O
SmI2, HMPA 5 min
TMS
TMS
HO
SmI2
79%
Intermolecular additions of ketyl radicals
97% 93:7
OTBS O
CO2Me Corey, JACS, 1987, 6187
+
CO2Et
SmI2 tBuOH
O
n-C7H15
O
>99:1 dr
ketyl can be intercepted:
S O OCN
OH
S
S SmI2, LiCl
S X2SmO X2Sm OCN
or radical addition
PMP
+3
_
O
O
OH
_
Less likely: via
SePhBr 50%
S Ph
S O
+
H
CN
SmI2 THF, MeOH
O
R
H OH
O N H Wood, ACIEE, 2004, 1270
O
CN
Ph H3C OH
99:1 dr
M
O CN
Intramolecular couplings: Pinacol Couplings with SmI2 O SmI2, HMPA THF, tBuOH
CO2Me
O
2 Mn
2
OMn+1
OH
2
CO2Me
HO
OH
80% H
H
SmI2, HMPA
O
O
OH
O
2 SmI2
-PhS OP H
HO
H
OH 80% poor dr
SmI2, HMPA 78% N
H
Ph
HN
2 SmI2
Ph
O PO
OP OP
Ph Ph
Ph
Ph
O
n-Hex
n-Hex
OP OP
OP
H
OH
O
OH OH
O
PO
With SmI2 (Chem Rev, 1996, 307)
H
O
86% O
PhS
NH
93%; 4:1
OP OP OP
SmI2
O
O
O
O
54% OP H
PO
HO OH
OH
O
OH OP 92:8
OMe N
HO OP OP
OH
O
OP
OH H
HO
OP
2.5 SmI2 tBuOH, THF
OH OH
O
O SmI2 ~65%
N Cbz
H2N O
Grayanotoxin III Shirahama, JOC, 1994, 5532 Note cleavage of N-OMe Nicolaou, en route to diazonamide JACS, 2004, 12897.
N
HO
OBn
NBn
NMOM
Cr-mediated reductive coupling of Sp2-X with aldehydes: the Nozaki-Hiyama-Kishi (NHK) reaction
X
+
CrCl2 (>2 equiv) Ni(II) cat. DMSO or DMF
O
OH X = Br, I, OTf Ni(II) 2Cr(II) 2Cr(III) 2Cr(III)
X
Ni(0)
2Cr(II)
Ni(II)
NiX
General characteristics Reliable for late-stage coupling Broad functional group compatibility (ketones, ester, nitriles) Nuclophile formed in presence of electrophile (Barbier), so intramolecular (cyclizations) possible Often poor diastereoselectivity Catalytic conditions (in Cr) have been developed: Furstner, JACS, 1996, 12349 Enantioselective versions have been developed: Kishi, JACS, 2004, 12248; OL, 2008, 3073. Review: Furstner, Chem Rev. 99, 991
Cr(III) O CrCl2 + OCrCl2
Intermolecular additions: From Chem. Rev. 1999, 991
Intramolecular additions:
Allylations and alkynylations: